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The Evolution of High-Throughput Experimentation in Pharmaceutical Development and Perspectives on the FutureClick to copy article linkArticle link copied!
- Steven M. Mennen*Steven M. Mennen*E-mail: [email protected]Drug Substance Technologies, Amgen, Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United StatesMore by Steven M. Mennen
- Carolina AlhambraCarolina AlhambraCentro de Investigación Lilly S. A., Avda. de la Industria 30, Alcobendas, Madrid 28108, SpainMore by Carolina Alhambra
- C. Liana AllenC. Liana AllenAPI Chemistry, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United StatesMore by C. Liana Allen
- Mario BarberisMario BarberisCentro de Investigación Lilly S. A., Avda. de la Industria 30, Alcobendas, Madrid 28108, SpainMore by Mario Barberis
- Simon BerrittSimon BerrittInternal Medicine, Applied Synthesis Technology, Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Simon Berritt
- Thomas A. BrandtThomas A. BrandtProcess Chemistry, Chemical R&D, Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Thomas A. Brandt
- Andrew D. CampbellAndrew D. CampbellPharmaceutical Technology and Development, AstraZeneca, Silk Road Business Park, Macclesfield, Cheshire SK10 2NA, United KingdomMore by Andrew D. Campbell
- Jesús CastañónJesús CastañónCentro de Investigación Lilly S. A., Avda. de la Industria 30, Alcobendas, Madrid 28108, SpainMore by Jesús Castañón
- Alan H. CherneyAlan H. CherneyDrug Substance Technologies, Amgen, Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United StatesMore by Alan H. Cherney
- Melodie ChristensenMelodie ChristensenProcess Research and Development, Merck & Co., Inc. Rahway, New Jersey 07065, United StatesMore by Melodie Christensen
- David B. DamonDavid B. DamonProcess Chemistry, Chemical R&D, Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by David B. Damon
- J. Eugenio de DiegoJ. Eugenio de DiegoCentro de Investigación Lilly S. A., Avda. de la Industria 30, Alcobendas, Madrid 28108, SpainMore by J. Eugenio de Diego
- Susana García-CerradaSusana García-CerradaCentro de Investigación Lilly S. A., Avda. de la Industria 30, Alcobendas, Madrid 28108, SpainMore by Susana García-Cerrada
- Pablo García-LosadaPablo García-LosadaCentro de Investigación Lilly S. A., Avda. de la Industria 30, Alcobendas, Madrid 28108, SpainMore by Pablo García-Losada
- Rubén HaroRubén HaroCentro de Investigación Lilly S. A., Avda. de la Industria 30, Alcobendas, Madrid 28108, SpainMore by Rubén Haro
- Jacob JaneyJacob JaneyChemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08901, United StatesMore by Jacob Janey
- David C. LeitchDavid C. LeitchAPI Chemistry, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United StatesMore by David C. Leitch
- Ling LiLing LiAPI Chemistry, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United StatesMore by Ling Li
- Fangfang LiuFangfang LiuPharmaceutical Sciences, Pfizer Global Supply Statistics, Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Fangfang Liu
- Paul C. LobbenPaul C. LobbenChemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08901, United StatesMore by Paul C. Lobben
- David W. C. MacMillanDavid W. C. MacMillanMerck Center for Catalysis at Princeton University, Washington Road, Princeton, New Jersey 08544, United StatesMore by David W. C. MacMillan
- Javier MaganoJavier MaganoProcess Chemistry, Chemical R&D, Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Javier Magano
- Emma McInturffEmma McInturffProcess Chemistry, Chemical R&D, Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Emma McInturff
- Sebastien MonfetteSebastien MonfetteProcess Chemistry, Chemical R&D, Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Sebastien Monfette
- Ronald J. PostRonald J. PostEngineering Group, Chemical R&D, Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Ronald J. Post
- Danielle SchultzDanielle SchultzProcess Research and Development, Merck & Co., Inc. Rahway, New Jersey 07065, United StatesMore by Danielle Schultz
- Barbara J. SitterBarbara J. SitterProcess Chemistry, Chemical R&D, Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Barbara J. Sitter
- Jason M. StevensJason M. StevensChemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08901, United StatesMore by Jason M. Stevens
- Iulia I. StrambeanuIulia I. StrambeanuAPI Chemistry, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United StatesMore by Iulia I. Strambeanu
- Jack TwiltonJack TwiltonMerck Center for Catalysis at Princeton University, Washington Road, Princeton, New Jersey 08544, United StatesMore by Jack Twilton
- Ke WangKe WangPharmaceutical Sciences, Pfizer Global Supply Statistics, Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Ke Wang
- Matthew A. ZajacMatthew A. ZajacAPI Chemistry, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United StatesMore by Matthew A. Zajac
Abstract
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High-throughput experimentation (HTE) has revolutionized the pharmaceutical industry, most notably allowing for rapid screening of compound libraries against therapeutic targets. The past decade has also witnessed the extension of HTE principles toward the realm of small-molecule process chemistry. Today, most major pharmaceutical companies have created dedicated HTE groups within their process development teams, invested in automation technology to accelerate screening, or both. The industry’s commitment to accelerating process development has led to rapid innovations in the HTE space. This review will deliver an overview of the latest best practices currently taking place within our teams in process chemistry by sharing frequently studied transformations, our perspective for the next several years in the field, and manual and automated tools to enable experimentation. A series of case studies are presented to exemplify state-of-the-art workflows developed within our laboratories.
Copyright © 2019 American Chemical Society
1. Introduction
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As pharmaceutical companies come under more pressure to accelerate the timelines of drug discovery and development, process chemistry departments must contribute to meeting this demand by delivering robust and efficient manufacturing routes to active pharmaceutical ingredients (APIs) faster than ever. This pressure extends to the academic space through an increased demand for novel chemical transformations.
In response to these challenges, new approaches to reaction discovery and optimization that allow for faster experimentation without sacrificing the quality of the results have been established and developed. One of these new approaches to process chemistry is high-throughput experimentation (HTE). (1,2) Inspired by many techniques first developed in the biology space, chemistry has adapted and advanced the use of HTE as a means to keep up with the increasing demand of pharmaceutical timelines and an ever-expanding toolkit of chemical reactions.
HTE can broadly be defined as the workflow of running multiple reactions in parallel. These sets of reactions are rationally designed to answer specific chemical questions (e.g., probing reaction mechanisms or examining the scope of reagents for desired chemical transformations) and to achieve specific process chemistry goals (such as determining the ranges of reaction parameters which still give acceptable quality products). The overarching goal can be achieved practically in the laboratory in many different ways, utilizing varied equipment and consumables, with or without the aid of laboratory automation. As such, laboratories which routinely use HTE have developed tailored approaches and workflows to best enable their organizational needs.
In the past decade, HTE has seen a sharp increase in adoption in major pharmaceutical companies, (3) and currently most of these companies have dedicated groups of technical experts to run and maintain an HTE platform. HTE has also seen adoption in academic institutions, (4,5) such as the University of Pennsylvania, which allows students to use this technology for their research projects. HTE is now used in many companies not only to accelerate the optimization of a route (including reaction conditions, work up, (6) and isolation) but also to ensure wider coverage of chemical space than possible with one-factor-at-a-time optimization. More recently, significant advances in laboratory automation and analytical technology have enabled HTE workflows to become even more efficient, utilizing less material to run more experiments (7) with less human intervention required.
In this review article, we aim to provide a comprehensive view of how HTE is being used in pharmaceutical companies for chemical transformations. The perspective is focused on chemical transformations which are intended for scale-up, and the primary objective is data generation and not necessarily miniaturization to minimize material demand. We will present detailed metrics of the current and projected future focus of HTE in our industry as well as an overview of equipment and consumables regularly found in our laboratories. We will also include six case studies to demonstrate the diverse workflows being developed by HTE specialists in process chemistry:
| 1. | The optimization of a Suzuki–Miyaura cross-coupling reaction (Pfizer) | ||||
| 2. | Class variable screening to achieve an aryldiazonium reduction (Bristol-Myers Squibb) | ||||
| 3. | Heterogeneous catalysis screening to enable a chemoselective hydrogenation (GlaxoSmithKline) | ||||
| 4. | Reaction development toward an asymmetric fluorination (Lilly) | ||||
| 5. | A screening platform for metallophotoredox catalysis (Merck) | ||||
| 6. | A design of experiment (DoE) workflow for ester hydrolysis (Pfizer) | ||||
2. HTE Metrics
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In this section, we provide the reader with a context for the breadth of reaction discovery and optimization that may be accomplished via HTE and provide insight into the most common reactions conducted within pharmaceutical and academic laboratories. A survey was sent to seven chemistry HTE groups—Amgen, AstraZeneca (AZ), Bristol-Myers Squibb (BMS), GlaxoSmithKline (GSK), Lilly, Merck, and Pfizer—and a survey subsection to HTE academic laboratories situated at Princeton and University of Pennsylvania (UPenn, Table 1). Pharmaceutical data is provided by process chemistry groups except for Lilly, whose team works at the medicinal and process chemistry boundary. We queried these groups to analyze data from 2013 to 2017 (Merck data is 2015–2017) and identify the reaction types being evaluated for each HTE project. The current data relates to small molecule synthesis (typically <600 molecular weight), and HTE screening outside this environment is not within the scope of this review.
Table 1. Survey Questions
| entry | question |
|---|---|
| 1 | What reaction types are being studied in your group? |
| 2 | What reaction types will be studied in your group in 3–5 years? |
| 3 | What is the stage of pharmaceutical development of your HTE projects? |
| 4 | Are HTE projects carried out by specialists or lab chemists? |
| 5 | What ratio of projects in your group study nonprecious vs precious metals? |
Regarding the reactions studied by HTE groups, we collated our survey responses and listed reaction type data as a percentage per institution to normalize the results (Table 2). Data from Princeton is not included because they currently only perform photomediated catalysis. The reaction types are sorted from largest to smallest by their industry-wide average. Importantly, this data is not an analysis of total screens run but rather of total projects being investigated by HTE teams.
Table 2. Relative Percent of the Most Common Reaction Types Studied by HTE Groups in Process Chemistry
Biocatalysis is almost uniformly the most common reaction type screened in the pharmaceutical environment. We have not further broken down the biocatalysis classification as was done with chemo-catalytic reactions, since the focus of the current perspective is on chemical transformations. We do however note that the most popular biocatalysis transformations include transaminases, keto-reductases, and hydrolases. For chemical transformations, Suzuki–Miyaura reactions are usually the most common of the cross-coupling reactions, followed by Buchwald–Hartwig amination. The prevalence of Suzuki–Miyaura coupling is tied to the broad substrate scope of the reaction, tolerance to acidic protons, mild conditions, and the stability/commercial availability of the boronic acid (or equivalents). As such, it is ideally suited to easily find the optimum conditions via HTE and deliver robust process control in API manufacture. Only at Merck are Suzuki–Miyaura couplings less prevalent in the HTE group, but this is because the reaction is often screened earlier in medicinal chemistry or provides sufficient yield without HTE intervention. Similarly, Buchwald–Hartwig aminations have a broad substrate scope and readily available amine starting materials. Heterogeneous catalysis is the fifth most common reaction type and typically includes protecting group removal (e.g., Bn, Cbz), reduction of double and triple bonds, and nitro group reductions. These reactions require specialist equipment for handling high pressure chemistry and may explain the differing data between companies.
Among noncatalytic reactions, chiral salt resolution, solvent/base, and scavenger screening were the most common. Scavenger screening’s prevalence highlights the empirical nature of removing unwanted metal impurities to regulatory specification (typically <20 ppm). Other common catalytic reactions include asymmetric hydrogenation, Pd-mediated borylation, and Ullmann coupling. As with heterogeneous catalysis, asymmetric hydrogenation relies on the availability of specialist HTE-hydrogenation equipment and bespoke ligand libraries. The Ullmann reaction has seen divergent uptake among pharmaceutical companies and is the most common coupling reaction within AZ. This may reflect the perceived benefits of Pd-mediated versus Cu-mediated couplings within the companies. AZ’s perspective is that Cu-mediated chemistry is greener, uses cheap and patent-free ligands, and is easier at removing the metal contaminants to the required specification, making this a prioritized method for C–O and C–N bond formation.
Our data includes a surprising number of low-ranking transformations as well. The lack of Pd-mediated C–H activation reactions is notable despite a large volume of academic literature on the subject. Process chemistry challenges may include high reaction temperatures, high metal loading, selectivity, substrate scope, or the need for directing groups. Another notable data point is the small value for non-Suzuki–Miyaura C–C cross-coupling reactions. As stated above, this probably relates to a combination of stability of organometallic nucleophiles, ease of screening, functional group tolerance, and the robustness of the Suzuki–Miyaura coupling. Catalytic amidation reactions were also widely overlooked among HTE groups, despite its potential to minimize process mass intensity (PMI), improve the environmental burden, and lower costs of a process. Despite some recent key advances, (8) the need for copious amounts of molecular sieves as drying agents and/or high temperatures has so far limited this reaction type’s utility. A step change to a lower temperature catalytic amide formation with a wide substrate scope without excess drying agents could shift the transformation toward wider applicability within an industrial setting.
As expected, the reaction types screened in an academic setting reflected the interests of the parent institution but maintained some alignment with industry results. Suzuki–Miyaura and Buchwald–Hartwig couplings were key transformations, as was photomediated catalysis, a field garnering lots of excitement among academic researchers. Little biocatalysis and no chiral salt screens were undertaken, indicating the university’s current chemo-catalytic focus and preference for stereoselective reactions, respectively.
HTE teams were also asked to predict which transformations would be screened most often in 3–5 years (Figure 1). Surprisingly, little change was predicted from where things are today. The key reactions of biocatalysis, Suzuki–Miyaura coupling, Buchwald–Hartwig amination, Pd-borylation, and asymmetric hydrogenation are still predicted to be workhorse transformations. Key changes appear to be increased adoption of photoredox catalysis, Pd-mediated C–H activation, and catalytic amide formation. While HTE techniques have seen rapid innovation over the last several years, these changes have yet to be reflected in the chemical transformation to be studied by HTE for process development chemistry. As a note to the academic community developing novel methodologies, adhering to governing principles such as the SELECT criteria (9) will support greater deployment in an industrial setting.
Figure 1
Figure 1. Prediction of the most frequently screened reactions in 3–5 years.
Our survey found that process chemistry HTE groups favor early engagement in order to best influence route selection, despite the high attrition rate of assets in drug development (Figure 2). This approach can minimize costs through reduced plant time, improved flexibility and speed of supply of drug substance, and lowered material requirements. An early change also has less regulatory burden and avoids expensive bridging toxicological studies to support an altered impurity profile. In contrast, post approval changes can be very expensive to implement, with large regulatory hurdles making route changes after regulated starting materials (RSMs) unlikely in all but the most financially compelling products. Despite these barriers, the opportunities to change prior to RSMs in launched products remains convincing, as cost savings can be attributed directly to lowered cost of goods over the product’s market lifetime. While these changes can be organizationally more challenging (different geographical locations or management structure), the opportunity exists for improving adoption of HTE for new or amended routes in this area.
Figure 2
Figure 2. Phase of development for HTE projects.
Within the pharmaceutical environment, the majority of HTE work is carried out by specialist teams who confirm that experimental work is carried out accurately and insightfully to ensure that project teams have quality data to improve their processes (Figure 3). While this has historically been the case, there is clear motivation to adapt to a more user-led approach. This may be motivated by reduced reliance on complicated deck-based robot systems that require substantial training to maintain and operate. While deck-based systems can be best used for standardized platform screens, such as solubility or salt-formation studies, more modular systems for automated weighing, solvent evaporation, liquid dispensing, reaction agitation, and sampling have a lower training burden and enable all chemists to utilize HTE. Academic institutions like UPenn and Princeton are ahead of industry groups in this regard, with end-users performing the vast majority of HTE screens. We expect this paradigm to progress into process development in the coming years.
Figure 3
Figure 3. Type of chemist performing HTE screens.
Key catalytic reactions have usually relied on expensive, scarce metal catalysts such as Pd, Pt, Ir, and Rh. These rare elements present a substantial geopolitical risk to ongoing supplies due to the limited number of countries that supply the market. As such, there has been a push to carry out similar and new chemical pathways with more earth-abundant metals. (10) We have found signs that nonprecious metal use is significant (Figure 4), but additional attention is needed within process development and academic settings for the discovery of novel couplings and asymmetric hydrogenations with abundant metals and cheap, available ligands.
Figure 4
Figure 4. Nonprecious metals screened in HTE groups.
3. HTE Equipment
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A brief survey of industrial and academic HTE laboratories was conducted to review equipment used frequently within the HTE ecosystem (Table 3). In order to successfully enable HTE technology within the laboratory, a core set of nonautomated, or “manual”, equipment is usually required to allow the end user to quickly design, execute, and analyze HTE projects. Within more specialized workflows and groups, laboratory automation begins to play a greater role.
Table 3. Equipment Found in HTE Labs
| manual | automation | analytical |
|---|---|---|
| pipettors | liquid handler | UPLC |
| well plates | solid handler | HPLC |
| gloveboxes | MS | |
| evaporators | GC | |
| stirrers | ||
| gas delivery |
HTE adoption relies on the ease of use of tools to dose/sample reagents and substrates at the micromole scale. Single and multichannel pipettors (Eppendorf, Rainin, Fisher, VWR) are universally found in the laboratories surveyed, reflecting their low barrier to entry and convenience, alongside an array of 24-, 48-, and 96-well plates of varying volumes (1, 2, and 4 mL; Unchained/Freeslate, Analytical Sales & Services, ChemGlass, and custom internal design). Most laboratories utilize nitrogen filled gloveboxes (mBraun, Vacuum Atmospheres) for the majority of screen setup, and most groups surveyed have nitrogen purge boxes for compound collection storage and other nonpristine inert atmosphere critical workflows. Centrifugal evaporators (Genevac HT-X, EZ-2, Thermo-Fisher) located within a nitrogen filled glovebox are used for solvent removal. Low-barrier HTE approaches use nitrogen blow-down tools (Analytical Sales & Services) for solvent removal. Reaction agitation/heating is achieved with tumble stirrers (V&P Scientific, Unchained/Freeslate Core Module), hot plate stirrers (IKA), incubators (ECHO Therm), heater/cooler shakers (Eppendorf Thermomixer C), and in some cases custom designed shaker/heaters. Reactive gas delivery platforms, useful for hydrogenations and carbonylations, are prevalent in most groups and allow experimentation at atmospheric and elevated pressures. These systems offer singleton reaction screening (Biotage Endeavor) and up to 96-well-plate screens (Unchained/Freeslate, Swagelok).
HTE can be augmented by automated platforms, such as liquid and solid handlers, to enable accurate and efficient screen setup. Consequently, some form of automation is employed by all groups surveyed. The overall usage of automated tools is lower compared to the nonautomated “manual” tools, possibly reflecting nontrivial setup and complexity of these systems; nevertheless, Unchained Laboratories/Freeslate/Symyx systems (core module 1–3, Junior) are listed across most teams surveyed. These systems offer either standalone liquid handling or liquid–solid handler capabilities, although most groups opt for separate liquid handling and solid handling platforms. Other vendors such as Chemspeed Swing, Swing XL, Tecan Freedom EVO, Thermo Matrix 2 × 3, Andrew Alliance, and Rainin Benchsmart are also utilized for liquid handling. Manually weighing solid reagents presents a challenge, especially when one considers multiple charges of the same or different reagents at milligram quantities! To address this, groups utilize solid handling platforms from a mix of vendors: Mettler-Toledo (Quantos QB5 and QX96, and XPE205), Unchained Laboratories (Solid-Junior), Chemspeed (SDU, GDU-P FD), and JKem (Eclipse).
Approximately 80% of automated platforms are situated under an inert nitrogen atmosphere, with the remaining 20% located on the bench, presumably being used for non-air/water sensitive applications.
Analysis of reaction outcome becomes the major bottleneck of processing HTE screens. Prior to the development of ultra-high-performance liquid chromatographic systems (UPLC), one could expect to spend 16–18 h of analysis time for a single 96-well plate (11) in order to collect high-quality data. UPLC systems provide rapid analytics allowing for superfast method development (20–30 s in some cases) while maintaining high-quality data. All groups utilize UPLC systems to some extent (Agilent 1290, Waters Classic, H-Class, I-Class, and Shimadzu). Mass spectrometers are coupled to approximately 40% of these systems. High-performance liquid chromatography (HPLC) is still in use across the groups surveyed but with lower usage when compared to UPLC systems. Finally, supercritical fluidic chromatographic systems (SFC) are being adopted, with low to medium usage reported (Waters UPC2, Agilent Aurora/1260). Gas chromatography with mass detector (GC-MSD) has limited use.
HTE can have its greatest impact when manual, automation, and analysis tools become rationally integrated. The ensuing case studies will provide greater detail for how different HTE teams in industry can convert their research tools into stream-lined workflows.
4. HTE Case Studies
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4.1. Case Study #1: Application of High-Throughput Experimentation to a Suzuki–Miyaura Step for the Synthesis of a PCSK9 Inhibitor
Compound 1 (Figure 5) is a small molecule inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) developed at Pfizer. (12) PCSK9 is a protein involved in the maintenance of plasma low density lipoprotein cholesterol (LDLC), and its inhibition can lead to low levels of LDLC, often called “bad cholesterol”, and decrease the risk of coronary heart disease. This case study describes our HTE efforts to install the tetrazole prodrug moiety of the molecule via a Pd-catalyzed Suzuki–Miyaura cross-coupling.
Figure 5
Figure 5. Structure of PCSK9 inhibitor 1.
Transition-metal-catalyzed chemistries are carried out at Pfizer inside a glovebox with an oxygen level below 10 ppm. The glovebox houses an Unchained Laboratories CM3 platform that is employed for liquid handling and controlled by Laboratory Execution and Automation (LEA) software. A very large percentage of our screening work involves transition-metal-catalyzed (Pd, Ni, Cu, Fe) cross-coupling reactions to support process chemistry projects, and over the past few years, our group has designed highly efficient HTE workflows that allow us to provide quick turnaround to meet our process chemistry colleagues’ timelines.
Screens are carried out in 96-well plates containing 1 mL glass vials, to which parylene-coated stir bars are added using a 96-stir bar dispenser; the vials are placed in a 96-well aluminum block, and after reagent addition, the plates are sealed using a solvent-resistant PTFE mat, followed by two silicon rubber mats, and then secured with a stainless steel cap that is screwed to the aluminum block using seven screws; the plate is then stirred using a tumble stirrer (typically at 300–500 rpm) and heated at the desired temperature on the CM3 deck inside the glovebox.
For a typical Pd-catalyzed Suzuki–Miyaura cross-coupling, our group has developed several types of plates for 96-well screening. The choice of plate depends on the stage and timelines of the project:
| 1. | Plate containing 6 Pd(0) and 18 Pd(II) precomplexed and commercially available Pd sources (4 sets of 24 Pd sources per plate): this plate is generally employed for fast moving, early stage projects, for which cost is not an issue. It has broad applicability in cross-coupling and allows for the screening of, e.g., two solvents and two bases per plate. This plate was designed with a fit-for-purpose approach in mind. | ||||
| 2. | Plates containing achiral ligands: We have developed two plates each containing 48 ligands (2 sets of ligands per plate) as well as a plate containing 96 less commonly used ligands, for a total of 192 ligands, mostly mono- and bidentate phosphines. In combination with a suitable Pd source, a very broad ligand screen can be carried out in a short time. This approach is usually followed for advanced and late stage projects heading toward commercialization, for which cost becomes one of the limiting factors. | ||||
| 3. | Plate containing 32 Buchwald palladacycles (third and fourth generation) (13) and 12 Johnson Matthey precomplexed allyl/crotyl palladium sources (14) (all 44 commercially available): this plate is employed for particularly difficult cross-couplings, in which a very active Pd catalyst is required. These Pd sources feature facile generation of the active Pd species and display applicability across a wide range of cross-coupling types. Drawbacks are a higher cost, intellectual property issues due to patented technologies, and the possibility that obtaining the Pd source in bulk can be problematic. | ||||
A key step in our process is exploiting the liquid handling capabilities of the Unchained Laboratories CM3 platform for the generation of 96-well plates containing Pd sources and ligands. Metal sources and ligands are dispensed as solutions/slurries in THF (50–100 μL/well) to achieve 1 μmol of metal/well (equivalent to 5 mol % based on limiting reagent). The solvent is then allowed to evaporate inside the glovebox, and the plates are capped and stored in a drybox under nitrogen at ambient temperature until the day of the screen.
On the day of the screen, the following steps are implemented:
| 1. | The plate is transferred back into the glovebox from the drybox. | ||||
| 2. | If a plate containing preplated ligands is employed, the metal source is dispensed to the wells as a stock solution in THF (50–100 mL) with the CM3 platform or via pipet (15) and the metal/ligand mixture in THF is vortexed or stirred uncapped to precomplex the ligand to the metal source (30–60 min) and evaporate the solvent. Traces of THF can then be removed under a vacuum inside the glovebox using an evaporator. | ||||
| 3. | If a solid base is required (2–3 equiv), the base is dispensed at this stage in an automated fashion with Mettler-Toledo’s QX96 platform, which is housed in a purge box. Alternatively, solid dispensing can be manually accomplished using a Biodot pipet for solids (16) if a higher degree of tolerance in the dispensed mass is acceptable. If an aqueous or liquid base is employed instead, see step 5 below. | ||||
| 4. | A mixture of both reactants (typically 10–20 μmol of limiting reagent) and internal standard (if required) in the desired solvent is added manually via pipet (15) to each well. | ||||
| 5. | Aqueous base (2–3 equiv) is added manually via pipet; (15) if a liquid organic base is required, it can be added neat at this point via pipet (15) or combined with the reactants/internal standard in step 4. | ||||
| 6. | The plate is then capped and stirred at temperature inside the glovebox on the CM3’s deck. After the desired reaction time, each well is diluted with an appropriate solvent that quenches the reaction and brings all components into solution. If solids still remain, the plate is centrifuged to allow them to settle. The plate is analyzed by UPLC-MS if a chromophore is present or by GC-MS. The analytical data is then processed using Waters’ Empower software, exported to Excel, and visualized using TIBCO Spotfire software. | ||||
Regarding the preparation of 1, our Medicinal Chemistry group developed conditions that employed Pd(OAc)2 and CatacXium A to cross-couple boronic ester 3, obtained via borylation of aryl bromide 2, with 4-iodopyrazole 4 to afford Suzuki–Miyaura product 5 (Scheme 1) as the penultimate intermediate en route to API 1.
Scheme 1
Scheme 1. Medicinal Chemistry Conditions for Suzuki–Miyaura Cross-Coupling
However, the isolation of 5 required chromatographic purification to remove phenol 6, homocoupling dimer 7, and prodrug cleavage 8 byproducts, which afforded a low-yielding process (Figure 6). We hypothesized that the formation of 6 and 7 was likely due to the presence of adventitious oxygen in the reaction (vide infra), (17) whereas increasing levels of 8 were correlated with higher reaction temperatures and when stronger bases were employed.
Figure 6
Figure 6. Impurities formed during the Suzuki–Miyaura coupling between 3 and 4.
The conditions described above were satisfactory for providing small amounts of API for early studies. However, project progression and the concomitant need to generate the first clinical lot resulted in a reevaluation of the cross-coupling step to make it amenable to scale and to avoid chromatographic purification.
Even though other alternatives such as Negishi cross-coupling were investigated, (18) the unsatisfactory results from these studies led us to focus our attention on the optimization of the Suzuki–Miyaura cross-coupling to turn it into a scalable process to generate kg quantities of API.
PCSK9 was a fast-moving project due to tight timelines to generate the first clinical batch. As a result, our group decided to initially investigate 24 commercially available precomplexed Pd(0) and Pd(II) sources plated out in 96-well format to couple pinacol ester 3 with iodopyrazole 4. A critical discovery by our Medicinal Chemistry group was the need to employ a very mild base in this coupling to avoid significant levels of prodrug cleavage byproduct 8. CsF (19) was identified as the preferred base to facilitate the Suzuki–Miyaura coupling while minimizing carbonate prodrug cleavage to the unprotected tetrazole, as has been previously disclosed in a Pfizer publication on a related compound in this series. (20)
The reactions were set up on a 5 mg (8.9 μmol) scale of boronic ester (limiting reagent) and 1.1 equiv of iodopyrazole 4 per well. Three solvents were tested (dioxane, toluene, and 2-MeTHF) in a 9:1 organic solvent/water ratio at 85 °C over 18 h using 4,4′-di-tert-butyl biphenyl as internal standard. UPLC analysis identified PdCl2(DCyPF), PdCl2(dppf), Pd(PCy3)2, (21) and dichloro[bis(dicyclohexylphosphinophenyl)ether]palladium(II) as the best catalysts in terms of Suzuki–Miyaura product/internal standard ratio (over 95% conversion based on boronic ester 3 consumption) while minimizing the formation of dimer 7 and prodrug cleavage byproduct 8. Phenol 6 was never detected, as it presumably forms in the presence of oxygen and our screen was carried out inside a glovebox with <10 ppm of O2. Toluene proved superior to dioxane and 2-MeTHF in terms of Suzuki–Miyaura product/internal standard ratio.
On the basis of these results, a second screen was carried out that focused on these four precatalysts and tested a broad range of solvents (toluene, THF, 1,2-dimethoxyethane (DME), MeCN, t-AmOH, DMF, DMAc, NMP, and iso-propyl acetate (IPAc); (22) 9:1 organic/aqueous), with CsF as base, at 70 °C (THF, MeCN) or 85 °C (rest of solvents). Results from this screen showed PdCl2(DCyPF) in toluene and Pd(PCy3)2 in toluene, DME, t-AmOH, and IPAc to be clearly superior, providing complete conversions with less than 5% prodrug cleavage and trace or no homocoupling product. NaHCO3 was investigated as an alternative mild base that would eliminate the need to avoid glass-lined tanks in our kilo lab facility, but it was outperformed by CsF for both Pd sources.
Despite their similar performance, we chose to focus on PdCl2(DCyPF) over Pd(PCy3)2 because Pd(II) sources are more air-stable and easily handled in a manufacturing facility than Pd(0) sources. Thus, further screening tested Pd loading (1, 3, and 5 mol %) as well as temperature (70, 80, and 90 °C) in aqueous toluene. Samples were manually pulled at 1, 4, 6, and 24 h to determine the kinetic profile as well as impurity levels over time (Figure 7). Only reactions at 3 and 5 mol % Pd showed full consumption of boronic ester (blue line). The amount of Suzuki–Miyaura product (yellow line) peaked at around 4 h in most reactions and then started to decrease as increasing amounts of prodrug cleavage byproduct 8 (red line) began to be generated. This decomposition was favored at higher reaction temperatures (90 °C). No homocoupling byproduct was detected in any of the reactions (green line).
Figure 7
Figure 7. Scattered plots showing experimental results for optimization reactions with PdCl2(DCyPF). Horizontal lines displayed at 0, 5, and 95% for clarity. Visualization was prepared in Spotfire.
As a compromise between conversion, Pd loading, and prodrug cleavage byproduct level, we selected 3 mol % Pd at 70 °C for further development, as these conditions afforded full conversion to product in 4 h or less while maintaining the amount of prodrug cleavage below 3%. To test the scalability of this process, a 2 g scale reaction was carried out in an Easymax 50 mL reactor with mechanical stirring at 70 °C in toluene. Surprisingly, very low conversion was observed (30–40%); increasing the reaction temperature to 80 or 90 °C or charging additional Pd precatalyst had only minor effects. While the lack of scalability remains unclear, the biphasic nature of the mixture and switching from magnetic to mechanical stirring are possible issues.
In view of these results, we decided to investigate the use of Pd(PCy3)2 as an alternative. This precatalyst would avoid the Pd(II) to Pd(0) reduction step, ruling out a possible factor for the lack of reproducibility seen on larger scale. A broad solvent screen was carried out that included THF, 2-MeTHF, 1,4-dioxane, IPAc, and t-AmOH at 70 °C (THF, 2-MeTHF) and 90 °C (1,4-dioxane, IPAc, t-AmOH) (9:1 organic/water ratio; 20 mL/g limiting reagent) with Pd(PCy3)2 (5 mol %) and aqueous CsF as base (3 equiv). Reaction sampling was carried out at 1, 2, 4, 6, and 18 h. Both 1,4-dioxane and IPAc afforded ≥98% consumption of boronic ester (limiting reagent; 1.1 equiv of aryl iodide) to product in 2 h, and most importantly, no prodrug cleavage or dimer formation byproducts were detected. When these two conditions were scaled up in an Easymax reactor on 1 g scale, slower reaction rates were observed in both cases: 5 h to completion in dioxane and 20 h to completion in IPAc. Even though no prodrug cleavage was observed, dimer formation was at 2.7 and 6.1% in dioxane and IPAc, respectively. In addition, reactions carried out on an even larger scale tended to produce increasing amounts of dimer. Further investigation determined that the cause of dimer formation was adventitious oxygen. We found that a reaction set up inside the glovebox and subsequently briefly exposed to air outside the glovebox afforded higher levels of dimer compared to an air-free control. However, no phenol byproduct was observed in the reaction exposed to air or in the previous scale-up experiments, which seem to indicate that either phenol formation is due to a factor other than adventitious oxygen or that Pd(PCy3)2 minimizes its formation. The true cause for the absence of phenol byproduct still remains unidentified at present. Under optimized conditions, reactions were sparged subsurface with nitrogen gas prior to the addition of the Pd catalyst and routinely afforded desired product in 92–94% isolated yield with no detectable amounts of dimer or phenol. As an additional precaution, Pd(PCy3)2 was weighed out inside a glovebox on the same day that the reaction was run, as samples of catalyst that had been kept in a sealed container outside of the glovebox for several days turned from white to pale green even under refrigeration, which was an indicator of exposure to oxygen.
Despite not being a desirable solvent in a manufacturing setting for toxicity reasons, dioxane was finally selected for the preparation of early batches for clinical studies due to its superior performance. A decision was made to investigate greener alternatives at a later stage of development.
With these precautions in place, the Suzuki–Miyaura cross-coupling step was successfully scaled up in our kilo lab facility to produce multi-kg quantities of intermediate 5. Further details on the optimization that led to the final Suzuki–Miyaura coupling conditions used on scale will be described in a future publication.
The power of combining automation and HTE has been demonstrated through the discovery of an efficient catalyst for a challenging Suzuki–Miyaura cross-coupling that allowed us to circumvent the lability of the prodrug moiety and the sensitivity of the reaction to oxygen. As the best catalytic system for a certain transformation is highly dependent on the structure of the reactants and may be difficult or impossible to predict, the ability offered by HTE to cover a broad reaction space is key to finding that particular metal/ligand combination. This project’s early stage of development allowed for the screening of a broad set of commercially available precomplexed Pd sources. Furthermore, the use of preplated Pd sources in a 96-well format facilitated the fast identification of several Pd sources that showed great promise. Additional optimization and scale-up experiments singled out Pd(PCy3)2 as the preferred catalyst to provide a high yielding, scalable, and chromatography-free process to support clinical studies.
4.2. Case Study #2: Identification of Improved Reaction Conditions for the Preparation of a BTK Inhibitor through Class Variable Screening (CVS)
The success of HTE for highly templated reaction types may lead to the misconception that HTE is a specific strategy for a targeted set of problems, such as metal-catalyzed cross-couplings, hydrogenation, amidation, etc. However, the strategic use of HTE infrastructure coupled with thoughtful experimental design and advanced data analysis techniques allows for the rapid assessment of a wide variety of challenging problems in chemical synthesis. In practice, any reaction that features class variables with sufficient diversity can take advantage of the opportunities afforded by HTE platforms.
The preparation of 11, (23) a reversible inhibitor of Bruton’s tyrosine kinase (BTK), (24) presented a challenging problem early in its synthesis. (25) The conversion of aniline 9 to hydrazine 10 through the intermediacy of a diazonium salt faced two undesirable options for the diazonium reduction (Scheme 2). In the first case, it had been demonstrated on a 20 kg scale that SnCl2 could effectively reduce the aryldiazonium to the desired product in 75% yield. However, the removal of the superstoichiometric tin salts from the reaction stream and the use of tin for the preparation of a pharmaceutical intermediate presented significant obstacles on a large scale. Thus, a greener option utilizing sodium sulfite was identified, although highly variable yields were observed for large scale (>20 kg) batches (70–86%). To highlight the severity of the latter case, a hypothetical 1 t synthesis of 10 would require 1092 kg of 9 if the yield were 86% and an input of 1342 kg if the yield were 70%, a difference of 250 kg! It was envisioned that a comprehensive HTE effort could identify reaction conditions with improved robustness and greenness.
Scheme 2
Scheme 2. Existing Multi-Kilo Syntheses of 10
Prior to initiating our HTE studies, it was important to align our experimental design with the goals of the project by balancing existing in-house knowledge of the transformation with information available in the literature. This step was necessary to avoid lead conditions that would present new downstream problems requiring subsequent rounds of HTE. With this perspective in mind, it was envisioned that the study would focus on the reduction of aryldiazonium chloride 12, derived from NaNO2 and HCl (Scheme 3), as opposed to alternative aryldiazonium salts prepared through different means. Aryldiazonium 12 had already been safely prepared multiple times on a >50 kg scale, and this system presented a homogeneous slurry that could be exploited for the execution of the HTE study. (26)
Scheme 3
Scheme 3. Strategy for HTE
Having established 12 as the reactive intermediate, the other variables for consideration were the reductants and solvents. As inorganic sulfur-based reducing agents had already been demonstrated as viable on a multi-kilo scale, and likely offered the greenest path forward, it was envisioned that a large portion of the study would focus on this general class of reductants. A design was formulated that balanced precedence while inviting opportunity for serendipity through the incorporation of a targeted selection of organic, phosphorus, and metallic reductants. As the diazonium salt was prepared in water, the ideal path forward would be an entirely aqueous system. Again, to achieve a balanced design, additional solvents would be added so as not to confine the study too narrowly.
The finalized experimental design contained a total of 96 experiments where sulfite-based reagents comprised 66% of the plate with six total reducing agents at varied equivalents, five solvents, a sparse array with sodium hydroxide as an additive, and varied concentrations. The remainder of the design incorporated seven different reducing agents at set equivalents with four solvents at a set concentration (Table 4). This strategy would more deeply interrogate the promising sulfite-based conditions while also providing an adequate assessment of a diverse pool of reducing agents.
Table 4. Class Variables for the HTE Study
| sulfite reductants | solvents (sulfite) | prospective reductants | solvents (prospective) |
|---|---|---|---|
| potassium metabisulfite | AcOH | ascorbic acid | AcOH |
| sodium bisulfite | DMAc | dithiothreitol (DTT) | MeCN |
| sodium dithionite | MeCN | iron(II) chloride | THF |
| sodium metabisulfite | THF | oxalic acid | water |
| sodium sulfite | water | sodium formate | |
| sodium thiosulfate | tris(2-carboxyethy)phosphine (TCEP) | ||
| PCy3 | |||
| PPh3 |
To execute the HTE, reducing agents were dispensed to a 96-well plate via an automated powder handling protocol (Unchained Laboratories CM3). The solvent and 5 N aq NaOH were added to the desired wells on the benchtop, and the plate was equilibrated to 0–5 °C over 20 min. Concurrently, a calculated 14.2 wt % stock slurry of 12 was prepared according to the existing procedure and was dispensed to each well as a homogeneous slurry by electronic pipettor (BrandTech HandyStep); additional solvent was added to wells designated for lower concentration. The plate was transferred to a 0–5 °C CM3 stirring deck, flushed with nitrogen using a custom-made plate housing connected to house nitrogen, sealed, and stirred at 300 rpm for 2 h followed by sampling for UPLC-MS analysis.
The analysis of the plate was split into two groups on the basis of the structure of the design, the sulfite reagent group, and the prospective reagent group. The prospective reagent group showed that dithiothreitol (DTT) and tris(2-carboxyethyl)phosphine (TCEP) afforded modest amounts of product in certain cases and may provide the opportunity for further investigation and optimization (Figure 8). The other organic reductants, phosphines, and FeCl2 reactions were largely ineffective.
Figure 8
Figure 8. HTE results for prospective reducing agents. Visualization was prepared in RStudio.
The sulfite reagent group was analyzed next (Figure 9). It was observed that water was the optimal solvent in most cases. Inspection of the median values for each reagent, as indicated by the horizontal line within the box for each respective reagent, revealed that sodium bisulfite gave the highest area percents (APs). Furthermore, every reaction with sodium bisulfite conducted in water afforded greater than 70 AP, regardless of the concentration of the reaction or the equivalents of the reducing agent across the range explored in this study. This was in contrast to other reagents that tended to show decreased AP of 10 with higher reducing agent equivalents.
Figure 9
Figure 9. HTE results for the targeted study of sulfite reducing agents. Visualization was prepared in RStudio.
The hits from the HTE were then subjected to more rigorous analysis and optimization. It was revealed that the robustness observed using the sodium bisulfite in the HTE study was related to its increased buffering capacity during the reaction that maintained a slightly acidic pH (2–4). In contrast, the more basic sulfite reducing agents that offered a much narrower window resulted in larger deviations due to small changes in reaction concentration or reagent equivalents. Under these conditions, it was found that deleterious SNAr side products were suppressed, resulting in higher yields. After continued optimization by the project team, the lead reaction conditions were successfully scaled to >100 kg and provided a yield of 85% across multiple batches.
In summary, the strategic application of HTE through thoughtful experimental design delivered an innovative solution to a unique challenge of aryldiazonium reduction. The HTE study enabled the use of existing intermediates and process knowledge, allowing for rapid optimization and technical transfer to an external vendor by the project team, while also providing confidence that the reagent pool had been thoroughly examined.
4.3. Case Study #3: Standardizing High-Throughput Screening of Heterogeneous Catalysts at GSK: A Case Study in Chemoselective Hydrogenation
One of the most frequently screened organic transformations at GlaxoSmithKline is hydrogenation using heterogeneous catalysts, (27) specifically the reduction of nitroarenes to anilines. (28) Because of the molecular complexity of pharmaceutical intermediates and targets, a given substrate often has many potential sites of reduction; identification of active and chemoselective reaction conditions, including catalyst identity, solvent, and pH, is therefore paramount. To facilitate these efforts, the High Throughput Chemistry and Chemical Catalysis groups within GSK’s API Chemistry department have designed and validated a series of standardized high-throughput screens for hydrogenations; we also maintain a sizable library of commercial heterogeneous catalysts for more in-depth screening. Herein, we describe the hydrogenation of 2-bromo-4-chloro-nitrobenzene using our standard nitroarene hydrogenation screens. By using these preplated kits, a wide array of commercial catalysts can be rapidly evaluated, leading to identification of promising chemoselective catalyst candidates for further process development.
A particularly powerful application of HTE in catalysis screening is to simultaneously evaluate a large suite of heterogeneous catalysts. Unlike homogeneous catalyst systems, where skilled practitioners can select appropriate metal/ligand combinations using mechanistic rationales, choosing the right hydrogenation catalyst is not as straightforward. Many organic chemists are unaware of the wide range of reactivities exhibited by “5% Pd/C” and “5% Pt/C” catalysts. While reactivity guides for commercial catalysts are available from vendors, there are many hidden factors in the design and formulation of these systems that dramatically change their reactivity.
Chemoselective reduction of nitroarenes that also contain aryl halides is often carried out using a mixture of metallic iron and acid, such as Fe/AcOH or Fe/NH4Cl, and a protic solvent. (29) These conditions often provide chemoselectivity but are not desirable to use on-scale due to exothermicity, mixing difficulties, and problematic filtrations. Catalytic hydrogenation is a far more efficient alternative; however, selection of the catalyst, solvent, additive, reaction temperature, and hydrogen pressure are all key factors in obtaining the desired chemoselectivity and reactivity of this transformation. (30) At the outset of development, it can be difficult to find an appropriate system using iterative optimization. To accelerate this process, the following reaction parameters are varied in the GSK standard aryl nitro reduction screens:
| 1. | Catalyst: Pd or Pt on carbon (Pd/C, Pt/C) catalysts can be used to promote the reduction of aryl and heteroaryl nitro compounds to the corresponding amine. (31) These same catalysts can be chosen for aliphatic nitro compounds, but the reaction conditions tend to be more vigorous to overcome the inhibitory effect of the alkylamine product. (32) Substrates containing halides typically utilize Pt/C as the catalyst to minimize dehalogenation. Wet Pd/C or Pt/C catalysts (∼50 wt %) are used to increase the safety and reactivity of these catalysts. | ||||
| 2. | Solvent: Many different reaction solvents can be used, so solvent choice is generally dictated by substrate solubility. Lower alcohols are frequently employed, as are aprotic solvents such as THF and EtOAc. A low polarity solvent such as cyclohexane may also be used. Aprotic solvents inhibit dehalogenation, and protic solvents tend to increase the reaction rate. The addition of water as a cosolvent can also have beneficial effects on reaction rate, provided the organic components remain in solution. | ||||
| 3. | Reaction pH: Many hydrogenations, especially those involving polar bonds, are accelerated by acidic media. Reduction of the nitro group to the amine can be achieved under neutral conditions; however, it may be necessary to utilize slightly acidic conditions to offset the inhibitory effect of the amine product, which is heightened in the case of aliphatic substrates. Acidic conditions can also help to inhibit dehalogenation. | ||||
| 4. | Modifiers and promoters: Modifiers such as organic bases, sulfur compounds, H3PO2, MnO, or ZnX2 can aid reaction selectivity. Using Pt/C catalysts doped with V, Fe, Cu, or Ru can increase the rate of reaction and decrease or prevent the accumulation of a hydroxylamine intermediate. V dopants specifically are known to effect disproportionation of the hydroxylamine intermediate to the aryl nitro starting material and the desired product. (33) | ||||
To efficiently evaluate these variables, GSK has developed two 48-well plate hydrogenation screens for reduction of aryl nitro compounds:
| 1. | Plate 1 contains 34 different Pd/C- and Pt/C-based catalysts. Three of these catalysts are repeated four times to allow different solvents and an acid modifier to be evaluated within a single screen. This plate can be used for aryl and heteroarylnitro compounds lacking halides or hydrogen sensitive groups (e.g., nitriles, ketones/aldehydes, olefins, O- or N-Bn, Cbz). The plate can also be utilized to screen for conditions to mediate aliphatic nitro compound reductions. | ||||
| 2. | Plate 2 contains 19 different Pt/C catalysts and is specifically designed for halogenated aryl and heteroaryl nitro compounds. Two of these catalysts are repeated four times to allow different solvents and an acid modifier to be evaluated in a single screen. | ||||
Chemists can consider executing two rounds of screening using one plate. Round 1 can be executed at 23 °C for 4–18 h. Round 2 can be executed at an elevated temperature to see if this reaction parameter affects conversion. On the basis of a 5–7% (w/w) catalyst loading, chemists need about 1 g of substrate per plate.
All solid heterogeneous catalysts are predispensed into 2 mL HPLC vials (each already containing a stir bar) using the Mettler Toledo QX96 solid handling automation located in a ventilated enclosure. These plates are then sealed and stored in the laboratory at ambient temperature for use at any time. Chemists need only add their reagents as stock solutions in the reaction solvents (at desired reaction concentration), followed by any additives such as an acid modifier. All 48 HPLC vials are then sealed using crimp septum caps, which are pierced with a needle to ensure gas ingress. The metal block containing the reaction vials is transferred to an HEL Cat96 pressure reactor, which automatically controls temperature, gas pressure, and reaction time.
After the desired reaction time, all 48 vials are decapped and the reactions are diluted with 1 mL of the appropriate HPLC solvent using an eight-channel multichannel pipet. The vials are then covered with a sealing mat and centrifuged to pelletize the heterogeneous catalyst to allow for sampling of the homogeneous supernatant. Next, HPLC samples are taken using an eight-channel multichannel pipet and transferred to an analytical block, where the samples are further diluted to HPLC sample concentration. The entire plate is submitted to an HPLC or LCMS as a batch, and the analysis is run with an appropriate method. “Hits” are determined by wt/wt assay against a known amount of internal standard, or by calibration curve if a product marker is available. Mass balance and levels of byproducts are carefully analyzed. Transfer of the lead conditions to a larger scale reactor is enacted as soon as possible, as heterogeneous reactions often exhibit mass-transfer-limited kinetics. Sufficient hydrogen volume (headspace) and efficient mixing are also key factors in a successful reaction.
Commercially available arene 13 was used as part of a validation project for the two plate designs. This case study (Scheme 4) illustrates that, in addition to the desired aniline, two frequently encountered byproducts arise from dehalogenation (15) (34) and hydrazine dimer formation (16). (35)
Scheme 4
Scheme 4. Hydrogenation of 2-Bromo-4-chloro-nitrobenzene
Performing the hydrogenation of 13 using nitro reduction plate 1 leads to a broad range of results (Figure 10). The Spotfire plot shows the area percent of 14 as a function of catalyst identity, revealing that few systems are capable of achieving >50% (by area) conversion to the desired aniline, despite the fact that full conversion of substrate is nearly always observed. Further data analysis illuminates several key aspects of this reaction. First, as can be seen with two catalysts (one Pd and one Pt), there is a dramatic solvent effect (highlighted by the nonblue data points), with aprotic solvents leading to much greater AP product. This is important to note, since the preferred solvent for most catalytic hydrogenation reactions is methanol. Second, Pt-based catalysts generally outperform their Pd and Pd/Pt counterparts, with five catalysts achieving >50% conversion. This screen also assessed the impact of added acetic acid (not shown in data), which was ambiguous in this case.
Figure 10
Figure 10. Area percent desired product (y-axis) versus catalyst (x-axis) for the catalytic hydrogenation of 13. Visualization was prepared in Spotfire.
Finally, the data from plate 1 reveal that divergent mechanistic regimes appear to be operating: a plot displaying AP desbromo-aniline 15 (y-axis) versus AP hydrazine 16 (x-axis) reveals two orthogonal sets of reaction conditions (Figure 11). The set favoring debromination is comprised of Pd and Pd/Pt catalysts, while that favoring formation of the hydrazine byproduct contains Pt catalysts, as well as one Pd catalyst in aprotic solvents. In contrast to 15, the hydrazine “dimer” is actually an intermediate en route to aniline 14 in the condensation mechanistic pathway (Scheme 5).
Figure 11
Figure 11. Area percent des-bromo product (y-axis) versus area percent hydrazine dimer (x-axis) for plate 1 (two mechanistic regimes are highlighted). Visualization was prepared in Spotfire.
Scheme 5
Scheme 5. Mechanistic Pathways for Reduction of Nitro Compounds into Anilines
On the basis of the results from plate 1, we hypothesized that nitro reduction plate 2, which contains mostly Pt/C catalysts, would also deliver a number of positive hits. Indeed, a screen of this second plate revealed that many systems are capable of high conversion to product, with only the sulfided-Pd catalysts (denoted by ◆) giving the desbromo-aniline (Figure 12). Note that promoters/inhibitors (such as Cu or V as promoters or S as an inhibitor) appear to have little effect on the case study reaction. The combination of both data sets thus provides a solid foundation to further develop a nitro reduction process through appropriate catalyst and solvent selection.
Figure 12
The preceding application of HTE to the discovery of effective heterogeneous catalysts demonstrates the vastly different reactivities and selectivities exhibited by these catalysts, despite their simple “5% Pd/C” or “5% Pt/C” names. The data from nitro reduction plate 1 demonstrates that two distinct sets of reaction conditions are operative, with Pd in protic solvents leading to dehalogenation, while Pt catalysts and Pd catalysts in aprotic solvents generate more of the diarylhydrazine intermediate. Application of plate 2, with a greater breadth of Pt/C catalysts, resulted in the identification of several systems capable of generating >90 AP product in a chemoselective manner. This high-throughput approach to comprehensive chemical space screening in heterogeneous catalysis has become a standard way of working for process development activities at GSK, due in no small part to the standardization of screening designs and ease with which any member of the department can execute and analyze a screen.
4.4. Case Study #4: Practical Asymmetric Fluorination Approach
Aminoalcohol 27 is an intermediate in the synthesis of the potent BACE1 inhibitor LY2886721 (24). (36) Over the course of the program, we also sought to prepare analogue 25 containing a fluorine at the bridgehead position of the bicyclic aminothiazine (Scheme 6). (37) We hypothesized that fluorinated aminoalcohol 26b could provide access to fluorinated bicyclic aminothiazine 25. Herein, we describe our reaction screening and optimization to develop a safe, enantioselective, and scalable route for the fluorination of the aldehyde precursor of 26b, prepared from the available key chiral amino alcohol intermediate 27. (38)
Scheme 6
Scheme 6. Route to Fluoro Analogues of LY2886721
Lilly’s Optimization and Parallel Synthesis Lab (OPSL) integrates commercially available laboratory automation with custom developed software and hardware to conduct high-throughput reaction optimization and automated parallel synthesis of compound sets. This approach allows our Automation Group to design, implement, and operate a system that effectively provides teams with data and materials. The OPSL system currently consists of seven automation platforms capable of performing independent laboratory processes, including reagent and reaction preparation, reaction vessel taring and weighing, solid and liquid dispensing, reaction incubation, automated workup, and reaction monitoring. These platforms are logically connected through a central database and custom-developed laboratory automation and information management system. This efficient design provides the automated laboratory tools with a large degree of flexibility, allowing our group to incorporate new laboratory automation technologies and easily develop additional automated synthesis and reaction optimization workflows (Figure 13).
Figure 13
Figure 13. OPSL reaction optimization workflow.
Autolab, a scientific informatics software, was developed to manage data flow and communicate experimental protocols across the OPSL automation platforms. Relying on a central relational database implemented using Oracle, Autolab acts as the focal piece to enable connectivity between electronic notebooks (eLN), experimental designs generated with JMP (Design of Experiments software), automation execution and control software called Experiment Preparation Software (EPS), and the final reporting of automated data analysis and results back to the eLN. Autolab performs all of the calculations required for each reaction, including stock solution preparations and amounts to be dispensed (either as solids or liquids). Experimental procedure and operational steps are also defined: dispensing, inert atmosphere purge, stirring, heating rate, incubation, aliquoting, and quenching. EPS uses this protocol to command the instrument, generating the corresponding scripts required for automated experimentation. After reaction sampling and analytical data processing, reaction results, including raw data for individual reactions, can be directly accessed within Autolab. Conversion and substrate and product purities are calculated and shown in a 96-well format from the HPLC-MS analysis. Reaction screening analysis can be customized to focus on multiple parameters such as conversion, impurity profile, or final product purity.
In terms of hardware, instruments are located inside a chemical fume hood and are running bespoke software connected to the database containing all experiment information. Stock solution/suspension recipes are retrieved from the database and prepared using an in-house customized Tecan liquid handler. The instrument labels and weighs the tubes, adds the appropriate amount of solvent, and caps the tubes in a fully automated process. Most solids are dispensed using a customized Chemspeed Flex Powerdose with GDU P-fd containers directly in the required tubes. This technology is implemented in an automated Flex platform that incorporates SWILE dispensing technology when only a limited amount of solid reagent is available. Alternatively, for nonautomatable solid dispensing, manual weighing is an option.
Reactions are performed using 8-tip Tecan liquid handlers that have been adapted to integrate a 96-well format H+P Variomag96 reactor that can fit either 8 mm × 100 mm or 16 mm × 100 mm reaction tubes to hold 50 μL to 1 mL final volume reactions. Reaction tubes are provided with individual stirring bars. We have designed a lid for this reactor that allows sealing of all tubes at once, inert atmosphere purge of the tubes, and aliquoting without removing the lid. The reaction block is connected to a Huber cryostat that operates from −65 to 165 °C. A CEM microwave is also integrated to an automated crimper–decrimper system to explore additional reaction conditions. A second 48-position H+P Variomag48 block is integrated in order to fit the stock solutions/suspensions required for the screening. This block holds either 16 mm × 100 mm or 25 mm × 100 mm tubes with individual stirring bars and can be heated and purged with inert atmosphere. Twelve additional solvent bottles (100 mL) are stored on an IKA plate in order to adjust the final reaction concentration. A Tecan SPE block is included to take filtered reaction aliquots in 96-well microplates. These samples are analyzed by an Agilent 1100 LCMS instrument set at 214 nm. Electrospray ionization mass spectrometry (ESI-MS) measurements are performed on an MSD quadrupole mass spectrometer (Agilent Technologies) interfaced to the above HPLC system. MS measurements are acquired in positive ionization mode over the mass range of 100–700. Data acquisition and integration for LC/UV and MS detection are performed using Chemstation software (Agilent Technologies).
Workflows are designed according to experiment objective, project needs, timelines, factors to be studied, and scope. In a generic OPSL reaction optimization experiment, the following workflow is executed:
| 1. | Reaction design: A user inputs reagents and variables to generate an eLN experiment that is exported as an XML file. | ||||||||||||||||||||||
| 2. | Experiment generation: The resulting XML file is imported into Autolab. The user specifies the phase of chemical reagents (solid, liquid, or stock solution with the corresponding concentration), so quantities can be calculated. Information within Autolab is stored in a central database that is shared by all lab instruments. | ||||||||||||||||||||||
| 3. | Design of Experiment (DoE): JMP software embedded within Autolab prepares an appropriate DoE and experimental plan. A procedure for distribution of reagents is automatically generated and can be exported to an Excel report file. | ||||||||||||||||||||||
| 4. | Platform operations: A drag and drop protocol in Autolab defines the sequence of operations for different modules (agitation, dispensing, purging, incubation) for experimental execution. | ||||||||||||||||||||||
| 5. | Experiment execution:
| ||||||||||||||||||||||
| 6. | Reaction analysis: Reaction monitoring can be done during or after incubation. An aliquot is aspirated to individual filters and directly loaded into a 96-well microplate that is transferred to an HPLC-MS. | ||||||||||||||||||||||
| 7. | Reporting: HPLC-MS results are automatically transferred to Autolab for quick visualization, exported to JMP for DoE analysis, and exported to the eLN for a final report. | ||||||||||||||||||||||
Our HTE plan toward 25 was encouraged by literature reports on the enantioselective fluorination of aldehydes in the presence of chiral amines. (39) Nonetheless, minimal precedent existed for the diastereoselective introduction of fluorine α to an aldehyde to obtain a quaternary center in such a congested steric environment. (40)
Fluoroalcohols 26a and 26b were originally prepared via an oxidation/fluorination/reduction sequence (Scheme 7). (41,42) One-pot formation of aldehyde pyrrolidine imine, followed by treatment with Select-Fluor, afforded fluoroaldehydes 29a and 29b. Reduction with NaBH4 provided a 7:1 mixture of amino alcohol diastereomers (26a/26b), delivering 5% isolated yield of the desired diastereomer 26b. All attempts at direct fluorination of the enamine derived from aldehyde 28 favored formation of the undesired diastereoisomer. (42)
Scheme 7
Scheme 7. Synthetic Sequence Validationa
a(i) TEA (2 equiv), Boc2O (1.2 equiv), 50 °C/2 h; (ii) citric acid; (iii) SO3·Py (2.3 equiv), Hunig’s base (1 equiv), DMSO, ethyl acetate, 5 °C/1 h; (iv) pyrrolidine (1.1 equiv), THF, 22 °C/14 min; (v) SelectFluor (1.2 equiv), 22 °C/2.5 h; (vi) NaHCO3 sat. aqueous solution; (vii) NaBH4 (1.2 equiv), MeOH, 22 °C/1 h; (viii) NaHCO3 sat. aqueous solution.
We hypothesized that a chiral amine in combination with a fluorinating agent might shift the selectivity of the fluorination (Figure 14). In the absence of a chiral amine, formation of diastereomer 26b was detected with Select-Fluor (30a), while other fluorinating agents delivered exclusively undesired 26a or led to decomposition. Focusing on Select-Fluor, we then studied chiral amines as organocatalysts to further improve diastereoselectivity. Under most conditions tested, slow conversion and significant amounts of side products were observed; fortunately, promising results were seen with 0.3 equiv of amines 31a, 31c, 31d, and 31e. Further screening showed that stoichiometric quantities of the chiral agent afforded the best results, with 31e being optimal. (42)
Figure 14
Figure 14. Selected fluorination agents and chiral amines.
A wide selection of solvents was also screened for the diastereoselective fluorination (Table 5). Alcoholic solvents (entries 2, 8, and 12) performed best, delivering up to 90% conversion and 3:1 selectivity for the desired diastereomer. Other solvents failed to provide a stable imine intermediate. Alcoholic solvents were rerun on a 5 g scale, confirming trifluoroethanol as the optimal choice. Scaled-up reactions using MeOH or EtOH gave mixtures of desired product with a significant amount of byproduct.
Table 5. Solvent Selection Screening
| entry | solvent | imine conversiona | 26aa (area %) | 26ba (area %) | ratio 26b/26a |
|---|---|---|---|---|---|
| 1 | dioxane | 65b | 33 | 60 | 1.8 |
| 2 | EtOH | 95b | 22 | 43 | 2.0 |
| 3 | ACN | 75b | 42 | 48 | 1.1 |
| 4 | toluene | 25c | 60 | 13 | 0.2 |
| 5 | NMP | 64b | 59 | 22 | 0.4 |
| 6 | DMA | 69b | 54 | 27 | 0.5 |
| 7 | MTBE | 40c | 38 | 40 | 1.1 |
| 8 | MeOH | 94d | 30 | 57 | 1.9 |
| 9 | IPA | 73b | 27 | 44 | 1.6 |
| 10 | DCM | 67b | 32 | 57 | 1.8 |
| 11 | MeTHF | 57b | 40 | 53 | 1.3 |
| 12 | trifluoroethanol | 96d | 20 | 61 | 3.1 |
| 13 | THF | 75b | 38 | 54 | 1.4 |
| 14 | EtOH–Tol (1:5) | 64b | 30 | 43 | 1.4 |
| 15 | MeOH–Tol (1:5) | 94b | 38 | 42 | 1.1 |
| 16 | EtOH–DCM (1:5) | 93d | 23 | 51 | 2.2 |
| 17 | MeOH–DCM (1:5) | 94d | 30 | 57 | 1.9 |
| 18 | MeOH–MTBE (1:5) | 59b | 38 | 53 | 1.4 |
| 19 | MeOH–MeTHF (1:5) | 81b | 38 | 52 | 1.4 |
a
Conversion and area % were calculated by HPLC.
b
Heterogenous suspension.
c
Sticky oily solid.
d
Homogeneous solution.
Temperature was found to have little impact on diastereoselectivity or reaction rate. Above 35 °C, larger amounts of side products were obtained regardless of the solvent used. On the other hand, trace water slowed down the reaction rate: almost full conversion was observed after 24 h when using freshly distilled trifluoroethanol or technical grade solvent, but reaction time could be further reduced to 4 h when dry solvent was used. (43)
Following our results, epimeric mixture 28 was fluorinated on a 1.6 mol scale using Select-Fluor (30a), d-proline (31e), and dry trifluoroethanol as solvent to provide 29a/29b in 90% yield and 1:7 selectivity. Amine 31e and Select-Fluor (30a) byproducts were removed by extraction, and salts were separated by filtration. After several unsuccessful attempts to isolate the desired isomer 29b by crystallization or bisulfite adduct formation, the crude fluoroaldehyde mixture 29a/29b was directly transformed into the desired chiral amino alcohol 26b by reduction with NaBH4 in EtOH. After 2 h, 98% conversion was achieved, and no isomerization was observed under the reaction conditions. It was confirmed that lowering the reaction temperature to 0 °C during the addition of NaBH4 afforded better results than running the chemistry at room temperature. (42)
In summary, the use of HTE allowed the rapid exploration and development of an efficient, practical, and scalable fluorination reaction mediated by d-proline in trifluoroethanol, generating a congested quaternary stereocenter in high yield and with good diastereoselectivity. The process was able to be scaled to kilogram quantities wherein the trifluoroethanol could be recovered and recycled. The optimization of the α-fluorination procedure was critical to shift the reaction diastereoselectivity from 1:7 to 7:1.
4.5. Case Study #5: HTE for Optimization of Metallophotoredox Catalysis Reactions
The resurgence of visible light photocatalysis over the past decade has enabled a multitude of unique and traditionally challenging bonds to be formed readily. (44) As a result, photocatalytic methods have been incorporated in the synthesis of pharmaceutically relevant compounds with increasing frequency. (45) Of recent interest are methods that merge photoredox catalysis with transition metal catalysis to facilitate coupling reactions under relatively mild conditions, often using readily available and inexpensive starting materials. This field is commonly referred to as metallophotoredox catalysis (Figure 15). (46)
Figure 15
Figure 15. General rationale behind metallophotoredox catalysis.
Our interest in metallophotoredox catalysis spans several different mechanistic regimes. We were particularly attracted to Ir- and Ni-catalyzed couplings of aryl halides with alcohols or amines to form carbon–heteroatom bonds; these methods were demonstrated to be complementary to existing Pd- and Cu-catalyzed methods with respect to substrate scope and functional group compatibility. (47) These transformations are proposed to be facilitated through photoredox-catalyzed oxidation of NiII to NiIII, driving facile reductive elimination of the coupled products (outlined in Figure 16a).
Figure 16
Figure 16. Three regimes of metallophotoredox catalysis.
Ir- and Ni-catalyzed couplings of aryl halides with radical precursors to form carbon–carbon bonds also caught our attention. (48) These methods rely on the assumption that carbon-centered radicals can be generated through photoredox-catalyzed oxidation of readily available radical precursors such as acids, keto acids, and trifluoroborate salts that then participate in Ni-catalyzed couplings with aryl halides (outlined in Figure 16b).
Finally, we were pleased to see reports detailing the formation of carbon–carbon bonds through Ir-, Ni-, and organo-catalyzed (OC) couplings of aryl halides with protected amines or ethers. (49) A proposed photoredox-catalyzed oxidation of a hydrogen atom transfer (HAT) catalyst, quinuclidine, generates a quinuclidinium radical cation that can then abstract hydrogen atoms from α-C–H positions of protected amines or ethers. The resultant carbon-centered radicals in turn participate in Ni-catalyzed couplings with aryl halides (outlined in Figure 16c).
During our initial foray into metallophotoredox catalysis, we found that optimization was required to effectively adapt conditions reported in the literature to pharmaceutically relevant substrates. Given the inherent complexity of these multicatalytic systems, we decided to leverage the power of rational HTE to accelerate optimization work and began development of a standardized platform.
In order to develop an effective platform, we elected to study a relatively complex HAT-metallophotoredox-catalyzed α-hydroxyl arylation method under development by MacMillan and co-workers (Figure 17). (50) The mechanistic hypothesis for this method was similar to that proposed for the α-amino/oxo arylation of amines and ethers (see Figure 16c). We envisioned that introduction of a Lewis acid to the system would promote hydrogen atom abstraction at the α-alkoxy C–H position of alcohols, generating carbon-centered radicals that would participate in Ni-catalyzed couplings with aryl halides. We hypothesized that judicious choice of a Lewis acid additive could suppress any undesired C–O coupling. In order to determine the optimal Lewis acid, we turned to HTE.
Figure 17
Figure 17. MSD/Princeton case study of α-hydroxyl arylation through HAT-metallophotoredox catalysis.
HTE was carried out in 96-well Para-dox photoredox optimization blocks with 1 mL glass vial inserts, under a positive pressure nitrogen atmosphere (MBraun Glovebox). (51) The reaction scale was fixed at 10 μmol of aryl halide in about 50 μL of reaction solvent to minimize the path length for optimal photon flux (<2 mm). (52) Dispense steps were carried out via hand-held pipets, following the general procedure outlined below, but minor changes were made in each screen to minimize the number of unit operations:
| 1. | A mixture of Ni precursor and ligand in acetonitrile was aged for at least 15 min to generate the precatalyst complex and then dispensed to the block. The acetonitrile was evaporated using a Genevac vacuum evaporator. | ||||
| 2. | Parylene coated magnetic tumble stir bars (V&P Scientific, VP 711D-1) were dispensed to the block using a stir bar dispensing tool (V&P Scientific, VP 711A-96-AS-1). | ||||
| 3. | A mixture of aryl halide, coupling partner, photocatalyst, quinuclidine, base, and additive was prepared in each reaction solvent and dispensed to the block. | ||||
| 4. | Two rubber mats and one PFA film were screwed down with a metal lid to prevent solvent evaporation. | ||||
| 5. | Illumination was carried out with Lumidox 470 nm 96 LED arrays set to 30 mA output, with tumble stirring (V&P Scientific, VP 710E5), under a positive pressure nitrogen atmosphere, for 24 h. Under these conditions, it was typical for the block temperature to reach 35 °C upon equilibration. | ||||
| 6. | A mixture of internal standard in acetonitrile and DMSO was added to the block, and the diluted mixtures were sampled into an analysis block containing acetonitrile and analyzed by UPLC-MS. | ||||
In the first array, we evaluated 23 Lewis acid additives in four solvents (dimethyl sulfoxide, acetonitrile, acetone, and ethyl acetate), alongside four control experiments containing no additive. Of the four solvents screened, appreciable reaction rates were observed only in DMSO. The distributions of the α-hydroxyl arylation product 37 and C–O coupling product 38 in DMSO are presented in Figure 18. In the absence of additive, C–O coupling proved to be the predominant pathway. However, the nature of the Lewis acid made a significant impact on product distribution, with zinc salts serving to suppress the competitive C–O coupling pathway and yielding roughly 45% of the desired product. The mass balance laid in the formation of dehalogenation and homocoupling byproducts, 39 and 40, respectively.
Figure 18
Figure 18. HTE evaluation of Lewis acid additives. [Performed on a 10 μmol scale with photocatalyst 32 (0.5 mol %), NiBr2·Me4Phen 33 (0.5 mol %), quinuclidine 34 (100 mol %), aryl halide 35 (1.0 equiv), alcohol 36 (5.0 equiv), and additive (1.5 equiv), in DMSO (0.25 M).] Visualization prepared in Tableau.
We next shifted our focus to reducing the dehalogenation and homocoupling byproducts through prudent selection of base, as earlier catalyst loading experiments indicated a positive correlation between the stoichiometry of the HAT catalyst, quinuclidine, and byproduct formation. We therefore reduced the quinuclidine loading to 25 mol % and evaluated 23 inorganic bases in the presence of two zinc salts, in two solvent systems. Control experiments with quinuclidine were also included in the study. We were pleased to uncover two inorganic bases, K3PO4 and NaOH, that reduced byproduct formation and yielded roughly 60% of the desired product (Figure 19).
Figure 19
Figure 19. HTE evaluation of inorganic bases. [Performed on a 10 μmol scale with photocatalyst 32 (0.5 mol %), NiBr2·Me4Phen 33 (0.5 mol %), quinuclidine 34 (25 mol %), aryl halide 35 (1.0 equiv), alcohol 36 (5.0 equiv), ZnX2 (1.5 equiv), and base (1.0 equiv) in DMSO (0.25 M) with and without water (10.0 equiv).] Visualization prepared in Excel.
At this point, we attempted scale-up experiments using cylindrical vials illuminated by a 40 W blue Kessil lamp and found that the photocatalyst loading needed to be reduced from 0.5 to 0.2 mol % and Ni catalyst loading increased from 0.5 to 1.5 mol % in order to effectively reproduce our findings with K3PO4. (53) Then, through optimization of the photocatalyst 32 structure, we improved yields further, resulting in the isolation of 75% of the α-hydroxyl arylation product 37 (Scheme 8).
Scheme 8
Scheme 8. Optimized Conditions Carried out in Cylindrical Vials Illuminated by a 40 W Blue Kessil Lampa
aPerformed on a 300 μmol scale with photocatalyst 41 (0.2 mol %), NiBr2·Me4Phen 33 (1.5 mol %), quinuclidine 34 (30 mol %), aryl halide 35 (1.0 equiv), alcohol 36 (5.0 equiv), ZnCl2 (1.5 equiv), and K3PO4 (1.0 equiv) in DMSO (0.25 M).
With an effective and reproducible workflow for custom HTE in place, we next turned to developing standardized, predispensed metallophotoredox catalysis kits for distribution across the Merck chemistry network. On the basis of our survey of the literature, we established four kit categories: metallophotoredox C–O, C–N, C–C, and HAT C–C (Figure 20).
Figure 20
Figure 20. Metallophotoredox kit designs.
For each category, we selected the optimal photocatalysts for robotic dispensing of stock solutions into 24-well kits and Ni catalysts for robotic dispensing into glass vials (Chemspeed Swing then Genevac). The selections presented here represent our second round of kit designs, as it was necessary to update the first round within a short time span to reflect rapid advances in the field. In particular, we incorporated dicyanobenzene-based donor–acceptor fluorophores such as 4CzIPN and 4DPAIPN into the kit designs, as they had been demonstrated to be competent organophotocatalysts in Ni photoredox catalysis reactions. (54) Finally, optimal photocatalyst loadings were determined to be between 2 and 5 mol % when illuminating 1 mL glass vials with 50 μL fill volumes using Lumidox 96 LED arrays.
Once the kit designs were complete, the photocatalysts were dissolved in acetonitrile and plated. The Ni complexes were generated in acetonitrile from NiBr2·glyme and the appropriate ligands and then dispensed to vials. Upon evaporation of the acetonitrile and stir bar addition, kits and vials were packaged and stored in purge boxes under positive pressure nitrogen atmosphere. (55)
To execute experiments, end-users prepared mixtures of starting material, base, and additive (if applicable) in each solvent and dispensed to the photocatalyst plates. They then prepared mixtures of each Ni complex in each solvent through redissolution of the predispensed vials; these mixtures were then added to the plate. Users sealed, illuminated, and agitated the blocks under an inert atmosphere to ensure optimal reaction performance. Finally, dilution and sampling steps were carried out.
We have performed multiple successful optimizations using these kits which are beyond the scope of this publication. In general, successful results were initially scaled up in PennOC photoreactors (56) and then gradually moved to photoflow reactors for larger scale syntheses. (57) Some photocatalyst and Ni loading optimization was needed when moving between photoreactors due to differences in light wavelength, bandwidth, and intensity.
We have presented an effective workflow for optimization of metallophotoredox catalysis reactions through HTE and successfully applied this to the optimization of a novel α-hydroxyl arylation method. We then demonstrated the scalability of these results by a factor of 30. Finally, we leveraged these learnings to develop standardized metallophotoredox catalysis kits for wide distribution across the MSD chemistry network. It is important to note that new reports have rendered it necessary to update kit designs frequently, and a continuation of this trend is expected due to the emerging nature of the field. Also inevitable is the arrival of new and improved photoreactors, which may necessitate further updates of kit designs. Nevertheless, the described metallophotoredox HTE workflow can be employed as a general framework for future optimization, even as new methods, mechanistic insights, and tools emerge.
4.6. Case Study #6: Application of Miniaturized Design of Experiments Studies to the Optimization of Methyl Ester Hydrolysis
As part of a research project at Pfizer, our group was tasked with the optimization of an ester hydrolysis to afford acid 43 (Scheme 9). The starting material 42, in addition to the methyl ester moiety, contains an acid-labile oxetane ring and a base-sensitive nitrile group that undergoes a competitive partial hydrolysis to afford amide impurity 44. This case study describes our efforts to optimize the hydrolysis of 42 under basic conditions while minimizing the amount of 44 through the use of Design of Experiments (DoE) and our Unchained Laboratories Freeslate Junior automated reaction screening platform.
Scheme 9
Scheme 9. Methyl Ester Hydrolysis with TBD in Aqueous Methyl Ethyl Ketone (MEK)
Miniaturized DoE studies are carried out at Pfizer on an Unchained Laboratories Freeslate Junior platform that is housed in a purge box with oxygen levels <20 ppm. The automation platform is controlled by the Laboratory Execution and Automation (LEA) software. Experiments are performed in 8 mL vials (Wheaton 224804) which are capped with a PTFE/silicone septum-containing cap (Wheaton 240842SP) and placed on a 6 × 8 aluminum block (Unchained Laboratories F157404) on the Freeslate Junior’s main deck. Each vial contains a stick stir bar (V&P Scientific, VP 775-20). (58) The total reaction volume is fixed at 4 mL per vial to eliminate the fill volume as an uncontrolled variable in the DoE study. This total reaction volume represents a compromise of both maintaining efficient mixing and having sufficient volume to enable 12–15 samples per reaction. Sampling is carried out in an automated fashion by the Freeslate Junior, and samples are quenched into 2 mL UPLC vials containing a flea stir bar and quench solution. The quench plates are maintained at 20 °C on the deck and stirred at 200 rpm to ensure complete reaction quenching. Our miniaturized DoE workflow is shown in Figure 21.
Figure 21
Figure 21. Miniaturized DoE workflow at Pfizer.
Prior to executing the DoE experiments, we conduct familiarization runs to reproduce previous results and determine potential variables and ranges. Once these variables and ranges for the DoE study have been explored and agreed upon with the process chemist, a set of experiments is generated using DoE software, such as Design Expert. The choice of DoE largely depends upon the study scope and material availability. Calculations for the amount of reactants, reagents, and solvents are performed in Excel or by means of the DoE import tool in Library Studio software. Solid dispensing into 8 mL vials can be performed manually or, preferably, using Mettler-Toledo’s Quantos QB5 platform. Liquid dispensing can be carried out using electronic repeater pipettes or, also preferably, in an automated fashion with the Freeslate Junior. The entire DoE recipe can be assembled in Unchained Laboratories’ Library Studio, including liquid reagent dispensing, stirring rates, heating/cooling, and sampling at desired intervals. Once the experiments have been carried out, the samples are analyzed by UPLC (if a chromophore is present), and the UPLC data is processed using Waters’ Empower software. The UPLC data are fed back into Design Expert and TIBCO Spotfire to generate plots and help visualize the results. On the basis of the DoE results, additional experiments, such as a second DoE or one-off trials, may be planned in 8 mL vials with fewer variables and/or narrower ranges to pinpoint the optimal conditions for the desired transformation. After work in 8 mL vials has been completed and all of the information is in hand, the team decides on a select group of conditions to scale up as confirmation runs in either an Easymax or Systag reactor (100 mL scale). These scale-up experiments may be replicates of previous small-scale runs or may be conditions that, according to the statistical model predictions, should give an adequate outcome. If the output from those scale-up runs is satisfactory, the information is passed on to the process chemist for further evaluation and optimization. Any discrepancies in the results between 8 mL vials and larger scale vessels must be addressed at this stage and may point to factors such as mixing sensitivity, especially for heterogeneous or biphasic reactions.
Our process chemistry group had previously developed a protocol for the methyl ester hydrolysis of 42 using 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as base. (59,60) The level of amide impurity 44 produced from this protocol (5–10%) could not be reduced to acceptable levels via recrystallization, and chromatographic purification was required. As a result, alternative conditions were evaluated to minimize the amount of 44 and avoid the need for chromatography to support larger scale campaigns.
Since acidic conditions for ester hydrolysis were precluded by the oxetane ring, our first step was screening for alternative basic conditions that completely suppressed or minimized the amount of amide impurity 44. Thus, high-throughput screening of 12 inorganic bases (carbonates, bicarbonates, phosphates, and hydroxides) identified a THF/DMSO/water combination with NaOH as a promising lead. Further screening on a larger scale with variable amounts of NaOH (2–5 equiv) and water (5–20 equiv) in a THF/DMSO mixture (16 volumes and 6% by volume, respectively) afforded incomplete reactions and, in some cases, very thick slurries that prevented efficient mixing. Side-by-side comparison with the original conditions in aqueous MEK and TBD as base showed no clear advantage to the new conditions. In view of these results and process chemistry’s familiarity with the TBD/aqueous MEK process, a decision was made to optimize this protocol using DoE.
Two DoE studies were executed in a sequential approach to examine four variables that, on the basis of preliminary work by our process chemistry group, could provide guidance of parameters to reduce production of 44. The four variables were initially incorporated into a first two-level full factorial DoE with replicates at center and two other design conditions for a total of 24 reactions split into four 6 × 8 aluminum plates to accommodate 8 mL vials. The variables and ranges in this first DoE were as follows: TBD, 1–3 equiv; water, 10–50 equiv; MEK, 5–15 volumes; temperature, 20–60 °C. Each reaction was sampled eight times at 0.8, 1.4, 2.5, 4.6, 6.7, 10.8, 16.9, and 25.1 h (61) and quenched into pH 5.4 buffer. (62) The replicates were chosen within and across plates to allow evaluation of experimental repeatability, temperature blocking effect, and plate-to-plate variability, as well as to test the lack of fit of the model. The goal of the initial design was to check the validity of initial parameter ranges and to examine parameter main effects and interactions.
The outcomes from this first DoE were the following:
| 1. | All variables were significant in that they influenced the amount of amide impurity. | ||||
| 2. | Replicates data revealed excellent reaction reproducibility. | ||||
| 3. | Desired product formation was favored at high temperature, high base, high water equiv, high concentration, and longer reaction time. See Figure 22 for contour plots. | ||||
| 4. | Unfortunately, the same conditions that favored acid 43 formation also favored amide impurity 44 formation at the expense of 43. | ||||
| 5. | In general, for conversions in the 50–60% range, the amide impurity level remained at ≤1%, especially at lower temperature (20–40 °C). | ||||
| 6. | Considerably faster reactions to acid 43 were in general observed at 60 °C than at lower temperatures but also provided much higher amide 44 levels (up to 61% UPLC AP after 25 h). | ||||
Figure 22
Figure 22. Contour plots for the predicted acid 43 formation as a function of dilution, water equiv, temperature, and reaction time. The plots have been produced at the center level of all other factors in the model except that time is at 17 h. Visualization prepared in Design Expert.
From the data in this study, it was concluded that complete suppression of amide 44 formation would be unlikely and that a compromise would have to be reached between conversion to acid 43 and the level of 44. As a result, a second DoE using a face-centered central composite design was executed to optimize the reaction with the following guidelines:
| 1. | Targets were no more than 5% for both methyl ester 42 and amide 44, as both impurities could be purged up to those levels during workup to meet specs. | ||||
| 2. | Due to the longer timelines to conduct IPC sampling and analysis in the plant, variable ranges were chosen to have a broad window of time (several hours) in which high conversion to product could be obtained while, at the same time, the amount of amide 44 would remain below the 5% threshold. | ||||
For this second DoE, narrower parameter ranges were selected as follows: TBD, 1–2 equiv; water, 20–40 equiv; MEK, 5–10 volumes; (63) temperature, 20–40 °C. The DoE design was split into five 6 × 8 aluminum plates with replicates at the center and several selected conditions within and across plates for a total of 42 reactions. Automated sampling was carried out as described above with the Freeslate Junior at 1, 2, 4, 6, 8, 10, 16, and 24 h. The experimental results from the second set of reactions are as follows:
| 1. | As in the first DoE, all reactions showed that, at some point, the amount of desired product peaked and then, at extended reaction times, amide 44 started forming in increasing amounts at the expense of desired product 43. | ||||
| 2. | Higher temperature and more equiv of both water and base increased the amounts of amide 44. | ||||
| 3. | The second round of experiments clearly confirmed that a compromise would have to be reached between conversion and amount of amide impurity. | ||||
After analysis of kinetic profiles, three reactions stood out as the most favorable in terms of conversion to product and minimization of amide 44 over an extended time window: these are labeled as experiments 1–3 in Table 6. The reaction end point was defined as ≥90% product and ≤5% ester starting material. The end point windows for experiments 1–3 as predicted by the statistical model were about 1.5, 4, and 6 h, respectively, in which the percentage of acid 43 is ≥90%, whereas amide 44 remains ≤5% (UPLC area %). On the basis of these data, the team decided to proceed with the scale-up of these three conditions. In addition, the statistical model predicted a fourth set of conditions that should afford the desired outcome (≤5% 42 and 44) over an approximately 3 h end point window (13.7–16.5 h): TBD, 2 equiv; water, 20 equiv; MEK, 7.5 volumes at 25 °C. This set of conditions was also scaled up to confirm the validity of the statistical model.
Table 6. Summary of Reaction Conditions for the Four Scale-up Confirmation Experiments
| experiment | T (°C) | TBD (equiv) | water (equiv) | MEK (vol) | predicted end point window (h) | sampling time (h) |
|---|---|---|---|---|---|---|
| 1 | 25 | 2 | 30 | 5 | 5.5–7 | 1, 3, 4, 5, 5.5, 6, 6.5, 7, 8, 10, 14, 18, 20, 24, 28 |
| 2 | 25 | 1.7 | 35 | 7.5 | 13–17 | 2, 4, 8, 10, 12, 13, 14, 15, 16, 17, 18, 20, 24, 28 |
| 3 | 20 | 2 | 20 | 5 | 14–20 | 2, 4, 8, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 28 |
| model prediction | 25 | 2 | 20 | 7.5 | 13.7–16.5 | 2, 4, 8, 10, 12, 13, 14, 15, 16, 17, 18, 20, 24, 28 |
A summary of the four scale-up confirmation experiments with sampling times is shown in Table 6. The scale-up experiments were carried out in a 100 mL Systag reactor equipped with a mechanical stirrer, a temperature probe, and a Mettler-Toledo Easysampler probe to sample the reactions. Sample frequency was increased during the predicted optimal time windows to keep close track of methyl ester 42 and amide 44 levels in those intervals.
The outcomes from these experiments are plotted in Figure 23, in which the kinetic profiles for the 8 mL experiments (circles) have been overlaid with the results from the scale-ups (crosses) to demonstrate reproducibility (experiments 1–3). The fourth plot in Figure 23 displays the results for the statistical model prediction experiment.
Figure 23
Figure 23. Overlay of experiments 1–3 on small and large scale; the fourth chart shows the kinetic profile for the statistical model prediction experiment. Horizontal lines at 5 and 90 AP for clarity. Observed end point windows are shown for scale-up experiments in Systag reactor. Visualization prepared in Spotfire.
Overall, the results for experiments 1–3 show very good reproducibility in going from 8 mL vials to the 100 mL Systag reactor, as demonstrated by the close overlapping of the kinetic profiles for 42, 43, and 44. Other conclusions from the scale-up experiments are as follows:
| 1. | Experiment 1: Slightly slower ester hydrolysis was seen on scale. The observed optimal time window to meet the desired ≤5% for both methyl ester 42 and amide 44 was very narrow (less than 1 h) and pushed out toward the end of the predicted 5.5–7 h interval. Also, of the four scale-ups, these conditions provided the largest amount of amide 44 over extended reaction times. | ||||
| 2. | Experiment 2: The reaction rates in 8 mL vials and on scale were virtually identical, and the observed end point window closely matched the predicted one (13–17 h). | ||||
| 3. | Experiment 3: As for experiment 1, a slower reaction was observed on scale, which pushed the end point window out to approximately 19–28 h. At a given time point, these reaction conditions provided the smallest amount of amide 44 out of experiments 1–3. A possible explanation for the slower reaction rate may be mixing sensitivity in going from magnetic to mechanical stirring, as this was the most concentrated reaction and large amounts of solids were present. | ||||
| 4. | Statistical model prediction experiment: A slower-than-expected reaction was also observed in this case, which pushed the end point window for sampling out from the expected 13.7–16.5 h to approximately 22–28 h. | ||||
In view of the data collected during scale-up work, a decision was made to select the reaction conditions in experiment 3 as the best compromise between reaction time to meet desired targets for 42 and 44 and have an extended time window to allow for sampling and reaction quenching in a pilot plant facility.
Optimized reaction conditions to minimize an amide byproduct during a methyl ester hydrolysis have been identified through the use of DoE studies. Even though DoE could not identify reaction conditions that totally suppressed the generation of amide 44, it directed us toward an experimental domain in which a compromise could be reached between high conversion to the desired acid and slow generation of the amide impurity. Through the combination of preliminary one-off experiments and a first DoE with broad variable range, a second DoE with narrower ranges was designed and executed that led to the identification of three sets of conditions that were scaled up in confirmation runs. In addition, the mathematical model predicted a fourth set of conditions which was also tested on scale. From this series of experiments, a particular set of conditions was identified as a potential replacement to the current process in future campaigns, providing an optimal compromise between reaction rate and amide 44 formation.
5. Conclusion
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Herein we have presented an overview of how HTE groups in both industry and academia have embraced recent technological and engineering advances to deliver improved insight to reaction discovery and chemical process development. HTE has provided a complementary paradigm toward process development to classical one-factor-at-a-time approaches, enabling an enhanced exploration of chemical space and process variables. When used in the chemical industry, HTE can support a variety of distinct workflows ranging from preclinical development to manufacturing support. To illuminate the impact of HTE across the pharmaceutical industry, we distributed a survey to the chemical technology groups at a number of leading companies. We learned that HTE approaches have been employed to assess over two dozen different bio- and chemocatalytic reaction types, looking at both discrete and continuous reaction variables. In addition to traditional reaction development, HTE has also been deployed to study downstream unit operations such as salt formation and metal scavenging.
We expect the chemical enterprise will place a greater emphasis on HTE techniques in the coming years. Our survey results demonstrate a continued interest in HTE workflows to optimize both the most commonly used transformations in organic synthesis as well as novel reaction paradigms (i.e., photoredox catalysis and C–H activation). They also support greater integration within process chemistry departments, as specialized equipment becomes more user-friendly and dedicated HTE teams begin to promote an end-user approach to basic reaction screening. As the value of HTE becomes more widely acknowledged, we believe its principles will also begin to be applied to other aspects of process development such as reaction workup and product isolation.
An increased focus on HTE and the use of micro- and nanoscale screening will require new tools to maximize insights and accelerate development. Several of our case studies revealed examples of screening hits that could not be effectively reproduced on a large scale. A better understanding of how screening platforms can mimic scaling effects will allow HTE to provide more robust leads. While reaction screening is routinely performed in parallel, reaction analysis remains a more linear endeavor. Adoption of faster or parallel analytics in chemistry laboratories will reduce the cycle time between a hypothesis and results generation. Additionally, the possibility of expanded analytical techniques that would allow for continuous monitoring of multiple reactions in parallel would enable a paradigm shift for experimental design and impact of chemical transformations. As the amount of data increases, the ability to interpret results efficiently and draw appropriate conclusions will require new data management and modeling tools and should also leverage recent advances in machine learning and first-principles modeling. With these holistic improvements to data generation and interpretation, the value of HTE will continue to broaden.
Author Information
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- Steven M. Mennen - Drug Substance Technologies, Amgen, Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States; Present Address: S.M.M.: Molecular Sciences, Fulcrum Therapeutics, 26 Landsdowne St, Cambridge, Massachusetts 02139, United States;
http://orcid.org/0000-0003-1905-5530;
- Carolina Alhambra - Centro de Investigación Lilly S. A., Avda. de la Industria 30, Alcobendas, Madrid 28108, Spain;http://orcid.org/0000-0001-9501-607X
- Simon Berritt - Internal Medicine, Applied Synthesis Technology, Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United States;http://orcid.org/0000-0001-5572-6771
- Alan H. Cherney - Drug Substance Technologies, Amgen, Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States;http://orcid.org/0000-0001-7440-6634
- Melodie Christensen - Process Research and Development, Merck & Co., Inc. Rahway, New Jersey 07065, United States;http://orcid.org/0000-0002-1393-9493
- David B. Damon - Process Chemistry, Chemical R&D, Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United States; Present Address: C.L.A., D.B.D.: Vertex Pharmaceuticals, 50 Northern Avenue, Boston, MA 02210, United States;http://orcid.org/0000-0003-0711-6818
- Pablo García-Losada - Centro de Investigación Lilly S. A., Avda. de la Industria 30, Alcobendas, Madrid 28108, Spain;http://orcid.org/0000-0002-8307-0033
- Jacob Janey - Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08901, United States;http://orcid.org/0000-0001-7697-1709
- David C. Leitch - API Chemistry, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States; Present Address: D.C.L.: Department of Chemistry, University of Victoria, P.O. Box 1700, STN CSC, Victoria, British Columbia V8W 2Y2, Canada;http://orcid.org/0000-0002-8726-3318
- David W. C. MacMillan - Merck Center for Catalysis at Princeton University, Washington Road, Princeton, New Jersey 08544, United States;http://orcid.org/0000-0001-6447-0587
- Javier Magano - Process Chemistry, Chemical R&D, Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United States;http://orcid.org/0000-0001-7151-8032
- Emma McInturff - Process Chemistry, Chemical R&D, Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United States;http://orcid.org/0000-0003-0426-3089
- Danielle Schultz - Process Research and Development, Merck & Co., Inc. Rahway, New Jersey 07065, United States;http://orcid.org/0000-0002-4811-2218
- Jason M. Stevens - Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08901, United States;http://orcid.org/0000-0003-1671-1539
- Iulia I. Strambeanu - API Chemistry, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States;http://orcid.org/0000-0002-1502-5484
- Jack Twilton - Merck Center for Catalysis at Princeton University, Washington Road, Princeton, New Jersey 08544, United States;http://orcid.org/0000-0003-3500-4901
- Matthew A. Zajac - API Chemistry, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States;http://orcid.org/0000-0001-8727-3922
Acknowledgments
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We gratefully acknowledge all of the companies that took the time to answer the questionnaires and the many helpful comments during the assembly of this HTE perspective.
References
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This article references 63 other publications.
- 1For a review on the application of HTE in chemical process development, see:Selekman, J. A.; Qiu, J.; Tran, K.; Stevens, J.; Rosso, V.; Simmons, E.; Xiao, Y.; Janey, J. High-Throughput Automation in Chemical Process Development. Annu. Rev. Chem. Biomol. Eng. 2017, 8, 525– 547, DOI: 10.1146/annurev-chembioeng-060816-101411Google Scholar1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1crivVyisQ%253D%253D&md5=c91f868eda8489a7094a9097357f76b0High-Throughput Automation in Chemical Process DevelopmentSelekman Joshua A; Qiu Jun; Tran Kristy; Stevens Jason; Rosso Victor; Simmons Eric; Xiao Yi; Janey JacobAnnual review of chemical and biomolecular engineering (2017), 8 (), 525-547 ISSN:.High-throughput (HT) techniques built upon laboratory automation technology and coupled to statistical experimental design and parallel experimentation have enabled the acceleration of chemical process development across multiple industries. HT technologies are often applied to interrogate wide, often multidimensional experimental spaces to inform the design and optimization of any number of unit operations that chemical engineers use in process development. In this review, we outline the evolution of HT technology and provide a comprehensive overview of how HT automation is used throughout different industries, with a particular focus on chemical and pharmaceutical process development. In addition, we highlight the common strategies of how HT automation is incorporated into routine development activities to maximize its impact in various academic and industrial settings.
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For selected articles on the use of HTE, see:
(a) Shevlin, M. Practical High-Throughput Experimentation for Chemists. ACS Med. Chem. Lett. 2017, 8, 601– 607, DOI: 10.1021/acsmedchemlett.7b00165Google Scholar2ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnvFCnt7w%253D&md5=4356ece5d6399f4a9c72c8a3bd5d118ePractical High-Throughput Experimentation for ChemistsShevlin, MichaelACS Medicinal Chemistry Letters (2017), 8 (6), 601-607CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)A review. Large arrays of hypothesis-driven, rationally designed expts. are powerful tools for solving complex chem. problems. Conceptual and practical aspects of chem. high-throughput experimentation are discussed. A case study in the application of high-throughput experimentation to a key synthetic step in a drug discovery program and subsequent optimization for the first large scale synthesis of a drug candidate is exemplified.(b) Krska, S. W.; DiRocco, D. A.; Dreher, S. D.; Shevlin, M. The Evolution of Chemical High-Throughput Experimentation to Address Challenging Problems in Pharmaceutical Synthesis. Acc. Chem. Res. 2017, 50, 2976– 2985, DOI: 10.1021/acs.accounts.7b00428Google Scholar2bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVGiu7bF&md5=95ab78d3e084b11009135f5a3d9fb111The Evolution of Chemical High-Throughput Experimentation To Address Challenging Problems in Pharmaceutical SynthesisKrska, Shane W.; DiRocco, Daniel A.; Dreher, Spencer D.; Shevlin, MichaelAccounts of Chemical Research (2017), 50 (12), 2976-2985CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. The structural complexity of pharmaceuticals presents a significant challenge to modern catalysis. Many published methods that work well on simple substrates often fail when attempts are made to apply them to complex drug intermediates. The use of high-throughput experimentation (HTE) techniques offers a means to overcome this fundamental challenge by facilitating the rational exploration of large arrays of catalysts and reaction conditions in a time- and material-efficient manner. Initial forays into the use of HTE in our labs. for solving chem. problems centered around screening of chiral precious-metal catalysts for homogeneous asym. hydrogenation. The success of these early efforts in developing efficient catalytic steps for late-stage development programs motivated the desire to increase the scope of this approach to encompass other high-value catalytic chemistries. Doing so, however, required significant advances in reactor and workflow design and automation to enable the effective assembly and agitation of arrays of heterogeneous reaction mixts. and retention of volatile solvents under a wide range of temps. Assocd. innovations in high-throughput anal. chem. techniques greatly increased the efficiency and reliability of these methods. These evolved HTE techniques have been utilized extensively to develop highly innovative catalysis solns. to the most challenging problems in large-scale pharmaceutical synthesis. Starting with Pd- and Cu-catalyzed cross-coupling chem., subsequent efforts expanded to other valuable modern synthetic transformations such as chiral phase-transfer catalysis, photoredox catalysis, and C-H functionalization. As our experience and confidence in HTE techniques matured, we envisioned their application beyond problems in process chem. to address the needs of medicinal chemists. Here the problem of reaction generality is felt most acutely, and HTE approaches should prove broadly enabling. However, the quantities of both time and starting materials available for chem. troubleshooting in this space generally are severely limited. Adapting to these needs led us to invest in smaller predefined arrays of transformation-specific screening "kits" and push the boundaries of miniaturization in chem. screening, culminating in the development of "nanoscale" reaction screening carried out in 1536-well plates. Grappling with the problem of generality also inspired the exploration of cheminformatics-driven HTE approaches such as the Chem. Informer Libraries. These next-generation HTE methods promise to empower chemists to run orders of magnitude more expts. and enable "big data" informatics approaches to reaction design and troubleshooting. With these advances, HTE is poised to revolutionize how chemists across both industry and academia discover new synthetic methods, develop them into tools of broad utility, and apply them to problems of practical significance.(c) Leitch, D. C.; John, M. P.; Slavin, P. A.; Searle, A. D. An Evaluation of Multiple Catalytic Systems for the Cyanation of 2,3-Dichlorobenzoyl Chloride: Application to the Synthesis of Lamotrigine. Org. Process Res. Dev. 2017, 21, 1815– 1821, DOI: 10.1021/acs.oprd.7b00262Google Scholar2chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1KnsbzJ&md5=e9e92ec943982a46c16d8a99df4b00adAn Evaluation of Multiple Catalytic Systems for the Cyanation of 2,3-Dichlorobenzoyl Chloride: Application to the Synthesis of LamotrigineLeitch, David C.; John, Matthew P.; Slavin, Paul A.; Searle, Andrew D.Organic Process Research & Development (2017), 21 (11), 1815-1821CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)2,3-Dichlorobenzoyl cyanide is a key intermediate in the synthesis of Lamotrigine (I). An assessment of various catalytic systems for the cyanation of 2,3-dichlorobenzoyl chloride with cyanide salts is described. High-throughput experimentation identified many conditions for effecting the requisite chem., including amine bases and phase-transfer catalysts, as well as catalyst-free conditions utilizing acetonitrile as a polar cosolvent. A novel catalyst, CuBr2, was identified by consideration of the possible oxidn. of Cu(I) during high-throughput screening experimentation. CuCN was found to be the best cyanide source for achieving clean conversion; however, the soly. of CuCN was the major factor limiting reaction rate under many conditions. Improving CuCN soly. by using acetonitrile as solvent enhanced the reaction rate even in the absence of the catalysts tested but significantly complicated isolation of the product. With no acetonitrile cosolvent, phase-transfer catalysts such as tetrabutylammonium bromide (TBABr) are effective; however, use of TBABr led to inconsistent reaction profiles from run-to-run, due to an unexpected clumping of the CuCN solid. Switching to cetyltrimethylammonium bromide (CTAB) alleviated this clumping behavior, leading to consistent reactivity. This CTAB-catalyzed process was scaled up, giving 560 kg of 2,3-dichlorobenzoyl cyanide in 77% isolated yield. Safety: care must be taken when carrying out chem. with metal cyanide salts.(d) Boga, S. B.; Christensen, M.; Perrotto, N.; Krska, S. W.; Dreher, S.; Tudge, M. T.; Ashley, E. R.; Poirier, M.; Reibarkh, M.; Liu, Y.; Streckfuss, E.; Campeau, L.-C.; Ruck, R. T.; Davies, I. W.; Vachal, P. Selective Functionalization of Complex Heterocycles via an Automated Strong Base Screening Platform. React. Chem. Eng. 2017, 2, 446– 450, DOI: 10.1039/C7RE00057JGoogle Scholar2dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXotVeltbY%253D&md5=047f6284854c6e3d5a8f04feb9a387f6Selective functionalization of complex heterocycles via an automated strong base screening platformBoga, Sobhana Babu; Christensen, Melodie; Perrotto, Nicholas; Krska, Shane W.; Dreher, Spencer; Tudge, Matthew T.; Ashley, Eric R.; Poirier, Marc; Reibarkh, Mikhail; Liu, Yong; Streckfuss, Eric; Campeau, Louis-Charles; Ruck, Rebecca T.; Davies, Ian W.; Vachal, PetrReaction Chemistry & Engineering (2017), 2 (4), 446-450CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)Knochel-Hauser bases, derived from 2,2,6,6-tetramethylpiperidinyl (TMP) metal amides, offered exceptional selectivity and functional group tolerance in the regioselective metalation of arenes and heteroarenes. The selectivity, stability and yield of these reactions were highly dependent on the nature of the base, additive and deprotonation temp. An automated micro-scale high throughput experimentation (HTE) approach to rapidly optimize base and temp. matrixes was developed and validated. The application of this approach to the regioselective functionalization of a variety of complex heterocycles and extension to the prepn. of organometallic reagents for transition metal catalyzed cross-coupling screens was described.(e) Brocklehurst, C. E.; Gallou, F.; Hartwieg, C. D.; Palmieri, M.; Rufle, D. Microtiter Plate (MTP) Reaction Screening and Optimization of Surfactant Chemistry: Examples of Suzuki–Miyaura and Buchwald–Hartwig Cross-Couplings in Water. Org. Process Res. Dev. 2018, 22, 1453– 1457, DOI: 10.1021/acs.oprd.8b00200Google Scholar2ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVaqtL7J&md5=89f171d501c5bf310fb4a22eb875a9ebMicrotiter Plate (MTP) Reaction Screening and Optimization of Surfactant Chemistry: Examples of Suzuki-Miyaura and Buchwald-Hartwig Cross-Couplings in WaterBrocklehurst, Cara E.; Gallou, Fabrice; Hartwieg, J. Constanze D.; Palmieri, Marco; Rufle, DominikOrganic Process Research & Development (2018), 22 (10), 1453-1457CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A screening method to evaluate Suzuki-Miyaura and Buchwald-Hartwig coupling reactions performed using aq. surfactant mixts. as solvents; plastic microtiter plates were used to perform optimization reactions on micromolar scales at 40-50°. In the reactions screened, Buchwald-Hartwig third generation precatalysts were effective as catalysts for both Suzuki-Miyaura and Buchwald-Hartwig coupling reactions in aq. surfactant mixts. - 3Schmink, J. R.; Bellomo, A.; Berritt, S. Scientist-Led High-Throughput Experimentation (HTE) and Its Utility in Academia and Industry. Aldrichimica Acta 2013, 46, 71– 80Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlCnu7vI&md5=c4742905de4898264eeaf02476850a49Scientist-led High-Throughput Experimentation (HTE) and its utility in academia and industrySchmink, Jason R.; Bellomo, Ana; Berritt, SimonAldrichimica Acta (2013), 46 (3), 71-80, 10 pp.CODEN: ALACBI; ISSN:0002-5100. (Aldrich Chemical Co.)High-Throughput Experimentation is emerging, in both the academic and industrial settings, as a powerful tool for developing new synthetic methodologies. This approach has the advantage of being highly transferable from one reaction type to another. The numerous variables assocd. with transition-metal-catalyzed methodol. development complement HTE techniques perfectly. This report highlights recent (2009-2013) advances in the application of HTE in synthetic org. chem.
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For applications of HTE in academia, see:
(a) Troshin, K.; Hartwig, J. F. Snap Deconvolution: An Informatics Approach to High-Throughput Discovery of Catalytic Reactions. Science 2017, 357, 175– 181, DOI: 10.1126/science.aan1568Google Scholar4ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFOjs7rL&md5=f9b731ac0d8b99c2d0fa6f716cdb67f1Snap deconvolution: An informatics approach to high-throughput discovery of catalytic reactionsTroshin, Konstantin; Hartwig, John F.Science (Washington, DC, United States) (2017), 357 (6347), 175-181CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)We present an approach to multidimensional high-throughput discovery of catalytic coupling reactions that integrates mol. design with automated anal. and interpretation of mass spectral data. We simultaneously assessed the reactivity of three pools of compds. that shared the same functional groups (halides, boronic acids, alkenes, and alkynes, among other groups) but carried inactive substituents having specifically designed differences in masses. The substituents were chosen such that the products from any class of reaction in multiple reaction sets would have unique differences in masses, thus allowing simultaneous identification of the products of all transformations in a set of reactants. In this way, we easily distinguished the products of new reactions from noise and known couplings. Using this method, we discovered an alkyne hydroallylation and a nickel-catalyzed variant of alkyne diarylation.(b) McNally, A.; Prier, C. K.; MacMillan, D. W. C. Discovery of an α-Amino C–H Arylation Reaction Using the Strategy of Accelerated Serendipity. Science 2011, 334, 1114– 1117, DOI: 10.1126/science.1213920Google Scholar4bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsV2mu7vP&md5=0c174902b9784e817801f5015c21566dDiscovery of an α-Amino C-H Arylation Reaction Using the Strategy of Accelerated SerendipityMcNally, Andrew; Prier, Christopher K.; MacMillan, David W. C.Science (Washington, DC, United States) (2011), 334 (6059), 1114-1117CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Serendipity has long been a welcome yet elusive phenomenon in the advancement of chem. We sought to exploit serendipity as a means of rapidly identifying unanticipated chem. transformations. By using a high-throughput, automated workflow and evaluating a large no. of random reactions, we have discovered a photoredox-catalyzed C-H arylation reaction for the construction of benzylic amines, an important structural motif within pharmaceutical compds. that is not readily accessed via simple substrates. The mechanism directly couples tertiary amines with cyano aroms. by using mild and operationally trivial conditions. - 5
For an example of the application of HTE in a collaboration between academia and industry, see:
Shevlin, M.; Friedfeld, M. R.; Sheng, H.; Pierson, N. A.; Hoyt, J. M.; Campeau, L.-C.; Chirik, P. J. Nickel-Catalyzed Asymmetric Alkene Hydrogenation of α,β-Unsaturated Esters: High-Throughput Experimentation-Enabled Reaction Discovery, Optimization, and Mechanistic Elucidation. J. Am. Chem. Soc. 2016, 138, 3562– 3569, DOI: 10.1021/jacs.6b00519Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XislOntr8%253D&md5=0fa0f704a79b5d039ff8d83e9ecb8a42Nickel-Catalyzed Asymmetric Alkene Hydrogenation of α,β-Unsaturated Esters: High-Throughput Experimentation-Enabled Reaction Discovery, Optimization, and Mechanistic ElucidationShevlin, Michael; Friedfeld, Max R.; Sheng, Huaming; Pierson, Nicholas A.; Hoyt, Jordan M.; Campeau, Louis-Charles; Chirik, Paul J.Journal of the American Chemical Society (2016), 138 (10), 3562-3569CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A highly active and enantioselective phosphine-nickel catalyst for the asym. hydrogenation of α,β-unsatd. esters has been discovered. The coordination chem. and catalytic behavior of nickel halide, acetate, and mixed halide-acetate with chiral bidentate phosphines have been explored and deuterium labeling studies, the method of continuous variation, nonlinear studies, and kinetic measurements have provided mechanistic understanding. Activation of mol. hydrogen by a trimeric (Me-DuPhos)3Ni3(OAc)5I complex was established as turnover limiting followed by rapid conjugate addn. of a nickel hydride and nonselective protonation to release the substrate. In addn. to reaction discovery and optimization, the previously unreported utility high-throughput experimentation for mechanistic elucidation is also described. - 6Selekman, J. A.; Tran, K.; Xu, Z.; Dummeldinger, M.; Kiau, S.; Nolfo, J.; Janey, J. High-Throughput Extractions: A New Paradigm for Workup Optimization in Pharmaceutical Process Development. Org. Process Res. Dev. 2016, 20, 1728– 1737, DOI: 10.1021/acs.oprd.6b00225Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVSkurbM&md5=31c85035f303b59613a01263958110a7High-Throughput Extractions: A New Paradigm for Workup Optimization in Pharmaceutical Process DevelopmentSelekman, Joshua A.; Tran, Kristy; Xu, Zhongmin; Dummeldinger, Michael; Kiau, Susanne; Nolfo, Joseph; Janey, JacobOrganic Process Research & Development (2016), 20 (10), 1728-1737CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)In the pharmaceutical industry, high throughput (HT) technol. is well developed and routinely utilized in chem. process development for reaction optimization and isolations via crystn. However, fewer HT technologies have been employed in the development of workup procedures, bridging optimized reaction and isolations. Frequently, extensive workups involving numerous unit operations are required to remove reaction stream components such as impurities, solvent and catalyst prior to isolation. Herein, we describe a systematic yet flexible approach using designed experimentation, lab. automation, and parallel experimentation to quickly and efficiently optimize unit operations that are required post reaction to remove reaction stream components (e.g. impurities, metal catalysts, solvent). This novel high throughput extn. (HTEx) platform has shown potential to broadly impact development by faster and more robustly improving process greenness, process mass intensity (PMI), cycle time, and ease of operation.
- 7(a) Santanilla, A. B.; Regalado, E. L.; Pereira, T.; Shevlin, M.; Bateman, K.; Campeau, L.-C.; Schneeweis, J.; Berritt, S.; Shi, Z.-C.; Nantermet, P.; Liu, Y.; Helmy, R.; Welch, C. J.; Vachal, P.; Davies, I. W.; Cernak, T.; Dreher, S. D. Nanomole-Scale High-Throughput Chemistry for the Synthesis of Complex Molecules. Science 2015, 347, 49– 53, DOI: 10.1126/science.1259203Google ScholarThere is no corresponding record for this reference.(b) Cernak, T.; Gesmundo, N. J.; Dykstra, K.; Yu, Y.; Wu, Z.; Shi, Z.-C.; Vachal, P.; Sperbeck, D.; He, S.; Murphy, B. A.; Sonatore, L.; Williams, S.; Madeira, M.; Verras, A.; Reiter, M.; Lee, C. H.; Cuff, J.; Sherer, E. C.; Kuethe, J.; Goble, S.; Perrotto, N.; Pinto, S.; Shen, D.-M.; Nargund, R.; Balkovec, J.; DeVita, R. J.; Dreher, S. D. Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinyl-1H-benzimidazole Diacylglycerol Acyltransferase 1 Inhibitors. J. Med. Chem. 2017, 60, 3594– 3605, DOI: 10.1021/acs.jmedchem.6b01543Google Scholar7bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjsFKktrw%253D&md5=0ad43c076c3f9ea766c5f4c05b5b84a9Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinyl-1H-benzimidazole Diacylglycerol Acyltransferase 1 InhibitorsCernak, Tim; Gesmundo, Nathan J.; Dykstra, Kevin; Yu, Yang; Wu, Zhicai; Shi, Zhi-Cai; Vachal, Petr; Sperbeck, Donald; He, Shuwen; Murphy, Beth Ann; Sonatore, Lisa; Williams, Steven; Madeira, Maria; Verras, Andreas; Reiter, Maud; Lee, Claire Heechoon; Cuff, James; Sherer, Edward C.; Kuethe, Jeffrey; Goble, Stephen; Perrotto, Nicholas; Pinto, Shirly; Shen, Dong-Ming; Nargund, Ravi; Balkovec, James; DeVita, Robert J.; Dreher, Spencer D.Journal of Medicinal Chemistry (2017), 60 (9), 3594-3605CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chem. challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on ∼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging SNAr reaction. The availability of robust synthetic chem. conditions discovered in these miniaturized investigations enabled the development of structure-activity relationships that ultimately led to the discovery of sol., selective, and potent inhibitors of DGAT1.
- 8Sabatini, M. T.; Boulton, L. T.; Sheppard, T. D. Borate esters: Simple catalysts for the sustainable synthesis of complex amides. Sci. Adv. 2017, 3, e1701028, DOI: 10.1126/sciadv.1701028Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXls1Khur0%253D&md5=8c12cb2a64f45569123f0d1e419a1726Borate esters: Simple catalysts for the sustainable synthesis of complex amidesSabatini, Marco T.; Boulton, Lee T.; Sheppard, Tom D.Science Advances (2017), 3 (9), e1701028/1-e1701028/8CODEN: SACDAF; ISSN:2375-2548. (American Association for the Advancement of Science)Chem. reactions for the formation of amide bonds are among the most commonly used transformations in org. chem., yet they are often highly inefficient. A novel protocol for amidation using a simple borate ester catalyst is reported. The process presents significant improvements over other catalytic amidation methods in terms of efficiency and safety, with an unprecedented substrate scope including functionalized heterocycles and even unprotected amino acids. The method was used to access a wide range of functionalized amide derivs., including pharmaceutically relevant targets, important synthetic intermediates, a catalyst, and a natural product.
- 9Butters, M.; Catterick, D.; Craig, A.; Curzons, A.; Dale, D.; Gillmore, A.; Green, S. P.; Marziano, I.; Sherlock, J.-P.; White, W. Critical Assessment of Pharmaceutical Processes – A Rationale for Changing the Synthetic Route. Chem. Rev. 2006, 106, 3002– 3027, DOI: 10.1021/cr050982wGoogle Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XitVOjurY%253D&md5=9bfc73e0b64651b345d5231274084a81Critical Assessment of Pharmaceutical Processes-A Rationale for Changing the Synthetic RouteButters, Mike; Catterick, David; Craig, Andrew; Curzons, Alan; Dale, David; Gillmore, Adam; Green, Stuart P.; Marziano, Ivan; Sherlock, Jon-Paul; White, WesleyChemical Reviews (Washington, DC, United States) (2006), 106 (7), 3002-3027CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. The focus of this review is to identify and characterize criteria for rejecting a synthetic route and thus trigger the search for a viable alternative in pharmaceutical industry.
- 10Chirik, P.; Morris, R. Getting Down to Earth: The Renaissance of Catalysis with Abundant Metals. Acc. Chem. Res. 2015, 48, 2495– 2495, DOI: 10.1021/acs.accounts.5b00385Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVKlsLrF&md5=72be4d92a8b18c0c99979d043c3a58b0Getting Down to Earth: The Renaissance of Catalysis with Abundant MetalsChirik, Paul; Morris, RobertAccounts of Chemical Research (2015), 48 (9), 2495CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)There is no expanded citation for this reference.
- 12(a) Darout, E.; McClure, K. F.; Piotrowski, D.; Raymer, B. CA 2907071 A1, 2016.Google ScholarThere is no corresponding record for this reference.(b) McClure, K. F.; Piotrowski, D. W.; Petersen, D.; Wei, L.; Xiao, J.; Londregan, A. T.; Kamlet, A. S.; Dechert-Schmitt, A.-M.; Raymer, B.; Ruggeri, R. B.; Canterbury, D.; Limberakis, C.; Liras, S.; DaSilva-Jardine, P.; Dullea, R. G.; Loria, P. M.; Reidich, B.; Salatto, C. T.; Eng, H.; Kimoto, E.; Atkinson, K.; King-Ahmad, A.; Scott, D.; Beaumont, K.; Chabot, J. R.; Bolt, M. W.; Maresca, K.; Dahl, K.; Arakawa, R.; Takano, A.; Halldin, C. Liver-Targeted Small-Molecule Inhibitors of Proprotein Convertase Subtilisin/Kexin Type 9 Synthesis. Angew. Chem., Int. Ed. 2017, 56, 16218– 16222, DOI: 10.1002/anie.201708744Google Scholar12bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVKqtbjI&md5=42947e0019380b6056fec16b4f4c33c2Liver-Targeted Small-Molecule Inhibitors of Proprotein Convertase Subtilisin/Kexin Type 9 SynthesisMcClure, Kim F.; Piotrowski, David W.; Petersen, Donna; Wei, Liuqing; Xiao, Jun; Londregan, Allyn T.; Kamlet, Adam S.; Dechert-Schmitt, Anne-Marie; Raymer, Brian; Ruggeri, Roger B.; Canterbury, Daniel; Limberakis, Chris; Liras, Spiros; DaSilva-Jardine, Paul; Dullea, Robert G.; Loria, Paula M.; Reidich, Benjamin; Salatto, Christopher T.; Eng, Heather; Kimoto, Emi; Atkinson, Karen; King-Ahmad, Amanda; Scott, Dennis; Beaumont, Kevin; Chabot, Jeffrey R.; Bolt, Michael W.; Maresca, Kevin; Dahl, Kenneth; Arakawa, Ryosuke; Takano, Akihiro; Halldin, ChristerAngewandte Chemie, International Edition (2017), 56 (51), 16218-16222CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Targeting of the human ribosome is an unprecedented therapeutic modality with a genome-wide selectivity challenge. A liver-targeted drug candidate is described that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small mols. Key to the concept was the identification of pharmacol. active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesterase 1. The synthesis of select tetrazole prodrugs was crucial. A cell-free in vitro translation assay contg. human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. In vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomog. 18F-isotopologue validated our liver-targeting approach.
- 13(a) Bruno, N. C.; Buchwald, S. L. Synthesis and Application of Palladium Precatalysts that Accommodate Extremely Bulky Di-tert-butylphosphino Biaryl Ligands. Org. Lett. 2013, 15, 2876– 2879, DOI: 10.1021/ol401208tGoogle Scholar13ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnslWmsLo%253D&md5=665c7c1949a64a975ba2bc88b5358ac7Synthesis and Application of Palladium Precatalysts that Accommodate Extremely Bulky Di-tert-butylphosphino Biaryl LigandsBruno, Nicholas C.; Buchwald, Stephen L.Organic Letters (2013), 15 (11), 2876-2879CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A series of palladacyclic precatalysts, e.g. I (L = TBuBrettPhos), that incorporate electron-rich di-tert-butylphosphino biaryl ligands is reported. These precatalysts are easily prepd., and their use provides a general means of employing bulky ligands in palladium-catalyzed cross-coupling reactions. The application of these palladium sources to various C-N and C-O bond-forming processes is also described. E.g., in presence of I (L = TBuBrettPhos), arylation of PhCONH2 with 1-chloro-2,5-dimethoxybenzene gave 97% arylated amide (II).(b) Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Design and Preparation of New Palladium Precatalysts for C–C and C–N Cross-Coupling Reactions. Chem. Sci. 2013, 4, 916– 920, DOI: 10.1039/C2SC20903AGoogle Scholar13bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFKjtr0%253D&md5=5b50ac18cb67251e5439199c6746dba8Design and preparation of new palladium precatalysts for C-C and C-N cross-coupling reactionsBruno, Nicholas C.; Tudge, Matthew T.; Buchwald, Stephen L.Chemical Science (2013), 4 (3), 916-920CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)A series of easily prepd., phosphine-ligated palladium precatalysts based on the 2-aminobiphenyl scaffold have been prepd. The role of the precatalyst-assocd. labile halide (or pseudohalide) in the formation and stability of the palladacycle has been examd. It was found that replacing the chloride in the previous version of the precatalyst with a mesylate leads to a new class of precatalysts with improved soln. stability and that are readily prepd. from a wider range of phosphine ligands. The differences between the previous version of precatalyst and that reported here are explored. In addn., the reactivity of the latter is examd. in a range of C-C and C-N bond forming reactions.
- 14(a) https://matthey.com/products-and-services/pharmaceutical-and-medical/catalysts/phosphine-pi-allyl-catalyst-kit (accessed June 28, 2018).Google ScholarThere is no corresponding record for this reference.(b) DeAngelis, A. J.; Gildner, P. G.; Chow, R.; Colacot, T. J. Generating Active “L-Pd(0)” via Neutral or Cationic π-Allylpalladium Complexes Featuring Biaryl/Bipyrazolylphosphines: Synthetic, Mechanistic, and Structure–Activity Studies in Challenging Cross-Coupling Reactions. J. Org. Chem. 2015, 80, 6794– 6813, DOI: 10.1021/acs.joc.5b01005Google Scholar14bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpsFaltb0%253D&md5=2ea299fdd0c2f08a3398d1cd7b5f29d2Generating Active "L-Pd(0)" via Neutral or Cationic π-Allylpalladium Complexes Featuring Biaryl/Bipyrazolylphosphines: Synthetic, Mechanistic, and Structure-Activity Studies in Challenging Cross-Coupling ReactionsDeAngelis, A. J.; Gildner, Peter G.; Chow, Ruishan; Colacot, Thomas J.Journal of Organic Chemistry (2015), 80 (13), 6794-6813CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Two new classes of highly active yet air- and moisture-stable π-R-allylpalladium complexes contg. bulky biaryl- and bipyrazolylphosphines with extremely broad ligand scope were developed. Neutral π-allylpalladium complexes incorporated a range of biaryl/bipyrazolylphosphine ligands, while extremely bulky ligands were accommodated by a cationic scaffold. These complexes are easily activated under mild conditions and are efficient for a wide array of challenging C-C and C-X (X = heteroatom) cross-coupling reactions. Their high activity is correlated to their facile activation to a 12-electron-based L-Pd(0) catalyst under commonly employed conditions for cross-coupling reactions, noninhibitory byproduct release upon activation, and suppression of the off-cycle pathway to form dinuclear (μ-allyl)(μ-Cl)Pd2(L)2 species, supported by structural (single crystal x-ray) and kinetic studies. A broad scope of C-C and C-X coupling reactions with low catalyst loadings and short reaction times highlight the versatility and practicality of these catalysts in org. synthesis.
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An electronic positive displacement repeater pipet is employed when the compound to be dispensed is in solution; if a slurry is obtained, the source is dispensed using a basic manual pipet one well at a time.
There is no corresponding record for this reference. - 16https://www.biodot.com (accessed May 19, 2018). However, the manufacturer has confirmed that this item has been discontinued and is no longer commercially available.Google ScholarThere is no corresponding record for this reference.
- 17(a) Adamo, C.; Amatore, C.; Ciofini, I.; Jutand, A.; Lakmini, H. Mechanism of the Palladium-Catalyzed Homocoupling of Arylboronic Acids: Key Involvement of a Palladium Peroxo Complex. J. Am. Chem. Soc. 2006, 128, 6829– 6836, DOI: 10.1021/ja0569959Google Scholar17ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xkt1Ogtrs%253D&md5=5c22a31342395f19be52a876eb414187Mechanism of the Palladium-Catalyzed Homocoupling of Arylboronic Acids: Key Involvement of a Palladium Peroxo ComplexAdamo, Carlo; Amatore, Christian; Ciofini, Ilaria; Jutand, Anny; Lakmini, HakimJournal of the American Chemical Society (2006), 128 (21), 6829-6836CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The mechanism of the palladium-catalyzed homocoupling of arylboronic acids ArB(OH)2 (Ar = 4-Z-C6H4 with Z = MeO, H, CN) in the presence of dioxygen, leading to sym. biaryls, has been fully elucidated. The peroxo complex (η2-O2)PdL2 (L = PPh3), generated in the reaction of dioxygen with the Pd(0) catalyst, was found to play a crucial role. Indeed, it reacts with the arylboronic acid to generate an adduct (coordination of one oxygen atom of the peroxo complex to the oxophilic boron atom of the arylboronic acid) characterized by 31P NMR spectroscopy and ab initio calcns. This adduct reacts with a second mol. of arylboronic acid to generate trans-ArPd(OH)L2 complexes. A transmetalation by the arylboronic acid gives trans-ArPdArL2 complexes. The biaryl is then released in a reductive elimination. This reaction is at the origin of the formation of biaryls as byproducts in palladium-catalyzed Suzuki-Miyaura reactions when they are not conducted under oxygen-free atm.(b) Kirai, N.; Yamamoto, Y. Homocoupling of Arylboronic Acids Catalyzed by 1,10-Phenanthroline-Ligated Copper Complexes in Air. Eur. J. Org. Chem. 2009, 2009, 1864– 1867, DOI: 10.1002/ejoc.200900173Google ScholarThere is no corresponding record for this reference.
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The results from these studies will be included in a future article covering the complete synthesis of compound 1 on a large scale.
There is no corresponding record for this reference. - 19Wright, S. W.; Hageman, D. L.; McClure, L. D. Fluoride-Mediated Boronic Acid Coupling Reactions. J. Org. Chem. 1994, 59, 6095– 6097, DOI: 10.1021/jo00099a049Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXmtlSntrk%253D&md5=32a4ec1c4d7ea069b5cf163b3caa2567Fluoride-Mediated Boronic Acid Coupling ReactionsWright, Stephen W.; Hageman, David L.; McClure, Lester D.Journal of Organic Chemistry (1994), 59 (20), 6095-7CODEN: JOCEAH; ISSN:0022-3263.Fluoride salts are effective in promoting boron to palladium transmetalation in the coupling of arylboronic and vinylboronic acids with aryl bromides and aryl triflates. The reactions may be carried out in a variety of aq., protic or aprotic media. The use of cesium fluoride in aprotic solvents is compatible with a variety of base- and nucleophile-sensitive functional groups. E.g., treating PhB(OH)2 with Me 4-bromophenylacetate in DME contg. 2 equiv CsF and 3 mol % Pd(PPh)4 gave 98% 4-PhC6H4CH2CO2Me.
- 20Akin, A.; Barrila, M. T.; Brandt, T. A.; Dechert-Schmitt, A.-M. R.; Dube, P.; Ford, D. D.; Kamlet, A. S.; Limberakis, C.; Pearsall, A.; Piotrowski, D. W.; Quinn, B.; Rothstein, S.; Salan, J.; Wei, L.; Xiao, J. A Scalable Route for the Regio- and Enantioselective Preparation of a Tetrazole Prodrug: Application to the Multi-Gram-Scale Synthesis of a PCSK9 Inhibitor. Org. Process Res. Dev. 2017, 21, 1990– 2000, DOI: 10.1021/acs.oprd.7b00304Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslOnsL3K&md5=67b0f5f390214681d725d4859944fd81A Scalable Route for the Regio- and Enantioselective Preparation of a Tetrazole Prodrug: Application to the Multi-Gram-Scale Synthesis of a PCSK9 InhibitorAkin, Anne; Barrila, Mark T.; Brandt, Thomas A.; Dechert-Schmitt, Anne-Marie R.; Dube, Pascal; Ford, David D.; Kamlet, Adam S.; Limberakis, Chris; Pearsall, Andrew; Piotrowski, David W.; Quinn, Brian; Rothstein, Sarah; Salan, Jerry; Wei, Liuqing; Xiao, JunOrganic Process Research & Development (2017), 21 (12), 1990-2000CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The synthesis of multigram quantities of small mol. PCSK9 inhibitor (R,S)-I is described. The route features a safe, multikilogram method to prep. 5-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2H-tetrazole (II). A three-component dynamic kinetic resoln. between tetrazole II, acetaldehyde, and isobutyric anhydride was catalyzed by a chiral DMAP catalyst to afford enantiomerically enriched hemiaminal ester (S)-III on multikilogram scale. Magnesiation, transmetalation, and Negishi coupling provided access to Boc-intermediate (R,S)-IV, which was deprotected to provide (R,S)-I in multigram quantities.
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Ligand abbreviations: DCyPF, dicyclohexylphosphinoferrocene; dppf, diphenylphosphinoferrocene; Cy, cyclohexyl.
There is no corresponding record for this reference. - 22
1,4-Dioxane was not included in this screen due to its toxicity.
There is no corresponding record for this reference. - 23
For papers on the discovery of 11, see:
(a) Watterson, S. H.; De Lucca, G. V.; Shi, Q.; Langevine, C. M.; Liu, Q.; Batt, D. G.; Bertrand, M. B.; Gong, H.; Dai, J.; Yip, S.; Li, P.; Sun, D.; Wu, D.-R.; Wang, C.; Zhang, Y.; Traeger, S. C.; Pattoli, M. A.; Skala, S.; Cheng, L.; Obermeier, M. T.; Vickery, R.; Discenza, L. N.; D’Arienzo, C. J.; Zhang, Y.; Heimrich, E.; Gillooly, K. M.; Taylor, T. L.; Pulicicchio, C.; McIntyre, K. W.; Galella, M. A.; Tebben, A. J.; Muckelbauer, J. K.; Chang, C.; Rampulla, R.; Mathur, A.; Salter-Cid, L.; Barrish, J. C.; Carter, P. H.; Fura, A.; Burke, J. R.; Tino, J. A. Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton’s Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers. J. Med. Chem. 2016, 59, 9173– 9200, DOI: 10.1021/acs.jmedchem.6b01088Google Scholar23ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVKjsrfF&md5=91098abc802521b9ad91563d20ac5893Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton's Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked AtropisomersWatterson, Scott H.; De Lucca, George V.; Shi, Qing; Langevine, Charles M.; Liu, Qingjie; Batt, Douglas G.; Beaudoin Bertrand, Myra; Gong, Hua; Dai, Jun; Yip, Shiuhang; Li, Peng; Sun, Dawn; Wu, Dauh-Rurng; Wang, Chunlei; Zhang, Yingru; Traeger, Sarah C.; Pattoli, Mark A.; Skala, Stacey; Cheng, Lihong; Obermeier, Mary T.; Vickery, Rodney; Discenza, Lorell N.; D'Arienzo, Celia J.; Zhang, Yifan; Heimrich, Elizabeth; Gillooly, Kathleen M.; Taylor, Tracy L.; Pulicicchio, Claudine; McIntyre, Kim W.; Galella, Michael A.; Tebben, Andy J.; Muckelbauer, Jodi K.; Chang, ChiehYing; Rampulla, Richard; Mathur, Arvind; Salter-Cid, Luisa; Barrish, Joel C.; Carter, Percy H.; Fura, Aberra; Burke, James R.; Tino, Joseph A.Journal of Medicinal Chemistry (2016), 59 (19), 9173-9200CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiol. of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clin. treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a redn. in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clin. studies.(b) De Lucca, G. V.; Shi, Q.; Liu, Q.; Batt, D. G.; Bertrand, M. B.; Rampulla, R.; Mathur, A.; Discenza, L.; D’Arienzo, C.; Dai, J.; Obermeier, M.; Vickery, R.; Zhang, Y.; Yang, Z.; Marathe, P.; Tebben, A. J.; Muckelbauer, J. K.; Chang, C. J.; Zhang, H.; Gillooly, K.; Taylor, T.; Pattoli, M. A.; Skala, S.; Kukral, D. W.; McIntyre, K. W.; Salter-Cid, L.; Fura, A.; Burke, J. R.; Barrish, J. C.; Carter, P. H.; Tino, J. A. Small Molecule Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK): Structure–Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide (BMS-935177). J. Med. Chem. 2016, 59, 7915– 7935, DOI: 10.1021/acs.jmedchem.6b00722Google Scholar23bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlCrsL3M&md5=7c7ec1a52121c541753c045c1cbf758bSmall Molecule Reversible Inhibitors of Bruton's Tyrosine Kinase (BTK): Structure-Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide (BMS-935177)De Lucca, George V.; Shi, Qing; Liu, Qingjie; Batt, Douglas G.; Beaudoin Bertrand, Myra; Rampulla, Rick; Mathur, Arvind; Discenza, Lorell; D'Arienzo, Celia; Dai, Jun; Obermeier, Mary; Vickery, Rodney; Zhang, Yingru; Yang, Zheng; Marathe, Punit; Tebben, Andrew J.; Muckelbauer, Jodi K.; Chang, ChiehYing J.; Zhang, Huiping; Gillooly, Kathleen; Taylor, Tracy; Pattoli, Mark A.; Skala, Stacey; Kukral, Daniel W.; McIntyre, Kim W.; Salter-Cid, Luisa; Fura, Aberra; Burke, James R.; Barrish, Joel C.; Carter, Percy H.; Tino, Joseph A.Journal of Medicinal Chemistry (2016), 59 (17), 7915-7935CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bruton's tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a crit. role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure-activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clin. development. - 24Garber, K. Principia Biopharma. Nat. Biotechnol. 2013, 31, 377, DOI: 10.1038/nbt0513-377Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntF2qtrc%253D&md5=75d9a15a69967849f1137126f74f4f44Principia BiopharmaGarber, KenNature Biotechnology (2013), 31 (5), 377CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)A University of California, San Francisco, startup offers a reversible twist on covalent drugs.
- 25
For the commercial synthesis of BMS-986142, see:
Beutner, G.; Carrasquillo, R.; Geng, P.; Hsiao, Y.; Huang, E. C.; Janey, J.; Katipally, K.; Kolotuchin, S.; La Porte, T.; Lee, A.; Lobben, P.; Lora-Gonzalez, F.; Mack, B.; Mudryk, B.; Qiu, Y.; Qian, X.; Ramirez, A.; Razler, T. M.; Rosner, T.; Shi, Z.; Simmons, E.; Stevens, J.; Wang, J.; Wei, C.; Wisniewski, S. R.; Zhu, Y. Adventures in Atropisomerism: Total Synthesis of a Complex Active Pharmaceutical Ingredient with Two Chirality Axes. Org. Lett. 2018, 20, 3736– 3740, DOI: 10.1021/acs.orglett.8b01218Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFeltrbE&md5=ab925c9f4992d77915b18d3140e28948Adventures in Atropisomerism: Total Synthesis of a Complex Active Pharmaceutical Ingredient with Two Chirality AxesBeutner, Gregory; Carrasquillo, Ronald; Geng, Peng; Hsiao, Yi; Huang, Eric C.; Janey, Jacob; Katipally, Kishta; Kolotuchin, Sergei; La Porte, Thomas; Lee, Andrew; Lobben, Paul; Lora-Gonzalez, Federico; Mack, Brendan; Mudryk, Boguslaw; Qiu, Yuping; Qian, Xinhua; Ramirez, Antonio; Razler, Thomas M.; Rosner, Thorsten; Shi, Zhongping; Simmons, Eric; Stevens, Jason; Wang, Jianji; Wei, Carolyn; Wisniewski, Steven R.; Zhu, YeOrganic Letters (2018), 20 (13), 3736-3740CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A strategy to prep. compds. with multiple chirality axes, which has led to a concise total synthesis of compd. I with complete stereocontrol, is reported. - 26
For a recent reference regarding the preparation of aryldiazonium salts, see:
Oger, N.; Le Grognec, E.; Felpin, F.-X. Handling Diazonium Salts in Flow for Organic and Material Chemistry. Org. Chem. Front. 2015, 2, 590– 614, DOI: 10.1039/C5QO00037HGoogle Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXksFWmsr4%253D&md5=5ddf50967098bf22ace7503011c9200eHandling diazonium salts in flow for organic and material chemistryOger, Nicolas; Le Grognec, Erwan; Felpin, Francois-XavierOrganic Chemistry Frontiers (2015), 2 (5), 590-614CODEN: OCFRA8; ISSN:2052-4129. (Royal Society of Chemistry)This review gives an overview of transformations involving the use of diazonium salts in flow. The efficiency of the strategies is critically discussed with a special emphasis on the design of the flow devices. If comparative studies with batch chem. is provided, the input of flow chem. with regard to the reaction yields and safety issues is discussed as well. - 27(a) Hamilton, P.; Sanganee, M. J.; Graham, J. P.; Hartwig, T.; Ironmonger, A.; Priestley, C.; Senior, L. A.; Thompson, D. R.; Webb, M. R. Using PAT to Understand, Control, and Rapidly Scale Up the Production of a Hydrogenation Reaction and Isolation of Pharmaceutical Intermediate. Org. Process Res. Dev. 2015, 19, 236– 243, DOI: 10.1021/op500285xGoogle Scholar27ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVegu7rI&md5=fa3d5dfa3c071f8d208fca0098a7f645Using PAT To Understand, Control, and Rapidly Scale Up the Production of a Hydrogenation Reaction and Isolation of Pharmaceutical IntermediateHamilton, Peter; Sanganee, Mahesh Jayantilal; Graham, Jonathan P.; Hartwig, Thoralf; Ironmonger, Alan; Priestley, Catherine; Senior, Lesley A.; Thompson, Duncan R.; Webb, Michael R.Organic Process Research & Development (2015), 19 (1), 236-243CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The development of a hydrogenation process and subsequent isolation for an intermediate in the manuf. of an active pharmaceutical ingredient is described. In-line process anal. technol. (PAT) approaches were applied to gain process understanding and control. First, a calibration-free, qual., scale-independent approach using in situ mid-IR (MIR) spectrometry to det. the end point of a hydrogenation reaction in real time is described. A curve-fitting algorithm was developed using MATLAB software to allow the reaction rate to be calcd. at any given time during the reaction on the basis of the consumption of an intermediate species. The algorithm, coupled with understanding of the process, allowed the end point to be correctly identified in triplicate during scale-up of the process from 0.2-20 L scale. Second, a quant. partial least-squares (PLS) regression model was developed using near-IR (NIR) spectrometry to det. the solvent compn. during the subsequent const.-vol. distn. process prior to the crystn. of the hydrogenated product. Here the application of in-line NIR spectroscopy allowed the correct crystn. seed point to be detd., enhancing the control of quality and manufacturability.(b) Leitch, D. C.; Greene, T. F.; O’Keeffe, R. O.; Lovelace, T. C.; Powers, J. D.; Searle, A. D. A Combined High-Throughput Screening and Reaction Profiling Approach toward Development of a Tandem Catalytic Hydrogenation for the Synthesis of Salbutamol. Org. Process Res. Dev. 2017, 21, 1806– 1814, DOI: 10.1021/acs.oprd.7b00261Google Scholar27bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1yhtrrM&md5=e50f0dab8b02253e35611acfd0879049A Combined High-Throughput Screening and Reaction Profiling Approach toward Development of a Tandem Catalytic Hydrogenation for the Synthesis of SalbutamolLeitch, David C.; Greene, Thomas F.; O'Keeffe, Roisin; Lovelace, Thomas C.; Powers, Jeremiah D.; Searle, Andrew D.Organic Process Research & Development (2017), 21 (11), 1806-1814CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A combined high-throughput screening and reaction profiling approach to the telescoping of two redns. in the synthesis of Salbutamol is described. Optimization studies revealed the beneficial effect of mildly acidic conditions, and the use of water as a cosolvent. Persistent formation of deoxygenated impurities using a Pd/C catalyst led to the initiation of reaction profiling studies, which revealed that the ketone intermediate formed after rapid debenzylation is the sole source of deoxygenated impurities, indicating that more rapid ketone hydrogenation should minimize this deoxygenation. A dual catalyst approach based on these insights has been developed, with both Pd/Pt and Ru/Pt catalyst systems as more selective than Pd-only systems. Based on reaction profiles that indicate the deoxygenation side reaction is first-order in the concn. of debenzylated ketone intermediate, Pt catalysts for rapid and selective ketone hydrogenation were paired with Pd and Ru catalysts known to perform selective debenzylation. Optimization of these dual catalyst processes led to conditions that were demonstrated on 20 g scale to prep. Salbutamol in 49% isolated yield after recrystn.
- 28(a) Boros, E. E.; Burova, S. A.; Erickson, G. A.; Johns, B. A.; Koble, C. S.; Kurose, N.; Sharp, M. J.; Tabet, E. A.; Thompson, J. B.; Toczko, M. A. A Scaleable Synthesis of Methyl 3-Amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate. Org. Process Res. Dev. 2007, 11, 899– 902, DOI: 10.1021/op7001326Google Scholar28ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpvVaksLY%253D&md5=50bb690cf065a568e1eb9bb54a71e75cA Scalable Synthesis of Methyl 3-Amino-5-(4-fluorobenzyl)-2-pyridinecarboxylateBoros, Eric E.; Burova, Svetlana A.; Erickson, Greg A.; Johns, Brian A.; Koble, Cecilia S.; Kurose, Noriyuki; Sharp, Matthew J.; Tabet, Elie A.; Thompson, James B.; Toczko, Matthew A.Organic Process Research & Development (2007), 11 (5), 899-902CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A scalable synthesis of Me 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (I, R = Me), starting from 5-bromo-2-methoxypyridine and 4-fluorobenzaldehyde, is described. Key steps in the process include lithium-bromine exchange of 5-bromo-2-methoxypyridine, addn. of the resulting lithiate to 4-fluorobenzaldehyde, regioselective nitration of pyridone II, and Pd-catalyzed alkoxycarbonylation of bromopyridine III. Overall yield of the five-stage synthesis was 23%; intermediates and final product I·HCl were isolated as filterable solids. Compds. I (R = Me, Et) are important intermediates in the synthesis of 7-benzylnaphthyridinones and related HIV-1 integrase inhibitors.(b) Crump, B. R.; Goss, C.; Lovelace, T.; Lewis, R.; Peterson, J. Influence of Reaction Parameters on the First Principles Reaction Rate Modeling of a Platinum and Vanadium Catalyzed Nitro Reduction. Org. Process Res. Dev. 2013, 17, 1277– 1286, DOI: 10.1021/op400116kGoogle Scholar28bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVSitL%252FO&md5=c900de4b5ab4231bde21024ef5203b2bInfluence of Reaction Parameters on the First Principles Reaction Rate Modeling of a Platinum and Vanadium Catalyzed Nitro ReductionCrump, Brian R.; Goss, Charles; Lovelace, Tom; Lewis, Rick; Peterson, JohnOrganic Process Research & Development (2013), 17 (10), 1277-1286CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)This paper describes the influence of key reaction parameters on the development of a rate model which can be used to forecast starting material conversion independent of scale. A nitro redn. was examd. via first principles reaction progress modeling. The reaction parameters, most notably hydrogen partial pressure and agitation rate, influenced the choice of rate model. At lower hydrogen partial pressures, the reaction rate was influenced by gas to liq. mass transfer, hydrogen pore diffusion, and the rate of the surface reaction during the overall reaction. No single model could be generated to explain the rate observations at lower hydrogen partial pressures. At higher hydrogen partial pressures, a kinetic reaction model was used to generate an equation to forecast the substrate concn. as a function of time and reaction parameters. This reaction model is independent of scale provided that the mass transfer coeff. exceeded a min. threshold value. The model can be used to set an appropriate design space for key reaction parameters and negates the need to validate the design space at scale.(c) Bowman, R. K.; Bullock, K. M.; Copley, R. C. B.; Deschamps, N. M.; McClure, M. S.; Powers, J. D.; Wolters, A. M.; Wu, Lianming; Xie, S. Conversion of a Benzofuran Ester to an Amide through an Enamine Lactone Pathway: Synthesis of HCV Polymerase Inhibitor GSK852A. J. Org. Chem. 2015, 80, 9610– 9619, DOI: 10.1021/acs.joc.5b01598Google Scholar28chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVygsr%252FJ&md5=1d9aad81e54f3030ccaa5d9deca7a56dConversion of a Benzofuran Ester to an Amide through an Enamine Lactone Pathway: Synthesis of HCV Polymerase Inhibitor GSK852ABowman, Roy K.; Bullock, Kae M.; Copley, Royston C. B.; Deschamps, Nicole M.; McClure, Michael S.; Powers, Jeremiah D.; Wolters, Andy M.; Wu, Lianming; Xie, ShipingJournal of Organic Chemistry (2015), 80 (19), 9610-9619CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)HCV NS5B polymerase inhibitor GSK852A (IV) was synthesized in only five steps from Et 4-fluorobenzoylacetate in 46% overall yield. Key to the efficient route was the synthesis of the highly functionalized benzofuran core I (X = Br) from the β-keto ester in one pot and the efficient conversion of ester I (X = c-Pr) to amide II via enamine lactone III. Serendipitous events led to identification of the isolable enamine lactone intermediate III. Single crystal X-ray diffraction and NMR studies supported the intramol. hydrogen bond in enamine lactone III. The hydrogen bond was considered an enabler in the proposed pathway from ester 6 to enamine lactone III and its rearrangement to amide II. GSK852A (IV) was obtained after reductive amination and mesylation with conditions amenable to the presence of the boronic acid moiety which was considered important for the desirable pharmacokinetics of IV. The overall yield of 46% in five steps was a significant improvement to the previous synthesis from the same β-keto ester in 5% yield over 13 steps.
- 29Hazlet, S. E.; Dornfeld, C. A. The Reduction of Aromatic Nitro Compounds with Activated Iron. J. Am. Chem. Soc. 1944, 66, 1781– 1782, DOI: 10.1021/ja01238a049Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaH2MXhslKi&md5=791c8b8fad14b32e9781b4634151f77eReduction of aromatic nitro compounds with activated FeHazlet, Stewart E.; Dornfeld, Clinton A.Journal of the American Chemical Society (1944), 66 (), 1781-2CODEN: JACSAT; ISSN:0002-7863.Activated Fe was prepd. by adding 10 ml. concd. HCl to 50 g. 40-mesh granulated Fe. Reduction was carried out by adding the Fe to 5 g. of the NO2 compds. in 200 ml. C6H6 on the water bath, refluxing 0.5 hr., adding 1 ml. H2O and refluxing 7 hrs., during which 20 ml. of H2O were added. The amines were isolated as the HCl salts or as the free base. The yields (%) of amines were: PhNO2 82, o- and p-O2NC6H4Me 61 and 91, 4-O2NC6H4Ph 93, 1-C10H7NO2 96, o-ClC6H4NO2 92, o-BrC6H4NO2 97, 2,4-Cl(O2N)C6H3Me 89, o-, m- and p-O2NC6H4NH2 33, 32 and 14, 6,2-O2NC10H6NH2 28, o- and p-O2NC6H4OH 28, small, p-O2NC6H4OAc 9, p-O2NC6H4CO2Bu 72; p-O2NC6H4O3SPh gives 90% of p-aminophenyl benzenesulfonate, m. 100-1°.
- 30(a) Kadam, H. K.; Tilve, S. G. Advancement in methodologies for reduction of nitroarenes. RSC Adv. 2015, 5, 83391– 83407, DOI: 10.1039/C5RA10076CGoogle Scholar30ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFWhurfF&md5=a91364ff6d1faf7eda190af93f4b75dbAdvancement in methodologies for reduction of nitroarenesKadam, Hari K.; Tilve, Santosh G.RSC Advances (2015), 5 (101), 83391-83407CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)The importance of aryl amines as raw materials for various applications has spurred extensive research in developing economic processes for the redn. of nitroarenes. Developing green methodologies is now a compelling discipline for synthetic org. chemists. The recent surge in nanochem. has led to the development of some interesting applications in nitro redn. processes. This review discusses some recent examples of reports in this field. The different methods are classified based on the source of hydrogen utilized during redn. and the mechanism involved in the redn. process.(b) Loos, P.; Alex, H.; Hassfeld, J.; Lovis, K.; Platzek, J.; Steinfeldt, N.; Hübner, S. Selective Hydrogenation of Halogenated Nitroaromatics to Haloanilines in Batch and Flow. Org. Process Res. Dev. 2016, 20, 452– 464, DOI: 10.1021/acs.oprd.5b00170Google Scholar30bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1Gnu77F&md5=c4f0af965f12364c3c37b3d2e3f4400dSelective Hydrogenation of Halogenated Nitroaromatics to Haloanilines in Batch and FlowLoos, Patrick; Alex, Hannes; Hassfeld, Jorma; Lovis, Kai; Platzek, Johannes; Steinfeldt, Norbert; Huebner, SandraOrganic Process Research & Development (2016), 20 (2), 452-464CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The selective hydrogenation of functionalized nitroaroms. poses a major challenge from both academic as well as industrial viewpoints. As part of the CHEM21 initiative (www.chem21.eu), we are interested in highly selective, catalytic hydrogenations of halogenated nitroaroms. Initially, the catalytic redn. of 1-iodo-4-nitrobenzene to 4-iodoaniline served as a model system to investigate com. heterogeneous catalysts. After detg. optimal hydrogenation conditions and profiling performances of the best catalysts, hydrogenations were transferred from batch to continuous flow. Finally, the optimized flow conditions were applied to transformations which represent important steps in the syntheses of the active pharmaceutical ingredients clofazimine and vismodegib.
- 31(a) Nishimura, S.. Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis; Wiley: New York, 2001.Google ScholarThere is no corresponding record for this reference.
- 32Orlandi, M.; Brenna, D.; Harms, R.; Jost, S.; Benaglia, M. Recent Developments in the Reduction of Aromatic and Aliphatic Nitro Compounds to Amines. Org. Process Res. Dev. 2018, 22, 430– 445, DOI: 10.1021/acs.oprd.6b00205Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1SktLjI&md5=d3d977219544e37be5dd25aa35385b06Recent Developments in the Reduction of Aromatic and Aliphatic Nitro Compounds to AminesOrlandi, Manuel; Brenna, Davide; Harms, Reentje; Jost, Sonja; Benaglia, MaurizioOrganic Process Research & Development (2018), 22 (4), 430-445CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A review. The redn. of the nitro group represents a powerful and widely used transformation that allows to introducing an amino group in the mol. New synthetic strategies for complex functionalized mol. architectures are deeply needed, including highly efficient and selective nitro redn. methods, tolerant of a diverse array of functional moieties and protecting groups. Since chiral amino groups are ubiquitous in a variety of bioactive mols. such as alkaloids, natural products, drugs and medical agents, the development of reliable catalytic methodologies for the nitro group redn. is attracting an increasing interest also in the prepn. of enantiomerically pure amines. In this context, the modern redn. methods should be chemoselective and respectful of the stereochem. integrity of the stereogenic elements of the mol. The review will offer an overview of the different possible methodologies available for this fundamental transformation, with a special attention on the most recent contributions in the field: hydrogenations, metal dissolving and hydride transfer redns., catalytic transfer hydrogenations and metal-free redns. The main advantages or limitations for the proposed methods will be briefly discussed, highlighting in some cases the most important features of the presented redn. methodologies from an industrial point of view.
- 33Blaser, H.-U.; Steiner, H.; Studer, M. Selective Catalytic Hydrogenation of Functionalized Nitroarenes: An Update. ChemCatChem 2009, 1, 210– 221, DOI: 10.1002/cctc.200900129Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1amt7nM&md5=1044185cf70d0c5bd48031a26a62c437Selective Catalytic Hydrogenation of Functionalized Nitroarenes: An UpdateBlaser, Hans-Ulrich; Steiner, Heinz; Studer, MartinChemCatChem (2009), 1 (2), 210-221CODEN: CHEMK3; ISSN:1867-3880. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Progress made in the last decade for the selective catalytic hydrogenation of nitroarenes in the presence of other reducible functions is reviewed. The main focus is on catalytic systems capable of reducing nitro groups with very high chemoselectivity in substrates contg. carbon-carbon or carbon-nitrogen double or triple bonds, carbonyl or benzyl groups, and multiple Cl, Br, or I substituents. The performance of new catalyst types is described, most notably of gold-based catalysts, but also of modified classical Pt, Pd, and Ni catalysts, as well as homogeneous catalysts. The best results for the various chemoselectivity problems are compiled and assessed with regard to their versatility and synthetic viability. In addn., progress in understanding mechanistic aspects are briefly described.
- 34Kasparian, A. J.; Savarin, C.; Allgeier, A. M.; Walker, S. D. Selective Catalytic Hydrogenation of Nitro Groups in the Presence of Activated Heteroaryl Halides. J. Org. Chem. 2011, 76, 9841– 9844, DOI: 10.1021/jo2015664Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht12jsb7J&md5=71ffb05ba937463faa12e5fb39efcc19Selective catalytic hydrogenation of nitro groups in the presence of activated heteroaryl halidesKasparian, Annie J.; Savarin, Cecile; Allgeier, Alan M.; Walker, Shawn D.Journal of Organic Chemistry (2011), 76 (23), 9841-9844CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Chemoselective redn. of nitro groups in the presence of activated heteroaryl halides was achieved via catalytic hydrogenation with a com. available sulfided platinum catalyst. The optimized conditions employ low temp., pressure, and catalyst loading (<0.1 mol % Pt) to afford heteroarom. amines with minimal hydrodehalogenation byproducts.
- 35(a) Haber, F. Gradual electrolytic reduction of nitrobenzene with limited cathode potential. Z. Elektrochem. Angew. Phys. Chem. 1898, 4, 506, DOI: 10.1002/bbpc.18980042204Google Scholar35ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaD28XltFWmsQ%253D%253D&md5=d7e497a060e89cd7dc71c2b7ee57d6d2On successive reductions of nitrobenzene under definite potential differencesHaber, F.Zeitschrift fuer Elektrochemie und Angewandte Physikalische Chemie (1898), 4 (), 506CODEN: ZEAPAA ISSN:.The author considers that oxidation and reduction processes depend chiefly on the potential difference between the solution and the electrode at which the reaction takes place. A platinum electrode in a solution consisting of 25 g nitrobenzene, 40 g sodium hydroxid, 50 g water and 350 g alcohol gave a value of 0.72 volt against a decinormal calomel electrode. If polarized until bubbles of hydrogen appeared the value rose to 1.29 volts. In the first experiment the current density was regulated so that the potential difference between the platinum electrode and the decinormal calomel electrode never exceeded 0.93 volt. The reaction products consisted almost exclusively of azoxybenzene, only traces of azobenzene, hydrazobenzene and anilin being present. Special experiments showed that the anilin was not formed by reduction of the hydrazobenzene. It appears that the primary reduction product is nitrosobenzene, C6H5NO, then β-phenylhydroxylamin. For the most part these two react, as observed by Bamberger, forming azoxybenzene; a small portion of the β-phenylhydroxylamin is however reduced to anilin. The hydrazobenzene comes from the partial reduction of the azoxybenzene, while the cause for the appearance of the azobenzene has not been worked out. In acid solutions the main products are azoxybenzene, p-amidophenol, p-phenetidin, benzidin and anilin. The first two stages are the same as in the alkaline reduction, nitrosobenzene and then phenylhydroxylamin. The two substances do not react rapidly in acid solution and therefore there is not so much azoxybenzene formed as in alkaline solutions. On the other hand in acid solutions β-phenylhydroxylamin changes readily to p-amidophenol and to p-phenetidin, while the hydrazobenzene formed from the azoxybenzene changes to benzidin. To show the formation of β-phenylhydroxylamin the author reduced nitrobenzene in aqueous acetic acid, with a high current density.(b) Corma, A.; Concepcion, P.; Serna, P. A Different Reaction Pathway for the Reduction of Aromatic Nitro Compounds on Gold Catalysts. Angew. Chem., Int. Ed. 2007, 46, 7266– 7269, DOI: 10.1002/anie.200700823Google Scholar35bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFCqtr3M&md5=f8ca1d821c8f4f581d9c2cc9954db44eA different reaction pathway for the reduction of aromatic nitro compounds on gold catalystsCorma, Avelino; Concepcion, Patricia; Serna, PedroAngewandte Chemie, International Edition (2007), 46 (38), 7266-7269CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)With an Au/TiO2 catalyst, the formation of condensation products during the hydrogenation of arom. nitro compds. is avoided. Macrokinetic expts. and in situ IR measurements, which showed that nitrosobenzene is generated in only small amts. and that hydroxylamine and nitrosobenzene interact strongly with the catalyst surface, led to the proposal of a novel reaction sequence.
- 36May, P. C.; Willis, B. A.; Lowe, S. L.; Dean, R. A.; Monk, S. A.; Cocke, P. J.; Audia, J. E.; Boggs, L. N.; Borders, A. R.; Brier, R. A.; Calligaro, D. O.; Day, T. A.; Ereshefsky, L.; Erickson, J. A.; Gevorkyan, H.; Gonzales, C. R.; James, D. E.; Jhee, S.; Komjathy, S. F.; Li, L.; Lindstrom, T. D.; Mathes, B. M.; Martényi, F.; Sheehan, S. M.; Stout, S. L.; Timm, D. E.; Vaught, G. M.; Watson, B. M.; Winneroski, L. L.; Yang, Z.; Mergott, D. J. The Potent BACE1 Inhibitor LY2886721 Elicits Robust Central Aβ Pharmacodynamic Responses in Mice, Dogs, and Humans. J. Neurosci. 2015, 35, 1199– 1210, DOI: 10.1523/JNEUROSCI.4129-14.2015Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXit1Oit78%253D&md5=7e16cc00767a8af4da7dd17b6e40e8f5The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humansMay, Patrick C.; Willis, Brian A.; Lowe, Stephen L.; Dean, Robert A.; Monk, Scott A.; Cocke, Patrick J.; Audia, James E.; Boggs, Leonard N.; Borders, Anthony R.; Brier, Richard A.; Calligaro, David O.; Day, Theresa A.; Ereshefsky, Larry; Erickso, Jon A.; Gevorkyan, Hykop; Gonzales, Celedon R.; James, Douglas E.; Jhee, Stanford S.; Komjathy, Steven F.; Li, Linglin; Lindstrom, Terry D.; Mathe, Brian M.; Martenyi, Ferenc; Sheehan, Scott M.; Stout, Stephanie L.; Timm, David E.; Vaught, Grant M.; Watson, Brian M.; Winneroski, Leonard L.; Yang, Zhixiang; Mergott, Dustin J.Journal of Neuroscience (2015), 35 (3), 1199-1210, 12 pp.CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclin. and early clin. development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clin. trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid β lowering in nonclin. animal models. Similar potent and persistent amyloid β lowering was obsd. in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.
- 37Mergott, D. J.; Green, S. J.; Shi, Y.; Watson, B. M.; Leonard, L. L.; Hembre, E. J. US Patent 20140371212, 2014.Google ScholarThere is no corresponding record for this reference.
- 38(a) Kolis, S. P.; Hansen, M. M.; Arslantas, E.; Brändli, L.; Buser, J.; DeBaillie, A. C.; Frederick, A. L.; Hoard, D. W.; Hollister, A.; Huber, D.; Kull, T.; Linder, R. J.; Martin, T. J.; Richey, R. N.; Stutz, A.; Waibel, M.; Ward, J. A.; Zamfir, A. Synthesis of BACE Inhibitor LY2886721. Part I. An Asymmetric Nitrone Cycloaddition Strategy. Org. Process Res. Dev. 2015, 19, 1203– 1213, DOI: 10.1021/op500351qGoogle Scholar38ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVKit7nI&md5=6b3d37701117c1b5b5efe381d6d27939Synthesis of BACE Inhibitor LY2886721. Part I. An Asymmetric Nitrone Cycloaddition StrategyKolis, Stanley P.; Hansen, Marvin M.; Arslantas, Enver; Brandli, Lukas; Buser, Jonas; DeBaillie, Amy C.; Frederick, Andrea L.; Hoard, David W.; Hollister, Adrienne; Huber, Dominique; Kull, Thomas; Linder, Ryan J.; Martin, Thomas J.; Richey, Rachel N.; Stutz, Alfred; Waibel, Michael; Ward, Jeffrey A.; Zamfir, AlexandruOrganic Process Research & Development (2015), 19 (9), 1203-1213CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A scalable, asym. synthesis of (3aS,6aS)-6a-(5-bromo-2-fluorophenyl)-1-((R)-1-phenylpropyl)tetrahydro-1H,3H-furo[3,4-c]isoxazole, I, a key intermediate in the synthesis of LY2886721, is reported. Highlights of the synthesis include the development of an asym. [3 + 2] intramol. cycloaddn. facilitated by trifluoroethanol, and the development of a new synthesis of (R)-N-(1-phenylpropyl)hydroxylamine tosylate which proceeds through a p-anisaldehyde imine and avoids the formation of toxic hydrogen cyanide gas as a byproduct. The synthesis proceeds over four steps and provides the product in 36% overall yield.(b) Zaborenko, N.; Linder, R. J.; Braden, T. M.; Campbell, B. M.; Hansen, M. M.; Johnson, M. D. Org. Process Res. Dev. 2015, 19, 1231– 1243, DOI: 10.1021/op5003177Google Scholar38bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlOjurvL&md5=0d0aab2b52ed037f943326ecd46c835cDevelopment of Pilot-Scale Continuous Production of an LY2886721 Starting Material by Packed-Bed HydrogenolysisZaborenko, Nikolay; Linder, Ryan J.; Braden, Timothy M.; Campbell, Bradley M.; Hansen, Marvin M.; Johnson, Martin D.Organic Process Research & Development (2015), 19 (9), 1231-1243CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The design, development, and implementation of a pilot-scale continuous hydrogenolysis in a catalytic packed bed to generate a starting material is described. Control of a crit. defluorination impurity under the reaction conditions was achieved by reducing residence time inside the catalyst bed to 15-30 min. A reactor vol. throughput of 206 kg/h·m3 was attained in a 3 L reactor (1.5 kg of 5% Pd/C catalyst) over a 9 h demonstration period, superior to the 1.3 kg/h·m3 vol. throughput obtained in batch. The reaction was successfully scaled up from 9 g/h to 550 g/h in packed beds ranging from 20 to 1500 g catalyst, demonstrating heat/mass transfer sufficiency at all examd. scales. The process was monitored by online HPLC, providing real-time reaction information, using an internally developed automation cart coupled to a std. HPLC. Significant tech. and business drivers for running the process in continuous flow mode were proposed and examd. during development, demonstrating superior control of crit. impurities and catalyst utilization with minimized risk to product and increased safety due to reduced handling of hydrogen and of palladium catalyst relative to equiv. substrate throughputs in a typical batch process.
- 39Marigo, M.; Fielenbach, D.; Braunton, A.; Kjaersgaard, A.; Jørgensen, K. A. Enantioselective Formation of Stereogenic Carbon–Fluorine Centers by a Simple Catalytic Method. Angew. Chem., Int. Ed. 2005, 44, 3703– 3706, DOI: 10.1002/anie.200500395Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlslelsLg%253D&md5=059636ce65a1a33ae0c7cde25f0e342eEnantioselective formation of stereogenic carbon-fluorine centers by a simple catalytic methodMarigo, Mauro; Fielenbach, Doris; Braunton, Alan; Kjoersgaard, Anne; Jorgensen, Karl AnkerAngewandte Chemie, International Edition (2005), 44 (24), 3703-3706CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)An easy protocol has been developed for the formation of stereogenic carbon-fluorine centers by the organocatalytic asym. α-fluorination of aldehydes RCH2CHO (R = Bn, Pr, Bu, hexyl, cyclohexyl, etc.). The 2-fluoroaldehydes are formed with (PhSO2)2NF as the fluorinating agent and only 1 mol% of a sterically demanding silylated prolinol I as catalyst. The 2-fluoroaldehydes are subsequently reduced to the corresponding alcs. without loss of enantiomeric excess.
- 40(a) Beeson, T. D.; MacMillan, D. W. C. Enantioselective Organocatalytic α-Fluorination of Aldehydes. J. Am. Chem. Soc. 2005, 127, 8826– 8828, DOI: 10.1021/ja051805fGoogle Scholar40ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXkt1WrtbY%253D&md5=a1bc3958c426a2cd1dbeecad6fec2e40Enantioselective Organocatalytic α-Fluorination of AldehydesBeeson, Teresa D.; MacMillan, David W. C.Journal of the American Chemical Society (2005), 127 (24), 8826-8828CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The direct enantioselective catalytic α-fluorination of aldehydes has been accomplished. The use of enamine catalysis has provided a new organocatalytic strategy for the enantioselective fluorination of aldehydes to generate α-fluoro aldehydes, an important chiral synthon for medicinal agent synthesis. The use of imidazolidinone I as the asym. catalyst mediates the fluorination of a large variety of aldehyde substrates with N-fluorobenzenesulfonimide as the electrophilic source of fluorine. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. While catalyst quantities of 20 mol % were generally employed in this study, successful halogenation can be accomplished using catalyst loadings as low as 2.5 mol %.(b) Pihko, P. M. Angew. Chem., Int. Ed. 2006, 45, 544– 547, DOI: 10.1002/anie.200502425Google Scholar40bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XpvVeqsw%253D%253D&md5=32a3db2aa28166dfb77df0ec37d79d90Enantioselective α-fluorination of carbonyl compounds: organocatalysis or metal catalysis?Pihko, Petri M.Angewandte Chemie, International Edition (2006), 45 (4), 544-547CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Five ground-breaking studies in stereoselective α-fluorination of carbonyl compds. have been disclosed. Four describe the use of amine organo-catalysts to promote the asym. fluorination of aldehydes, whereas the fifth describes a highly enantioselective fluorination of carbonyl compds. capable of two-point binding (e.g. β-keto esters). A review.(c) Fjelbye, K.; Marigo, M.; Clausen, R. P.; Juhl, K. Diastereodivergent Access to Syn and Anti 3,4-Substituted β-Fluoropyrrolidines: Enhancing or Reversing Substrate Preference. Org. Lett. 2016, 18, 1170– 1173, DOI: 10.1021/acs.orglett.6b00293Google Scholar40chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivVOhs78%253D&md5=a4678d6d17e895bcdc424d1eed49d6b1Diastereodivergent Access to Syn and Anti 3,4-Substituted β-Fluoropyrrolidines: Enhancing or Reversing Substrate PreferenceFjelbye, Kasper; Marigo, Mauro; Clausen, Rasmus Praetorius; Juhl, KarstenOrganic Letters (2016), 18 (5), 1170-1173CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A practical diastereodivergent access to β-fluoropyrrolidines with two adjacent stereocenters has been demonstrated, by either enhancing or completely reversing the substrate control, in the diastereoselective fluorination of a series of diverse pyrrolidinyl carbaldehydes using organocatalysis. Furthermore, enamine catalysis has been successfully utilized for kinetic resoln., obtaining a fluorinated β-prolinol analog with two adjacent tetrasubstituted chiral centers in 95% ee from a racemic substrate.
- 41(a) Parikh, J. R.; Doering, W. v. E. Sulfur trioxide in the oxidation of alcohols by dimethyl sulfoxide. J. Am. Chem. Soc. 1967, 89, 5505– 5507, DOI: 10.1021/ja00997a067Google Scholar41ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1cXjtV2q&md5=fa83f740ef49cb695547ae90c1ae291aSulfur trioxide in the oxidation of alcohols by dimethyl sulfoxideParikh, Jekishan R.; Doering, William v. E.Journal of the American Chemical Society (1967), 89 (21), 5505-7CODEN: JACSAT; ISSN:0002-7863.A soln. of pyridine-SO3 complex in Me2SO is used to oxidize p-nitrobenzyl alc., l-menthol, and many steroidal alcs. to the corresponding aldehydes and ketones.(b) Chen, L.; Lee, S.; Renner, M.; Tian, Q.; Nayyar, N. A Simple Modification to Prevent Side Reactions in Swern-Type Oxidations Using Py·SO3. Org. Process Res. Dev. 2006, 10, 163– 164, DOI: 10.1021/op0502203Google Scholar41bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtlWmu7zO&md5=c8c36f24f15ea0d613b120284d5b5b3dA Simple Modification to Prevent Side Reactions in Swern-Type Oxidations Using Py·SO3Chen, Lijian; Lee, Steven; Renner, Matt; Tian, Qingping; Nayyar, NareshOrganic Process Research & Development (2006), 10 (1), 163-164CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Addnl. pyridine was used to convert pyridine sulfuric acid 1:1 salt in com. pyridine sulfur trioxide to the inactive 2:1 salt and prevent side reactions in the Swern oxidn. The starting material, [(1S)-1-(hydroxymethyl)-2-[(3S)-2-oxo-3-pyrrolidinyl]ethyl]carbamic acid tert-Bu ester, was dissolved in DMSO and methylene chloride. Pyridine sulfur trioxide complex, pyridine and DMSO were added to [(1S)-1-(hydroxymethyl)-2-[(3S)-2-oxo-3-pyrrolidinyl]ethyl]carbamic acid ester to give a preformed mixt. contg. [1-formyl-2-(2-oxo-3-pyrrolidinyl)ethyl]-, carbamic acid tert-Bu ester (in situ Swern oxidn.). A Wittig reagent was added to the aldehyde deriv. to give (4S)-4-[[(1,1-dimethylethoxy)carbonyl]amino]-5-[(3S)-2-oxo-3-pyrrolidinyl]-2-pentenoic acid Et ester.(c) Omura, K.; Swern, D. Oxidation of Alcohols by “Activated” Dimethyl Sulfoxide. A Preparative, Steric and Mechanistic Study. Tetrahedron 1978, 34, 1651– 1660, DOI: 10.1016/0040-4020(78)80197-5Google Scholar41chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXos1Cjtg%253D%253D&md5=b242305766e00a62b9220db412ca84ceOxidation of alcohols by "activated" dimethyl sulfoxide. A preparative steric and mechanistic studyOmura, Kanji; Swern, DanielTetrahedron (1978), 34 (11), 1651-60CODEN: TETRAB; ISSN:0040-4020.The oxidn. of allylic and arom. alcs., cycloalkanols and alkanols with Me2SO activated by electrophiles to give carbonyl compds., was studied. Paths for carbonyl and by-product formation are presented. In general, yields of carbonyl compds. increased with increased steric hindrance in the alcs. Steric effects of tertiary amines on the oxidns. were also studied. With (COCl)2 as activator, yields of carbonyl compds. were generally >95%. E.g., oxidn. of PhCH:CHCH2OH with Me2SO/(COCl)2 gave 100% PhCH:CHCHO. High yields were also obtained using SOCl2 as activator. ROCH2SMe [R = Me(CH2)9, Me(CH2)5CHMe, cyclohexyl, Ph(CH2)2, trans-PrCH:CHCH2] were prepd. (60-70%) by treatment of ROH with Me2SO/NEt3 contg. BF3.Et2O.(d) Liu, C.; Ng, J. S.; Behling, J. R.; Yen, C. H.; Campbell, A. L.; Fuzail, K. S.; Yonan, E. E.; Mehrotra, D. V. Development of a Large-Scale Process for an HIV Protease Inhibitor. Org. Process Res. Dev. 1997, 1, 45– 54, DOI: 10.1021/op960040gGoogle Scholar41dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXps1yisA%253D%253D&md5=3bb77c2dd63da4c87f518a0175560735Development of a Large-Scale Process for an HIV Protease InhibitorLiu, Chin; Ng, John S.; Behling, James R.; Yen, Chung H.; Campbell, Arthur L.; Fuzail, Kalim S.; Yonan, Edward E.; Mehrotra, Devan V.Organic Process Research & Development (1997), 1 (1), 45-54CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)An efficient large-scale process to prep. the HIV protease inhibitor urea intermediate, N-[3(S)-[bis(phenylmethyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N '-(1,1-dimethylethyl)-N-(2-methylpropyl)urea (I) was developed. The protected alc., β(S)-[bis(phenylmethyl)amino]benzenepropanol, was in 95% yield in one step by the benzylation of L-phenylalaninol with benzyl bromide under aq. conditions. Oxidn. of protected alc. with sulfur trioxide pyridine complex in DMSO at 15 °C gave the corresponding aldehyde in quant. yield. The di-Me sulfide byproduct was easily removed by nitrogen sparging and treatment of the effluent gas stream with bleach soln. Diastereoselective reaction of the chiral amino aldehyde with (chloromethyl)lithium at -35 °C followed by warming to room temp. gave the desired epoxide stereoselectively in good yield. A DOE (statistical design of expt.) study indicated that the reaction concn. and halogen reagent were important factors for this reaction. To simplify the operations and to increase the productivity of epoxide, a continuous process was developed. Regioselective ring opening of epoxides with isobutylamine followed by reaction of the resulting amine with tert-Bu isocyanate in iso-Pr alc. gave I in good yield. The process improvements for the crystn. of urea are also discussed.(e) Caron, S.; Dugger, R. W.; Ruggeri, S. G.; Ragan, J. A.; Brown Ripin, D. H. Large-Scale Oxidations in the Pharmaceutical Industry. Chem. Rev. 2006, 106, 2943– 2989, DOI: 10.1021/cr040679fGoogle Scholar41ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xmt12lsL4%253D&md5=2cbcc9b4256afdc6060e5471ffc28505Large-Scale Oxidations in the Pharmaceutical IndustryCaron, Stephane; Dugger, Robert W.; Ruggeri, Sally Gut; Ragan, John A.; Ripin, David H. BrownChemical Reviews (Washington, DC, United States) (2006), 106 (7), 2943-2989CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review covering oxidn. reactions in pharmaceutical manufg. run in 1980 or later, on a scale of around 100 g or larger or clearly developed by a process chem. group to be run on a large scale.(f) Urban, F. J.; Breitenbach, R.; Murtiashaw, C. W.; Vanderplas, B. C. Synthesis of an Optically Active Octahydro-2H-pyrido[1,2-a]pyrazine Based CNS Agent. Tetrahedron: Asymmetry 1995, 6, 321– 324, DOI: 10.1016/0957-4166(95)00003-8Google Scholar41fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXkt1OktLw%253D&md5=172837ea2f7a7ff7688a9e4e5278793aSynthesis of an optically active octahydro-2H-pyrido[1,2-a]pyrazine based CNS agentUrban, Frank J.; Breitenbach, Ralph; Murtiashaw, Charles W.; Vanderplas, Brian C.Tetrahedron: Asymmetry (1995), 6 (2), 321-4CODEN: TASYE3; ISSN:0957-4166. (Elsevier)A synthesis of an optically active octahydro-2H-pyrido[1,2-a]pyrazine (I) is presented. The key sequence involved the equilibration of an optically active cis-aldehyde to give the thermodn. trans-aldehyde that was trapped by nitromethane anion.(g) Waizumi, N.; Itoh, T.; Fukuyama, T. Total Synthesis of (−)-CP-263,114 (Phomoidride B). J. Am. Chem. Soc. 2000, 122, 7825– 7826, DOI: 10.1021/ja001664bGoogle Scholar41ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXltF2is70%253D&md5=767ba8156ece2713efeed0f8239ce76cTotal Synthesis of (-)-CP-263,114 (Phomoidride B)Waizumi, Nobuaki; Itoh, Tetsuji; Fukuyama, TohruJournal of the American Chemical Society (2000), 122 (32), 7825-7826CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Total synthesis of (-)-CP 263,114 I [R = (E)-MeCH:CH(CH2)2, R1 = (E)-MeCH:CH(CH2)5], a.k.a. phomoidride B, was accomplished via intramol. Diels Alder cycloaddn. of diester II.(h) Toyota, M.; Odashima, T.; Wada, T.; Ihara, M. Application of Palladium-Catalyzed Cycloalkenylation Reaction to C20 Gibberellin Synthesis: Formal Syntheses of GA12, GA111, and GA112. J. Am. Chem. Soc. 2000, 122, 9036– 9037, DOI: 10.1021/ja0017413Google Scholar41hhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmtVaisLk%253D&md5=482c6b674fbbda52e76cc680575b095dApplication of Palladium-Catalyzed Cycloalkenylation Reaction to C20 Gibberellin Synthesis: Formal Syntheses of GA12, GA111, and GA112Toyota, Masahiro; Odashima, Tomoyuki; Wada, Toshihiro; Ihara, MasatakaJournal of the American Chemical Society (2000), 122 (37), 9036-9037CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Stereoselective formal syntheses of GA12, GA111, and GA112 were achieved from a common intermediate by a combination of palladium-catalyzed cycloalkenylation reaction and reverse electron demand intramol. Diels-Alder reaction. All stereoisomers produced were used and most of the reaction yields were good.(i) Smith, A. B.; Lee, D.; Adams, C. M.; Kozlowski, M. C. SmI2-Promoted Oxidation of Aldehydes in the Presence of Electron-Rich Heteroatoms. Org. Lett. 2002, 4, 4539– 4541, DOI: 10.1021/ol027095pGoogle Scholar41ihttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XosFGjt7c%253D&md5=6623a5bb05eaad5b7ad54a28173b8a51SmI2-Promoted Oxidation of Aldehydes in the Presence of Electron-Rich HeteroatomsSmith, Amos B.; Lee, Dongjoo; Adams, Christopher M.; Kozlowski, Marisa C.Organic Letters (2002), 4 (25), 4539-4541CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)Carboxylic acids contg. a variety of sensitive heteroat. moieties such as 1,3-dithiane, phenylselenide, phosphine, morpholine, and stannane are prepd. using the Evans-Tischenko oxidn. of the corresponding aldehydes with sacrificial β-hydroxy ketones mediated by samarium diiodide. Stirring aldehydes with β-hydroxy ketones Me2CHCOCH2CH(OH)CHR (R = Me, Et, Me2CH, Ph, H2C:CH, Et, 4-MeOC6H4) and samarium diiodide in the dark at approx. -10° in THF provides 1,3-diol monoesters such as I in 70-89% yields. The desired carboxylic acids such as II can be obtained by hydrolysis of the ester with lithium hydroxide in methanol or by oxidn. of the 1,3-diol monoester with pyridine-sulfur trioxide complex and triethylamine in DMSO followed by elimination of the carboxylate with DBU. 1,3-Diol monoesters substituted with vinyl groups can also be deprotected by tetrakis(triphenylphosphine)palladium-catalyzed allylic isomerization; the 1,3-diol monoesters substituted with the p-methoxyphenyl group can be deprotected with DDQ in aq. DMSO, while those substituted with the Ph group can be deprotected with 1,3-propanedithiol and boron trifluoride etherate. Careful selection of the sacrificial β-hydroxy ketone thus provides considerable subsequent flexibility to access the desired carboxylic acid.(j) Bio, M. M.; Leighton, J. L. An Approach to the Synthesis of the Phomoidrides. J. Org. Chem. 2003, 68, 1693– 1700, DOI: 10.1021/jo026478yGoogle Scholar41jhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXotlai&md5=ae037edcb4a920b39217adac576964d2An Approach to the Synthesis of the PhomoidridesBio, Matthew M.; Leighton, James L.Journal of Organic Chemistry (2003), 68 (5), 1693-1700CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)The phomoidrides are a structurally fascinating family of natural products which possess moderate inhibitory activity against Ras farnesyl transferase and squalene synthase (no data). Since their discovery they have inspired a great deal of attention from synthetic chemists. Our own work, culminating in an efficient synthesis of the fully elaborated tetracyclic core of phomoidrides B and D, is described herein. The synthesis relies on a late stage tandem reaction involving a novel carbonylation reaction that delivers the strained bicyclic pseudoester system, which strain in turn drives a highly efficient silyloxy-Cope rearrangement that delivers the tetracyclic core of phomoidrides B and D. Several examples of this powerful tandem reaction are presented that document its tolerance of significant structural variation. The application of this methodol. to the synthesis of a phomoidride D precursor I, lacking only the maleic anhydride, is described, and the prospects for the completion of a total synthesis are discussed.
- 42Garcia-Losada, P.; Barberis, M.; Shi, Y.; Hembre, E.; Alhambra Jimenez, C.; Winneroski, L. L.; Watson, B. M.; Jones, C.; DeBaillie, A. C.; Martínez-Olid, F.; Mergott, D. J. Practical Asymmetric Fluorination Approach to the Scalable Synthesis of New Fluoroaminothiazine BACE Inhibitors. Org. Process Res. Dev. 2018, 22, 650– 654, DOI: 10.1021/acs.oprd.8b00069Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXot1eqtLk%253D&md5=1a89ba756547f0a6d97edba47dc9a8b0Practical Asymmetric Fluorination Approach to the Scalable Synthesis of New Fluoroaminothiazine BACE InhibitorsGarcia-Losada, Pablo; Barberis, Mario; Shi, Yuan; Hembre, Erik; Alhambra Jimenez, Carolina; Winneroski, Leonard L.; Watson, Brian M.; Jones, Chauncey; De Baillie, Amy C.; Martinez-Olid, Francisco; Mergott, Dustin J.Organic Process Research & Development (2018), 22 (5), 650-654CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Here authors report an optimized protocol for the asym. introduction of a fluorine atom into a quaternary center facilitated by D-proline, Selectfluor, and trifluoroethanol. The synthesis proceeds over four steps starting from a chiral amino alc. precursor and provides the desired enantiomer with no erosion of chiral purity and good diastereoselectivity. The process optimization allowed diastereoselective prepn. of the key intermediate on a multigram scale.
- 43Technically pure trifluoroethanol purchased from Solvay Fluor GMBH or purified following the procedure reported in EP patent EP1427524 B1, by Böse, O.; Peterkord, K.Google ScholarThere is no corresponding record for this reference.
- 44(a) Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis. Chem. Rev. 2016, 116, 10075– 10166, DOI: 10.1021/acs.chemrev.6b00057Google Scholar44ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpsVSnsrw%253D&md5=82228f21987c3d000c62cf672cdcea82Organic Photoredox CatalysisRomero, Nathan A.; Nicewicz, David A.Chemical Reviews (Washington, DC, United States) (2016), 116 (17), 10075-10166CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Use of org. photoredox catalysts in a myriad of synthetic transformations with a range of applications was reviewed. This overview was arranged by catalyst class where the photophysics and electrochem. characteristics of each was discussed to underscore the differences and advantages to each type of single electron redox agent. Net reductive and oxidative as well as redox neutral transformations that could be accomplished using purely org. photoredox-active catalysts was highlighted. An overview of the basic photophysics and electron transfer theory was presented in order to provide a comprehensive guide for employing this class of catalysts in photoredox manifolds.(b) Gentry, E. C.; Knowles, R. R. Synthetic Applications of Proton-Coupled Electron Transfer. Acc. Chem. Res. 2016, 49, 1546– 1556, DOI: 10.1021/acs.accounts.6b00272Google Scholar44bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1Crur7E&md5=4607445b7504808ee630a35f397f10cdSynthetic Applications of Proton-Coupled Electron TransferGentry, Emily C.; Knowles, Robert R.Accounts of Chemical Research (2016), 49 (8), 1546-1556CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. Redox events in which an electron and proton are exchanged in a concerted elementary step are commonly referred to as proton-coupled electron transfers (PCETs). PCETs are known to operate in numerous important biol. redox processes, as well as recent inorg. technologies for small mol. activation. These studies suggest that PCET catalysis might also function as a general mode of substrate activation in org. synthesis. Over the past three years, our group has worked to advance this hypothesis and to demonstrate the synthetic utility of PCET through the development of novel catalytic radical chemistries. The central aim of these efforts has been to demonstrate the ability of PCET to homolytically activate a wide variety of common org. functional groups that are energetically inaccessible using known mol. H atom transfer catalysts. To do so, we made use of a simple formalism first introduced by Mayer and co-workers that allowed us to predict the thermodn. capacity of any oxidant/base or reductant/acid pair to formally add or remove H· from a given substrate. With this insight, we were able to rationally select catalyst combinations thermodynamically competent to homolyze the extraordinarily strong E-H σ-bonds found in many common protic functional groups (BDFEs > 100 kcal/mol) or to form unusually weak bonds to hydrogen via the reductive action of common org. π-systems (BDFEs < 35 kcal/mol). These ideas were reduced to practice through the development of new catalyst systems for reductive PCET activations of ketones and oxidative PCET activation of amide N-H bonds to directly furnish reactive ketyl and amidyl radicals, resp. In both systems, the reaction outcomes were found to be successfully predicted using the effective bond strength formalism, suggesting that these simple thermochem. considerations can provide useful and actionable insights into PCET reaction design. The ability of PCET catalysis to control enantioselectivity in free radical processes has also been established. Specifically, multisite PCET requires the formation of a pre-equil. hydrogen bond between the substrate and a proton donor/acceptor prior to charge transfer. We recognized that these H-bond interfaces persist following the PCET event, resulting in the formation of noncovalent complexes of the nascent radical intermediates. When chiral proton donors/acceptors are employed, this assocn. can provide a basis for asym. induction in subsequent bond-forming steps. We discuss our efforts to capitalize on this understanding via the development of a catalytic protocol for enantioselective aza-pinacol cyclizations. Lastly, we highlight an alternative PCET mechanism that exploits the ability of redox-active metals to homolytically weaken the bonds in coordinated ligands, enabling nominally strong bonds (BDFEs ∼ 100 kcal) to be abstracted by weak H atom acceptors with concomitant oxidn. of the metal center. This "soft homolysis" mechanism enables the generation of metalated intermediates from protic substrates under completely neutral conditions. The first example of this form of catalysis is presented in the context of a catalytic C-N bond forming reaction jointly mediated by bulky titanocene complexes and the stable nitroxyl radical TEMPO.(c) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis. Chem. Rev. 2013, 113, 5322– 5363, DOI: 10.1021/cr300503rGoogle Scholar44chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktFKgtLc%253D&md5=e09e6cf6a4c64fd3e8f21d55e151266eVisible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic SynthesisPrier, Christopher K.; Rankic, Danica A.; MacMillan, David W. C.Chemical Reviews (Washington, DC, United States) (2013), 113 (7), 5322-5363CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. This review will highlight the early work on the use of transition metal complexes as photoredox catalysts to promote reactions of org. compds. (prior to 2008), as well as cover the surge of work that has appeared since 2008. We have for the most part grouped reactions according to whether the org. substrate undergoes redn., oxidn., or a redox neutral reaction and throughout have sought to highlight the variety of reactive intermediates that may be accessed via this general reaction manifold.(d) Tucker, J. W.; Stephenson, C. R. J. Shining Light on Photoredox Catalysis: Theory and Synthetic Applications. J. Org. Chem. 2012, 77, 1617– 1622, DOI: 10.1021/jo202538xGoogle Scholar44dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpsVygsA%253D%253D&md5=103844fa19d8d4485d11de658b309027Shining Light on Photoredox Catalysis: Theory and Synthetic ApplicationsTucker, Joseph W.; Stephenson, Corey R. J.Journal of Organic Chemistry (2012), 77 (4), 1617-1622CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)A review. Photoredox catalysis is emerging as a powerful tool in synthetic org. chem. The aim of this synopsis is to provide an overview of the photoelectronic properties of photoredox catalysts as they are applied to org. transformations. In addn., recent synthetic applications of photoredox catalysis are presented.
- 45Douglas, J. J.; Sevrin, M. J.; Stephenson, C. R. J. Visible Light Photocatalysis: Applications and New Disconnections in the Synthesis of Pharmaceutical Agents. Org. Process Res. Dev. 2016, 20, 1134– 1147, DOI: 10.1021/acs.oprd.6b00125Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XptVSht7k%253D&md5=02be4e42349d1175ff3f2b18612a3337Visible Light Photocatalysis: Applications and New Disconnections in the Synthesis of Pharmaceutical AgentsDouglas, James J.; Sevrin, Martin J.; Stephenson, Corey R. J.Organic Process Research & Development (2016), 20 (7), 1134-1147CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Photoredox catalysis has emerged as a powerful tool for the synthetic chemist to access challenging targets and to generate new structural complexity. This review focuses on the application of this mode of catalysis to arrive at known pharmaceutically active compds. Within this setting, the growing synergy with other modes of catalysis, such as nickel/photoredox dual catalysis, as well as pioneering examples utilizing continuous flow to transition photoredox catalysis to preparative scale will be highlighted.
- 46(a) Twilton, J.; Le, C. C.; Zhang, P.; Shaw, M. H.; Evans, R. W.; MacMillan, D. W. C. The Merger of Transition Metal and Photocatalysis. Nat. Rev. Chem. 2017, 1, 0052, DOI: 10.1038/s41570-017-0052Google Scholar46ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVyksbzJ&md5=6f3cdda2c704c2bdaa298d31604ec0e7The merger of transition metal and photocatalysisTwilton, Jack; Le, Chi; Zhang, Patricia; Shaw, Megan H.; Evans, Ryan W.; MacMillan, David W. C.Nature Reviews Chemistry (2017), 1 (7), 0052CODEN: NRCAF7; ISSN:2397-3358. (Nature Research)A review. The merger of transition metal catalysis and photocatalysis, termed metallaphotocatalysis, has recently emerged as a versatile platform for the development of new, highly enabling synthetic methodologies. Photoredox catalysis provides access to reactive radical species under mild conditions from abundant, native functional groups, and, when combined with transition metal catalysis, this feature allows direct coupling of non-traditional nucleophile partners. In addn., photocatalysis can aid fundamental organometallic steps through modulation of the oxidn. state of transition metal complexes or through energy-transfer-mediated excitation of intermediate catalytic species. Metallaphotocatalysis provides access to distinct activation modes, which are complementary to those traditionally used in the field of transition metal catalysis, thereby enabling reaction development through entirely new mechanistic paradigms. This Review discusses key advances in the field of metallaphotocatalysis over the past decade and demonstrates how the unique mechanistic features permit challenging, or previously elusive, transformations to be accomplished.(b) Shaw, M. H.; Twilton, J.; MacMillan, D. W. C. Photoredox Catalysis in Organic Chemistry. J. Org. Chem. 2016, 81, 6898– 6926, DOI: 10.1021/acs.joc.6b01449Google Scholar46bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1Cqs77N&md5=b6ae8ae6e8fe632344b2f0409ad9698bPhotoredox Catalysis in Organic ChemistryShaw, Megan H.; Twilton, Jack; MacMillan, David W. C.Journal of Organic Chemistry (2016), 81 (16), 6898-6926CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)In recent years, photoredox catalysis has come to the forefront in org. chem. as a powerful strategy for the activation of small mols. In a general sense, these approaches rely on the ability of metal complexes and org. dyes to convert visible light into chem. energy by engaging in single-electron transfer with org. substrates, thereby generating reactive intermediates. In this Perspective, we highlight the unique ability of photoredox catalysis to expedite the development of completely new reaction mechanisms, with particular emphasis placed on multicatalytic strategies that enable the construction of challenging carbon-carbon and carbon-heteroatom bonds.(c) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Dual Catalysis Strategies in Photochemical Synthesis. Chem. Rev. 2016, 116, 10035– 10074, DOI: 10.1021/acs.chemrev.6b00018Google Scholar46chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmsFCrs78%253D&md5=cbaba2217953b11cb1cff0a517b2b172Dual Catalysis Strategies in Photochemical SynthesisSkubi, Kazimer L.; Blum, Travis R.; Yoon, Tehshik P.Chemical Reviews (Washington, DC, United States) (2016), 116 (17), 10035-10074CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. The interaction between an electronically excited photocatalyst and an org. mol. can result in the generation of a diverse array of reactive intermediates that can be manipulated in a variety of ways to result in synthetically useful bond constructions. This Review summarizes dual-catalyst strategies that have been applied to synthetic photochem. Mechanistically distinct modes of photocatalysis are discussed, including photoinduced electron transfer, hydrogen atom transfer, and energy transfer. We focus upon the cooperative interactions of photocatalysts with redox mediators, Lewis and Bronsted acids, organo-catalysts, enzymes, and transition metal complexes.
- 47(a) Corcoran, E. B.; Pirnot, M. T.; Lin, S.; Dreher, S. D.; DiRocco, D. A.; Davies, I. W.; Buchwald, S. L.; MacMillan, D. W. C. Aryl Amination Using Ligand-Free Ni(II) Salts and Photoredox Catalysis. Science 2016, 353, 279– 283, DOI: 10.1126/science.aag0209Google Scholar47ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFCktbfL&md5=83da5ffd11588cb691a8e6b3a137fd48Aryl amination using ligand-free Ni(II) salts and photoredox catalysisCorcoran, Emily B.; Pirnot, Michael T.; Lin, Shishi; Dreher, Spencer D.; DiRocco, Daniel A.; Davies, Ian W.; Buchwald, Stephen L.; MacMillan, David W. C.Science (Washington, DC, United States) (2016), 353 (6296), 279-283CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Over the past two decades, there have been major developments in transition metal-catalyzed aminations of aryl halides to form anilines, a common structure found in drug agents, natural product isolates, and fine chems. Many of these approaches have enabled highly efficient and selective coupling through the design of specialized ligands, which facilitate reductive elimination from a destabilized metal center. We postulated that a general and complementary method for carbon-nitrogen bond formation could be developed through the destabilization of a metal amido complex via photoredox catalysis, thus providing an alternative approach to the use of structurally complex ligand systems. Here, we report the development of a distinct mechanistic paradigm for aryl amination using ligand-free nickel(II) salts, in which facile reductive elimination from the nickel metal center is induced via a photoredox-catalyzed electron-transfer event.(b) Terrett, J. A.; Cuthbertson, J. D.; Shurtleff, V. W.; MacMillan, D. W. C. Switching on Elusive Organometallic Mechanisms with Photoredox Catalysis. Nature 2015, 524, 330– 334, DOI: 10.1038/nature14875Google Scholar47bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlaju73K&md5=f59cb031932dd23095f59bd03249ee18Switching on elusive organometallic mechanisms with photoredox catalysisTerrett, Jack A.; Cuthbertson, James D.; Shurtleff, Valerie W.; MacMillan, David W. C.Nature (London, United Kingdom) (2015), 524 (7565), 330-334CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Alkoxylation of arenes and heterocyclic compds. was achieved by photochem. coupling reaction of aryl bromides with aliph. alcs. catalyzed by iridium cyclometalated phenylpyridine photocatalyst and nickel 2,2'-bipyridine complexes under irradn. with blue LED light. Transition-metal-catalyzed cross-coupling reactions have become one of the most used carbon-carbon and carbon-heteroatom bond-forming reactions in chem. synthesis. Recently, nickel catalysis has been shown to participate in a wide variety of C-C bond-forming reactions, most notably Negishi, Suzuki-Miyaura, Stille, Kumada and Hiyama couplings. Despite the tremendous advances in C-C fragment couplings, the ability to forge C-O bonds in a general fashion via nickel catalysis has been largely unsuccessful. The challenge for nickel-mediated alc. couplings has been the mechanistic requirement for the crit. C-O bond-forming step (formally known as the reductive elimination step) to occur via a Ni(III) alkoxide intermediate. Here we demonstrate that visible-light-excited photoredox catalysts can modulate the preferred oxidn. states of nickel alkoxides in an operative catalytic cycle, thereby providing transient access to Ni(III) species that readily participate in reductive elimination. Using this synergistic merger of photoredox and nickel catalysis, we have developed a highly efficient and general carbon-oxygen coupling reaction using abundant alcs. and aryl bromides. More notably, we have developed a general strategy to 'switch on' important yet elusive organometallic mechanisms via oxidn. state modulations using only weak light and single-electron-transfer catalysts.(c) Tasker, S. Z.; Jamison, T. F. Highly Regioselective Indoline Synthesis under Nickel/Photoredox Dual Catalysis. J. Am. Chem. Soc. 2015, 137, 9531– 9534, DOI: 10.1021/jacs.5b05597Google Scholar47chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtF2ltrjM&md5=298b3ddddd59fc734eb3d9f6bfad574fHighly Regioselective Indoline Synthesis under Nickel/Photoredox Dual CatalysisTasker, Sarah Z.; Jamison, Timothy F.Journal of the American Chemical Society (2015), 137 (30), 9531-9534CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Nickel/photoredox catalysis is used to synthesize indolines in one step from iodoacetanilides and alkenes. Very high regioselectivity for 3-substituted indoline products I (R1 = H, 6-MeO, 6-F, 5-Me, 6-Cl, 4-Me, 5,7-diMe; R2 = n-hexyl, Bn, -CH2TMS, -CH2OTBS, cyclohexyl, Ph, 4-MeOC6H4, 4-CF3C6H4, etc.) is obtained for both aliph. and styryl olefins. Mechanistic investigations indicate that oxidn. to Ni(III) is necessary to perform the difficult C-N bond-forming reductive elimination, producing a Ni(I) complex, which in turn is reduced to Ni(0). This process serves to further demonstrate the utility of photoredox catalysts as controlled single electron transfer agents in multioxidn. state nickel catalysis.
- 48(a) Zuo, Z.; Cong, H.; Li, W.; Choi, J.; Fu, G. C.; MacMillan, D. W. C. Enantioselective Decarboxylative Arylation of α-Amino Acids via the Merger of Photoredox and Nickel Catalysis. J. Am. Chem. Soc. 2016, 138, 1832– 1835, DOI: 10.1021/jacs.5b13211Google Scholar48ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVynt7c%253D&md5=3fe6155cc5e8ec412844dad88f66ed51Enantioselective Decarboxylative Arylation of α-Amino Acids via the Merger of Photoredox and Nickel CatalysisZuo, Zhiwei; Cong, Huan; Li, Wei; Choi, Junwon; Fu, Gregory C.; MacMillan, David W. C.Journal of the American Chemical Society (2016), 138 (6), 1832-1835CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)An asym. decarboxylative Csp3-Csp2 cross-coupling has been achieved via the synergistic merger of photoredox and nickel catalysis. This mild, operationally simple protocol transforms a wide variety of naturally abundant α-amino acids and readily available aryl halides into valuable chiral benzylic amines in high enantiomeric excess, thereby producing motifs found in pharmacol. active agents.(b) Zhang, X.; MacMillan, D. W. C. Alcohols as Latent Coupling Fragments for Metallaphotoredox Catalysis: sp3–sp2 Cross-Coupling of Oxalates with Aryl Halides. J. Am. Chem. Soc. 2016, 138, 13862– 13865, DOI: 10.1021/jacs.6b09533Google Scholar48bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1CgsLrM&md5=05c79f350d5cb5bc39020f02e6084275Alcohols as Latent Coupling Fragments for Metallaphotoredox Catalysis: sp3-sp2 Cross-Coupling of Oxalates with Aryl HalidesZhang, Xiaheng; MacMillan, David W. C.Journal of the American Chemical Society (2016), 138 (42), 13862-13865CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Alkyl oxalates, prepd. from their corresponding alcs., are engaged for the first time as carbon radical fragments in metallaphotoredox catalysis. In this report, we demonstrate that alcs., native org. functional groups, can be readily activated with simple oxalyl chloride to become radical precursors in a net redox-neutral Csp3-Csp2 cross-coupling with a broad range of aryl halides. This alc.-activation coupling is successfully applied to the functionalization of a naturally occurring steroid and the expedient synthesis of a medicinally relevant drug lead.(c) El Khatib, M.; Serafim, R. A. M.; Molander, G. A. α-Arylation/Heteroarylation of Chiral α-Aminomethyltrifluoroborates by Synergistic Iridium Photoredox/Nickel Cross-Coupling Catalysis. Angew. Chem., Int. Ed. 2016, 55, 254– 258, DOI: 10.1002/anie.201506147Google Scholar48chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVOlt73L&md5=0b62c527e2d72f6671703b06d8921c9aα-Arylation/Heteroarylation of Chiral α-Aminomethyltrifluoro-borates by Synergistic Iridium Photoredox/Nickel Cross-Coupling CatalysisEl Khatib, Mirna; Serafim, Ricardo Augusto Massarico; Molander, Gary A.Angewandte Chemie, International Edition (2016), 55 (1), 254-258CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Direct access to complex, enantiopure benzylamine architectures using a synergistic iridium photoredox/nickel cross-coupling dual catalysis strategy has been developed. New C(sp3)-C(sp2) bonds are forged starting from abundant and inexpensive natural amino acids.(d) Chu, L.; Lipshultz, J. M.; MacMillan, D. W. C. Merging Photoredox and Nickel Catalysis: The Direct Synthesis of Ketones by the Decarboxylative Arylation of α-Oxo Acids. Angew. Chem., Int. Ed. 2015, 54, 7929– 7933, DOI: 10.1002/anie.201501908Google Scholar48dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXptFertb4%253D&md5=0632673f7ccd8e44a0729973abef6cf0Merging Photoredox and Nickel Catalysis: The Direct Synthesis of Ketones by the Decarboxylative Arylation of α-Oxo AcidsChu, Lingling; Lipshultz, Jeffrey M.; MacMillan, David W. C.Angewandte Chemie, International Edition (2015), 54 (27), 7929-7933CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The direct decarboxylative arylation of α-oxo acids has been achieved by synergistic visible-light-mediated photoredox and nickel catalysis. This method offers rapid entry to aryl and alkyl ketone architectures from simple α-oxo acid precursors via an acyl radical intermediate. Significant substrate scope is obsd. with respect to both the oxo acid and arene coupling partners. This mild decarboxylative arylation can also be utilized to efficiently access medicinal agents, as demonstrated by the rapid synthesis of fenofibrate.(e) Karakaya, I.; Primer, D. N.; Molander, G. A. Photoredox Cross-Coupling: Ir/Ni Dual Catalysis for the Synthesis of Benzylic Ethers. Org. Lett. 2015, 17, 3294– 3297, DOI: 10.1021/acs.orglett.5b01463Google Scholar48ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVansL7F&md5=8ad7ea3b807a84ceeb6ad3554a29a85bPhotoredox Cross-Coupling: Ir/Ni Dual Catalysis for the Synthesis of Benzylic EthersKarakaya, Idris; Primer, David N.; Molander, Gary A.Organic Letters (2015), 17 (13), 3294-3297CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)Single-electron transmetalation has emerged as an enabling paradigm for the cross-coupling of Csp3 hybridized organotrifluoroborates. Cross-coupling of α-alkoxymethyltrifluoroborates with aryl and heteroaryl bromides has been demonstrated by employing dual catalysis with a combination of an iridium photoredox catalyst and a Ni cross-coupling catalyst. The resulting method enables the alkoxymethylation of diverse (hetero)arenes under mild, room-temp. conditions.(f) Primer, D. N.; Karakaya, I.; Tellis, J. C.; Molander, G. Single-Electron Transmetalation: An Enabling Technology for Secondary Alkylboron Cross-Coupling. J. Am. Chem. Soc. 2015, 137, 2195– 2198, DOI: 10.1021/ja512946eGoogle Scholar48fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXit1Sgtro%253D&md5=a508cac50de311fd10f2c1a4a16a4ecbSingle-Electron Transmetalation: An Enabling Technology for Secondary Alkylboron Cross-CouplingPrimer, David N.; Karakaya, Idris; Tellis, John C.; Molander, Gary A.Journal of the American Chemical Society (2015), 137 (6), 2195-2198CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Sluggish transmetalation rates limit the use of organoboron nucleophiles in secondary alkyl cross-coupling. In cases where productive reactivity occurs, significant isomerization and byproducts in highly hindered systems are obsd. Single-electron-mediated alkyl transfer affords a novel mechanism for transmetalation, enabling cross-coupling under mild conditions. Here, general conditions are reported for cross-coupling of secondary alkyltrifluoroborates with an array of aryl bromides mediated by an Ir photoredox catalyst and a Ni cross-coupling catalyst [e.g., potassium cyclopentyltrifluoroborate + Me 4-bromobenzoate → Me 4-cyclopentylbenzoate (92%)].(g) Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle, A. G.; MacMillan, D. W. C. Merging Photoredox with Nickel Catalysis: Coupling of α-Carboxyl sp3-Carbons with Aryl Halides. Science 2014, 345, 437– 440, DOI: 10.1126/science.1255525Google Scholar48ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFyks73N&md5=e6b961c1b8b7ecae359d64252de5910bMerging photoredox with nickel catalysis: Coupling of α-carboxyl sp3-carbons with aryl halidesZuo, Zhiwei; Ahneman, Derek T.; Chu, Lingling; Terrett, Jack A.; Doyle, Abigail G.; MacMillan, David W. C.Science (Washington, DC, United States) (2014), 345 (6195), 437-440CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A review. Over the past 40 years, transition metal catalysis has enabled bond formation between aryl and olefinic (sp2) carbons in a selective and predictable manner with high functional group tolerance. Couplings involving alkyl (sp3) carbons proved more challenging. Here, the synergistic combination of photoredox catalysis and nickel catalysis provides an alternative cross-coupling paradigm, in which simple and readily available org. mols. can be systematically used as coupling partners. By using this photoredox-metal catalysis approach, the authors have achieved a direct decarboxylative sp3-sp2 cross-coupling of amino acids, as well as α-O- or phenyl-substituted carboxylic acids, with aryl halides. Also, this mode of catalysis can be applied to direct cross-coupling of Csp3-H in dimethylaniline with aryl halides via C-H functionalization.(h) Tellis, J. C.; Primer, D. N.; Molander, G. A. Single-Electron Transmetalation in Organoboron Cross-Coupling by Photoredox/Nickel Dual Catalysis. Science 2014, 345, 433– 436, DOI: 10.1126/science.1253647Google Scholar48hhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFyks7zE&md5=4ff7191df8dd2e790b6c326f79645263Single-electron transmetalation in organoboron cross-coupling by photoredox/nickel dual catalysisTellis, John C.; Primer, David N.; Molander, Gary A.Science (Washington, DC, United States) (2014), 345 (6195), 433-436CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)The routine application of Csp3-hybridized nucleophiles in cross-coupling reactions remains an unsolved challenge in org. chem. The sluggish transmetalation rates obsd. for the preferred organoboron reagents in such transformations are a consequence of the two-electron mechanism underlying the std. catalytic approach. We describe a mechanistically distinct single-electron transfer-based strategy for the activation of organoboron reagents toward transmetalation that exhibits complementary reactivity patterns. Application of an iridium photoredox catalyst in tandem with a nickel catalyst effects the cross-coupling of potassium alkoxyalkyl- and benzyltrifluoroborates with an array of aryl bromides under exceptionally mild conditions (visible light, ambient temp., no strong base). The transformation has been extended to the asym. and stereoconvergent cross-coupling of a secondary benzyltrifluoroborate.
- 49(a) Ahneman, D. T.; Doyle, A. G. C–H Functionalization of Amines with Aryl Halides by Nickel-Photoredox Catalysis. Chem. Sci. 2016, 7, 7002– 7006, DOI: 10.1039/C6SC02815BGoogle Scholar49ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1Crt7fK&md5=ee262ccd4c8809b85783c292b3dfad29C-H functionalization of amines with aryl halides by nickel-photoredox catalysisAhneman, Derek T.; Doyle, Abigail G.Chemical Science (2016), 7 (12), 7002-7006CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Synthesis of phenylpyrrolidines e.g., I via functionalization of α-amino C-H bonds with aryl halides using a combination of nickel and photoredox catalysis was described. This direct C-H, C-X coupling uses inexpensive and readily available starting materials to generate benzylic amines, an important class of bioactive mols. Mechanistically, this method features the direct arylation of α-amino radicals mediated by a nickel catalyst. This reactivity was demonstrated for a range of aryl halides and N-aryl amines, with orthogonal scope to existing C-H activation and photoredox methodologies. Reactions with several complex aryl halides, demonstrating the potential utility of this approach in late-stage functionalization was also reported.(b) Shaw, M. H.; Shurtleff, V. W.; Terrett, J. A.; Cuthbertson, J. D.; MacMillan, D. W. C. Native Functionality in Triple Catalytic Cross-Coupling: sp3 C–H Bonds as Latent Nucleophiles. Science 2016, 352, 1304– 1308, DOI: 10.1126/science.aaf6635Google Scholar49bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xpt1Gnur8%253D&md5=f514617a8a36c474a3c473d7c968aae5Native functionality in triple catalytic cross-coupling: sp3 C-H bonds as latent nucleophilesShaw, Megan H.; Shurtleff, Valerie W.; Terrett, Jack A.; Cuthbertson, James D.; MacMillan, David W. C.Science (Washington, DC, United States) (2016), 352 (6291), 1304-1308CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)The use of sp3 C-H bonds-which are ubiquitous in org. mols.-as latent nucleophile equiv. for transition metal-catalyzed cross-coupling reactions has the potential to substantially streamline synthetic efforts in org. chem. while bypassing substrate activation steps. Through the combination of photoredox-mediated hydrogen atom transfer (HAT) and nickel catalysis, we have developed a highly selective and general C-H arylation protocol that activates a wide array of C-H bonds as native functional handles for cross-coupling. This mild approach takes advantage of a tunable HAT catalyst that exhibits predictable reactivity patterns based on enthalpic and bond polarity considerations to selectively functionalize α-amino and α-oxy sp3 C-H bonds in both cyclic and acyclic systems.(c) Shields, B. J.; Doyle, A. G. Direct C(sp3)–H Cross Coupling Enabled by Catalytic Generation of Chlorine Radicals. J. Am. Chem. Soc. 2016, 138, 12719– 12722, DOI: 10.1021/jacs.6b08397Google Scholar49chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFals7bL&md5=9f8fa36266ff44aaa227194d10757d35Direct C(sp3)-H Cross Coupling Enabled by Catalytic Generation of Chlorine RadicalsShields, Benjamin J.; Doyle, Abigail G.Journal of the American Chemical Society (2016), 138 (39), 12719-12722CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Here we report the development of a C(sp3)-H cross-coupling platform enabled by the catalytic generation of chlorine radicals by nickel and photoredox catalysis. Aryl chlorides serve as both cross-coupling partners and the chlorine radical source for the α-oxy C(sp3)-H arylation of cyclic and acyclic ethers. Mechanistic studies suggest that photolysis of a Ni(III) aryl chloride intermediate, generated by photoredox-mediated single-electron oxidn., leads to elimination of a chlorine radical in what amts. to the sequential capture of two photons. Arylations of a benzylic C(sp3)-H bond of toluene and a completely unactivated C(sp3)-H bond of cyclohexane demonstrate the broad implications of this manifold for accomplishing numerous C(sp3)-H bond functionalizations under exceptionally mild conditions.
- 50Twilton, J.; Christensen, M.; DiRocco, D. A.; Ruck, R. T.; Davies, I. W.; MacMillan, D. W. C. Selective Hydrogen Atom Abstraction through Induced Bond Polarization: Direct α-Arylation of Alcohols through Photoredox, HAT, and Nickel Catalysis. Angew. Chem., Int. Ed. 2018, 57, 5369– 5373, DOI: 10.1002/anie.201800749Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXntFOksLc%253D&md5=4c300647add5c0d147fed2ef3f8d0887Selective Hydrogen Atom Abstraction through Induced Bond Polarization: Direct α-Arylation of Alcohols through Photoredox, HAT, and Nickel CatalysisTwilton, Jack; Christensen, Melodie; Di Rocco, Daniel A.; Ruck, Rebecca T.; Davies, Ian W.; MacMillan, David W. C.Angewandte Chemie, International Edition (2018), 57 (19), 5369-5373CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The combination of nickel metallaphotoredox catalysis, hydrogen atom transfer catalysis, and a Lewis acid activation mode, led to the development of an arylation method for the selective functionalization of alc. α-hydroxy C-H bonds. This approach employs zinc-mediated alc. deprotonation to activate α-hydroxy C-H bonds while simultaneously suppressing C-O bond formation by inhibiting the formation of nickel alkoxide species. The use of Zn-based Lewis acids also deactivates other hydridic bonds such as α-amino and α-oxy C-H bonds. This approach facilitates rapid access to benzylic alcs., an important motif in drug discovery. A 3-step synthesis of the drug Prozac exemplifies the utility of this new method.
- 51DiRocco, D. A.; Dykstra, K.; Krska, S.; Vachal, P.; Conway, D. V.; Tudge, M. Late-Stage Functionalization of Biologically Active Heterocycles Through Photoredox Catalysis. Angew. Chem., Int. Ed. 2014, 53, 4802– 4806, DOI: 10.1002/anie.201402023Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2crotFCnsQ%253D%253D&md5=ca31296d61c97e944eaaf326a8190458Late-stage functionalization of biologically active heterocycles through photoredox catalysisDirocco Daniel A; Dykstra Kevin; Krska Shane; Vachal Petr; Conway Donald V; Tudge MatthewAngewandte Chemie (International ed. in English) (2014), 53 (19), 4802-6 ISSN:.The direct C H functionalization of heterocycles has become an increasingly valuable tool in modern drug discovery. However, the introduction of small alkyl groups, such as methyl, by this method has not been realized in the context of complex molecule synthesis since existing methods rely on the use of strong oxidants and elevated temperatures to generate the requisite radical species. Herein, we report the use of stable organic peroxides activated by visible-light photoredox catalysis to achieve the direct methyl-, ethyl-, and cyclopropylation of a variety of biologically active heterocycles. The simple protocol, mild reaction conditions, and unique tolerability of this method make it an important tool for drug discovery.
- 52Shvydkiv, O.; Gallagher, S.; Nolan, K.; Oelgemöller, M. From Conventional to Microphotochemistry: Photodecarboxylation Reactions Involving Phthalimides. Org. Lett. 2010, 12, 5170– 5173, DOI: 10.1021/ol102184uGoogle Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1yktL%252FI&md5=f8b98b24b5e57d0c5c48e62d1716ecdaFrom Conventional to Microphotochemistry: Photodecarboxylation Reactions Involving PhthalimidesShvydkiv, Oksana; Gallagher, Sonia; Nolan, Kieran; Oelgemoller, MichaelOrganic Letters (2010), 12 (22), 5170-5173CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)A series of acetone-sensitized photodecarboxylation reactions involving phthalimides have been investigated using conventional and microphotochem. Intra- and intermol. transformations were compared. In all cases examd., the reactions performed in microreactors were superior in terms of conversions or isolated yields. These findings unambiguously prove the advantage of microphotochem. over conventional photochem. techniques.
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We attribute this observation to differences in light wavelength and intensity between the Lumidox LED array and Kessil lamp.
There is no corresponding record for this reference. - 54Luo, J.; Zhang, J. Donor–Acceptor Fluorophores for Visible-Light-Promoted Organic Synthesis: Photoredox/Ni Dual Catalytic C(sp3)–C(sp2) Cross-Coupling. ACS Catal. 2016, 6, 873– 877, DOI: 10.1021/acscatal.5b02204Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVGks7w%253D&md5=5a0a4b4dea7900247422ec669f5013eaDonor-Acceptor Fluorophores for Visible-Light-Promoted Organic Synthesis: Photoredox/Ni Dual Catalytic C(sp3)-C(sp2) Cross-CouplingLuo, Jian; Zhang, JianACS Catalysis (2016), 6 (2), 873-877CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)We describe carbazolyl dicyanobenzene (CDCB)-based donor-acceptor (D-A) fluorophores as a class of cheap, easily accessible, and efficient metal-free photoredox catalysts for org. synthesis. By changing the no. and position of carbazolyl and cyano groups on the center benzene ring, CDCBs with a wide range of photoredox potentials are obtained to effectively drive the energetically demanding C(sp3)-C(sp2) cross-coupling of carboxylic acids and alkyltrifluoroborates with aryl halides via a photoredox/Ni dual catalysis mechanism. This work validates the utility of D-A fluorophores in guiding the rational design of metal-free photoredox catalysts for visible-light-promoted org. synthesis.
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The first round of kits was validated using test reactions from each category with success, and one selected category was retested after 5 months to ensure catalyst stability over time.
There is no corresponding record for this reference. - 56Le, C. C.; Wismer, M. K.; Shi, Z.-C.; Zhang, R.; Conway, D. V.; Li, G.; Vachal, P.; Davies, I. W.; MacMillan, D. W. C. A General Small-Scale Reactor to Enable Standardization and Acceleration of Photocatalytic Reactions. ACS Cent. Sci. 2017, 3, 647– 653, DOI: 10.1021/acscentsci.7b00159Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnslOqu70%253D&md5=b5a94b91c2e8800dd7167e4859783755A general small-scale reactor to enable standardization and acceleration of photocatalytic reactionsLe, Chi "Chip"; Wismer, Michael K.; Shi, Zhi-Cai; Zhang, Rui; Conway, Donald V.; Li, Guoqing; Vachal, Petr; Davies, Ian W.; MacMillan, David W. C.ACS Central Science (2017), 3 (6), 647-653CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)Photocatalysis for org. synthesis has experienced an exponential growth in the past 10 years. However, the variety of exptl. procedures that have been reported to perform photon-based catalyst excitation has hampered the establishment of general protocols to convert visible light into chem. energy. To address this issue, we have designed an integrated photoreactor for enhanced photon capture and catalyst excitation. Moreover, the evaluation of this new reactor in eight photocatalytic transformations that are widely employed in medicinal chem. settings has confirmed significant performance advantages of this optimized design while enabling a standardized protocol.
- 57(a) Politano, F.; Oksdath-Mansilla, G. Light on the Horizon: Current Research and Future Perspectives in Flow Photochemistry. Org. Process Res. Dev. 2018, 22, 1045– 1062, DOI: 10.1021/acs.oprd.8b00213Google Scholar57ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVegt7nN&md5=6e79f34c1b4ec557d581579243a9d36eLight on the Horizon: Current Research and Future Perspectives in Flow PhotochemistryPolitano, Fabrizio; Oksdath-Mansilla, GabrielaOrganic Process Research & Development (2018), 22 (9), 1045-1062CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Synthetic org. photochem. is a powerful tool for creating both natural products and mols. with high structural complexity in a simple way and under mild conditions. However, because of the challenges in scaling-up, it has been difficult to apply a photochem. reaction in an industrial process. Flow chem. provides an opportunity for better control over the conditions of the reaction and, addnl., improved reaction selectivity and enhanced reproducibility. Taking into account that significant interest has focused on the use of flow photochem. as a method for the synthesis of heterocycles and its applications in target-oriented synthesis over the past few years, the aim of this review is to highlight recent efforts to apply flow photochem. methodol. to diverse reactions as a greener and more scalable process for the pharmaceutical and fine chem. industries. Addnl., the review highlights future perspectives in the development of scale-up strategies, combining photochem. reactions in the continuous-flow multistep synthesis of org. mols., which is of interest for scientists and engineers alike.(b) Cambié, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noël, T. Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment. Chem. Rev. 2016, 116, 10276– 10341, DOI: 10.1021/acs.chemrev.5b00707Google Scholar57bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjsVOjs7g%253D&md5=327c368f6e090142204920993c4faadaApplications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water TreatmentCambie, Dario; Bottecchia, Cecilia; Straathof, Natan J. W.; Hessel, Volker; Noel, TimothyChemical Reviews (Washington, DC, United States) (2016), 116 (17), 10276-10341CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Continuous-flow photochem. in microreactors receives a lot of attention from researchers in academia and industry as this technol. provides reduced reaction times, higher selectivities, straightforward scalability, and the possibility to safely use hazardous intermediates and gaseous reactants. In this review, an up-to-date overview is given of photochem. transformations in continuous-flow reactors, including applications in org. synthesis, material science, and water treatment. In addn., the advantages of continuous-flow photochem. are pointed out and a thorough comparison with batch processing is presented.
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The choice of stir bar was determined after mixing studies carried out in our laboratory that focused on a Bourne reaction as an example of mixing-sensitive reaction. On the basis of the outcome of those studies, we decided to employ this stir bar in all future project work carried out on our Freeslate Junior platform.
There is no corresponding record for this reference. - 59
For examples of TBD as a catalyst for amide bond formation between esters and amines, see:
(a) Rankic, D. A.; Stiff, C. M.; am Ende, C. W.; Humphrey, J. M. Protocol for the Direct Conversion of Lactones to Lactams Mediated by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene: Synthesis of Pyridopyrazine-1,6-diones. J. Org. Chem. 2017, 82, 12791– 12797, DOI: 10.1021/acs.joc.7b02079Google Scholar59ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1yhsbvF&md5=71e169fb5e2f0a97de4d334099e915a0Protocol for the Direct Conversion of Lactones to Lactams Mediated by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene: Synthesis of Pyridopyrazine-1,6-dionesRankic, Danica A.; Stiff, Cory M.; am Ende, Christopher W.; Humphrey, John M.Journal of Organic Chemistry (2017), 82 (23), 12791-12797CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)We present an operationally simple lactone-to-lactam transformation utilizing diverse amine nucleophiles. The key steps of amidation, alc. activation, and cyclization are all mediated by one reagent (TBD) in a single vessel at room temp. We illustrate the convenience of this protocol by synthesizing a wide range of N-alkyl, N-aryl, and N-hetereoaryl pyridopyrazine-1,6-diones, an important class of medicinally significant lactams. Furthermore, the reported methodol. can be applied to the synthesis of milligram to hundred gram quantities of pyridopyrazine-1,6-diones without the use of specialized equipment.(b) Weiberth, F. J.; Yu, Y.; Subotkowski, W.; Pemberton, C. J. Demonstration on Pilot-Plant Scale of the Utility of 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD) as a Catalyst in the Efficient Amidation of an Unactivated Methyl Ester. Org. Process Res. Dev. 2012, 16, 1967– 1969, DOI: 10.1021/op300210jGoogle Scholar59bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1GlsrbN&md5=3633eeae4e93b82673c4040fd0afd578Demonstration on Pilot-Plant Scale of the Utility of 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD) as a Catalyst in the Efficient Amidation of an Unactivated Methyl EsterWeiberth, Franz J.; Yu, Yong; Subotkowski, Witold; Pemberton, CliveOrganic Process Research & Development (2012), 16 (12), 1967-1969CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The utility of 1,5,7-triazabicyclo[4.4.0]dec-5-ene as a reagent to facilitate efficient amide formation by reaction of an amine with an unactivated ester was demonstrated on pilot-plant scale as a key step in the synthesis of an H-PGDS inhibitor.(c) Kiesewetter, M. K.; Scholten, M. D.; Kirn, N.; Weber, R. L.; Hedrick, J. L.; Waymouth, R. M. Cyclic Guanidine Organic Catalysts: What Is Magic About Triazabicyclodecene?. J. Org. Chem. 2009, 74, 9490– 9496, DOI: 10.1021/jo902369gGoogle Scholar59chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVKhs7nP&md5=0f263f5a0f48749b17ed6bbd486e7f32Cyclic guanidine organic catalysts: What is magic about triazabicyclodecene?Kiesewetter, Matthew K.; Scholten, Marc D.; Kirn, Nicole; Weber, Ryan L.; Hedrick, James L.; Waymouth, Robert M.Journal of Organic Chemistry (2009), 74 (24), 9490-9496CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)The bicyclic guanidine 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) is an effective organocatalyst for the formation of amides from esters and primary amines. Mechanistic and kinetic studies support a nucleophilic mechanism where TBD reacts reversibly with esters to generate an acyl-TBD intermediate that acylates amines to generate the amides. Comparative studies of the analogous bicyclic guanidine 1,4,6-triazabicyclo[3.3.0]oct-4-ene (TBO) reveal it to be a much less active acylation catalyst than TBD. Theor. and mechanistic studies imply that the higher reactivity of TBD is a consequence of both its higher basicity and nucleophilicity than TBO and the high reactivity of the acyl-TBD intermediate, which is sterically prevented from adopting a planar amide structure. - 60
For examples of TBD as a catalyst in transesterification reactions, see:
(a) Soeyler, Z.; Meier, M. A. R. Catalytic Transesterification of Starch with Plant Oils: A Sustainable and Efficient Route to Fatty Acid Starch Esters. ChemSusChem 2017, 10, 182– 188, DOI: 10.1002/cssc.201601215Google Scholar60ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFahtLjN&md5=ed430193fb5ffc9d16f672e346e223a0Catalytic Transesterification of Starch with Plant Oils: A Sustainable and Efficient Route to Fatty Acid Starch EstersSoeyler, Zafer; Meier, Michael A. R.ChemSusChem (2017), 10 (1), 182-188CODEN: CHEMIZ; ISSN:1864-5631. (Wiley-VCH Verlag GmbH & Co. KGaA)The transesterification of maize starch with olive oil or high oleic sunflower oil was studied under homogeneous conditions in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as catalyst. Most importantly, this method used two renewable resources directly, without any pretreatment or derivatization, for the synthesis of polymeric materials with desirable properties. Moreover, the solvent, oils, and catalyst could be recovered through facile work-up and reused for further modifications. The obtained fatty acid starch esters (FASEs) were highly sol. in common org. solvents and were thoroughly characterized. Degrees of substitution (DS) were calcd. using 31P NMR spectroscopy, and DS values of approx. 1.3 were obtained. Differential scanning calorimetry anal. revealed thermal transitions of the modified starches at approx. 80-90 °C. Films were produced from these FASEs, and their hydrophobic surfaces were characterized using contact-angle measurements. Furthermore, mech. properties were examd. using tensile strength measurements and showed approx. 40 and 80 % elongation at break for modified maize starch and modified amylose from maize, resp.(b) Schuchardt, U.; Vargas, R. M.; Gelbard, G. Alkylguanidines as catalysts for the transesterification of rapeseed oil. J. Mol. Catal. A: Chem. 1995, 99, 65– 70, DOI: 10.1016/1381-1169(95)00039-9Google Scholar60bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXmvVGgs7c%253D&md5=419450b41475983a94123c1a0970ac65Alkylguanidines as catalysts for the transesterification of rapeseed oilSchuchardt, Ulf; Vargas, Rogerio Matheus; Gelbard, GeorgesJournal of Molecular Catalysis A: Chemical (1995), 99 (2), 65-70CODEN: JMCCF2; ISSN:1381-1169. (Elsevier)The transesterification of rapeseed oil with methanol was studied in the presence of one of 8 substituted cyclic and acyclic guanidines. The catalytic activity of substituted guanidines was compared with that of unsubstituted guanidine. The catalytic activity of the guanidines depends mainly on their intrinsic base strength. With a long alkyl chain on the guanidine, no lipophilic effect was obsd. The best catalyst found is com. 1,5,7-triazabicyclo-[4.4.0]-dec-5-ene which, when used at 1 mol %, produces a 90% yield of Me esters in 1 h reaction time. - 61
The exact sampling times were determined from Polyview data collected by the LEA software.
There is no corresponding record for this reference. - 62
pH 5.4 buffer (made by mixing 0.1 M aqueous citric acid (44 mL) and 0.2 M aqueous dibasic sodium phosphate (56 mL) and diluting with 100 mL of MeCN) was required to neutralize the base and stop the reaction. Also, this pH was not acidic enough to cause oxetane ring opening.
There is no corresponding record for this reference. - 63
DoE volumes (L/kg) were selected on the basis of tank capacity in the plant and to avoid multiple runs for this step.
There is no corresponding record for this reference.
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Abstract
Figure 1
Figure 1. Prediction of the most frequently screened reactions in 3–5 years.
Figure 2
Figure 2. Phase of development for HTE projects.
Figure 3
Figure 3. Type of chemist performing HTE screens.
Figure 4
Figure 4. Nonprecious metals screened in HTE groups.
Figure 5
Figure 5. Structure of PCSK9 inhibitor 1.
Scheme 1
Scheme 1. Medicinal Chemistry Conditions for Suzuki–Miyaura Cross-CouplingFigure 6
Figure 6. Impurities formed during the Suzuki–Miyaura coupling between 3 and 4.
Figure 7
Figure 7. Scattered plots showing experimental results for optimization reactions with PdCl2(DCyPF). Horizontal lines displayed at 0, 5, and 95% for clarity. Visualization was prepared in Spotfire.
Scheme 2
Scheme 2. Existing Multi-Kilo Syntheses of 10Scheme 3
Scheme 3. Strategy for HTEFigure 8
Figure 8. HTE results for prospective reducing agents. Visualization was prepared in RStudio.
Figure 9
Figure 9. HTE results for the targeted study of sulfite reducing agents. Visualization was prepared in RStudio.
Scheme 4
Scheme 4. Hydrogenation of 2-Bromo-4-chloro-nitrobenzeneFigure 10
Figure 10. Area percent desired product (y-axis) versus catalyst (x-axis) for the catalytic hydrogenation of 13. Visualization was prepared in Spotfire.
Figure 11
Figure 11. Area percent des-bromo product (y-axis) versus area percent hydrazine dimer (x-axis) for plate 1 (two mechanistic regimes are highlighted). Visualization was prepared in Spotfire.
Scheme 5
Scheme 5. Mechanistic Pathways for Reduction of Nitro Compounds into AnilinesFigure 12
Scheme 6
Scheme 6. Route to Fluoro Analogues of LY2886721Figure 13
Figure 13. OPSL reaction optimization workflow.
Scheme 7
Scheme 7. Synthetic Sequence Validationaa(i) TEA (2 equiv), Boc2O (1.2 equiv), 50 °C/2 h; (ii) citric acid; (iii) SO3·Py (2.3 equiv), Hunig’s base (1 equiv), DMSO, ethyl acetate, 5 °C/1 h; (iv) pyrrolidine (1.1 equiv), THF, 22 °C/14 min; (v) SelectFluor (1.2 equiv), 22 °C/2.5 h; (vi) NaHCO3 sat. aqueous solution; (vii) NaBH4 (1.2 equiv), MeOH, 22 °C/1 h; (viii) NaHCO3 sat. aqueous solution.
Figure 14
Figure 14. Selected fluorination agents and chiral amines.
Figure 15
Figure 15. General rationale behind metallophotoredox catalysis.
Figure 16
Figure 16. Three regimes of metallophotoredox catalysis.
Figure 17
Figure 17. MSD/Princeton case study of α-hydroxyl arylation through HAT-metallophotoredox catalysis.
Figure 18
Figure 18. HTE evaluation of Lewis acid additives. [Performed on a 10 μmol scale with photocatalyst 32 (0.5 mol %), NiBr2·Me4Phen 33 (0.5 mol %), quinuclidine 34 (100 mol %), aryl halide 35 (1.0 equiv), alcohol 36 (5.0 equiv), and additive (1.5 equiv), in DMSO (0.25 M).] Visualization prepared in Tableau.
Figure 19
Figure 19. HTE evaluation of inorganic bases. [Performed on a 10 μmol scale with photocatalyst 32 (0.5 mol %), NiBr2·Me4Phen 33 (0.5 mol %), quinuclidine 34 (25 mol %), aryl halide 35 (1.0 equiv), alcohol 36 (5.0 equiv), ZnX2 (1.5 equiv), and base (1.0 equiv) in DMSO (0.25 M) with and without water (10.0 equiv).] Visualization prepared in Excel.
Scheme 8
Scheme 8. Optimized Conditions Carried out in Cylindrical Vials Illuminated by a 40 W Blue Kessil LampaaPerformed on a 300 μmol scale with photocatalyst 41 (0.2 mol %), NiBr2·Me4Phen 33 (1.5 mol %), quinuclidine 34 (30 mol %), aryl halide 35 (1.0 equiv), alcohol 36 (5.0 equiv), ZnCl2 (1.5 equiv), and K3PO4 (1.0 equiv) in DMSO (0.25 M).
Figure 20
Figure 20. Metallophotoredox kit designs.
Scheme 9
Scheme 9. Methyl Ester Hydrolysis with TBD in Aqueous Methyl Ethyl Ketone (MEK)Figure 21
Figure 21. Miniaturized DoE workflow at Pfizer.
Figure 22
Figure 22. Contour plots for the predicted acid 43 formation as a function of dilution, water equiv, temperature, and reaction time. The plots have been produced at the center level of all other factors in the model except that time is at 17 h. Visualization prepared in Design Expert.
Figure 23
Figure 23. Overlay of experiments 1–3 on small and large scale; the fourth chart shows the kinetic profile for the statistical model prediction experiment. Horizontal lines at 5 and 90 AP for clarity. Observed end point windows are shown for scale-up experiments in Systag reactor. Visualization prepared in Spotfire.
References
This article references 63 other publications.
- 1For a review on the application of HTE in chemical process development, see:Selekman, J. A.; Qiu, J.; Tran, K.; Stevens, J.; Rosso, V.; Simmons, E.; Xiao, Y.; Janey, J. High-Throughput Automation in Chemical Process Development. Annu. Rev. Chem. Biomol. Eng. 2017, 8, 525– 547, DOI: 10.1146/annurev-chembioeng-060816-1014111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1crivVyisQ%253D%253D&md5=c91f868eda8489a7094a9097357f76b0High-Throughput Automation in Chemical Process DevelopmentSelekman Joshua A; Qiu Jun; Tran Kristy; Stevens Jason; Rosso Victor; Simmons Eric; Xiao Yi; Janey JacobAnnual review of chemical and biomolecular engineering (2017), 8 (), 525-547 ISSN:.High-throughput (HT) techniques built upon laboratory automation technology and coupled to statistical experimental design and parallel experimentation have enabled the acceleration of chemical process development across multiple industries. HT technologies are often applied to interrogate wide, often multidimensional experimental spaces to inform the design and optimization of any number of unit operations that chemical engineers use in process development. In this review, we outline the evolution of HT technology and provide a comprehensive overview of how HT automation is used throughout different industries, with a particular focus on chemical and pharmaceutical process development. In addition, we highlight the common strategies of how HT automation is incorporated into routine development activities to maximize its impact in various academic and industrial settings.
- 2
For selected articles on the use of HTE, see:
(a) Shevlin, M. Practical High-Throughput Experimentation for Chemists. ACS Med. Chem. Lett. 2017, 8, 601– 607, DOI: 10.1021/acsmedchemlett.7b001652ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnvFCnt7w%253D&md5=4356ece5d6399f4a9c72c8a3bd5d118ePractical High-Throughput Experimentation for ChemistsShevlin, MichaelACS Medicinal Chemistry Letters (2017), 8 (6), 601-607CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)A review. Large arrays of hypothesis-driven, rationally designed expts. are powerful tools for solving complex chem. problems. Conceptual and practical aspects of chem. high-throughput experimentation are discussed. A case study in the application of high-throughput experimentation to a key synthetic step in a drug discovery program and subsequent optimization for the first large scale synthesis of a drug candidate is exemplified.(b) Krska, S. W.; DiRocco, D. A.; Dreher, S. D.; Shevlin, M. The Evolution of Chemical High-Throughput Experimentation to Address Challenging Problems in Pharmaceutical Synthesis. Acc. Chem. Res. 2017, 50, 2976– 2985, DOI: 10.1021/acs.accounts.7b004282bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVGiu7bF&md5=95ab78d3e084b11009135f5a3d9fb111The Evolution of Chemical High-Throughput Experimentation To Address Challenging Problems in Pharmaceutical SynthesisKrska, Shane W.; DiRocco, Daniel A.; Dreher, Spencer D.; Shevlin, MichaelAccounts of Chemical Research (2017), 50 (12), 2976-2985CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. The structural complexity of pharmaceuticals presents a significant challenge to modern catalysis. Many published methods that work well on simple substrates often fail when attempts are made to apply them to complex drug intermediates. The use of high-throughput experimentation (HTE) techniques offers a means to overcome this fundamental challenge by facilitating the rational exploration of large arrays of catalysts and reaction conditions in a time- and material-efficient manner. Initial forays into the use of HTE in our labs. for solving chem. problems centered around screening of chiral precious-metal catalysts for homogeneous asym. hydrogenation. The success of these early efforts in developing efficient catalytic steps for late-stage development programs motivated the desire to increase the scope of this approach to encompass other high-value catalytic chemistries. Doing so, however, required significant advances in reactor and workflow design and automation to enable the effective assembly and agitation of arrays of heterogeneous reaction mixts. and retention of volatile solvents under a wide range of temps. Assocd. innovations in high-throughput anal. chem. techniques greatly increased the efficiency and reliability of these methods. These evolved HTE techniques have been utilized extensively to develop highly innovative catalysis solns. to the most challenging problems in large-scale pharmaceutical synthesis. Starting with Pd- and Cu-catalyzed cross-coupling chem., subsequent efforts expanded to other valuable modern synthetic transformations such as chiral phase-transfer catalysis, photoredox catalysis, and C-H functionalization. As our experience and confidence in HTE techniques matured, we envisioned their application beyond problems in process chem. to address the needs of medicinal chemists. Here the problem of reaction generality is felt most acutely, and HTE approaches should prove broadly enabling. However, the quantities of both time and starting materials available for chem. troubleshooting in this space generally are severely limited. Adapting to these needs led us to invest in smaller predefined arrays of transformation-specific screening "kits" and push the boundaries of miniaturization in chem. screening, culminating in the development of "nanoscale" reaction screening carried out in 1536-well plates. Grappling with the problem of generality also inspired the exploration of cheminformatics-driven HTE approaches such as the Chem. Informer Libraries. These next-generation HTE methods promise to empower chemists to run orders of magnitude more expts. and enable "big data" informatics approaches to reaction design and troubleshooting. With these advances, HTE is poised to revolutionize how chemists across both industry and academia discover new synthetic methods, develop them into tools of broad utility, and apply them to problems of practical significance.(c) Leitch, D. C.; John, M. P.; Slavin, P. A.; Searle, A. D. An Evaluation of Multiple Catalytic Systems for the Cyanation of 2,3-Dichlorobenzoyl Chloride: Application to the Synthesis of Lamotrigine. Org. Process Res. Dev. 2017, 21, 1815– 1821, DOI: 10.1021/acs.oprd.7b002622chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1KnsbzJ&md5=e9e92ec943982a46c16d8a99df4b00adAn Evaluation of Multiple Catalytic Systems for the Cyanation of 2,3-Dichlorobenzoyl Chloride: Application to the Synthesis of LamotrigineLeitch, David C.; John, Matthew P.; Slavin, Paul A.; Searle, Andrew D.Organic Process Research & Development (2017), 21 (11), 1815-1821CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)2,3-Dichlorobenzoyl cyanide is a key intermediate in the synthesis of Lamotrigine (I). An assessment of various catalytic systems for the cyanation of 2,3-dichlorobenzoyl chloride with cyanide salts is described. High-throughput experimentation identified many conditions for effecting the requisite chem., including amine bases and phase-transfer catalysts, as well as catalyst-free conditions utilizing acetonitrile as a polar cosolvent. A novel catalyst, CuBr2, was identified by consideration of the possible oxidn. of Cu(I) during high-throughput screening experimentation. CuCN was found to be the best cyanide source for achieving clean conversion; however, the soly. of CuCN was the major factor limiting reaction rate under many conditions. Improving CuCN soly. by using acetonitrile as solvent enhanced the reaction rate even in the absence of the catalysts tested but significantly complicated isolation of the product. With no acetonitrile cosolvent, phase-transfer catalysts such as tetrabutylammonium bromide (TBABr) are effective; however, use of TBABr led to inconsistent reaction profiles from run-to-run, due to an unexpected clumping of the CuCN solid. Switching to cetyltrimethylammonium bromide (CTAB) alleviated this clumping behavior, leading to consistent reactivity. This CTAB-catalyzed process was scaled up, giving 560 kg of 2,3-dichlorobenzoyl cyanide in 77% isolated yield. Safety: care must be taken when carrying out chem. with metal cyanide salts.(d) Boga, S. B.; Christensen, M.; Perrotto, N.; Krska, S. W.; Dreher, S.; Tudge, M. T.; Ashley, E. R.; Poirier, M.; Reibarkh, M.; Liu, Y.; Streckfuss, E.; Campeau, L.-C.; Ruck, R. T.; Davies, I. W.; Vachal, P. Selective Functionalization of Complex Heterocycles via an Automated Strong Base Screening Platform. React. Chem. Eng. 2017, 2, 446– 450, DOI: 10.1039/C7RE00057J2dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXotVeltbY%253D&md5=047f6284854c6e3d5a8f04feb9a387f6Selective functionalization of complex heterocycles via an automated strong base screening platformBoga, Sobhana Babu; Christensen, Melodie; Perrotto, Nicholas; Krska, Shane W.; Dreher, Spencer; Tudge, Matthew T.; Ashley, Eric R.; Poirier, Marc; Reibarkh, Mikhail; Liu, Yong; Streckfuss, Eric; Campeau, Louis-Charles; Ruck, Rebecca T.; Davies, Ian W.; Vachal, PetrReaction Chemistry & Engineering (2017), 2 (4), 446-450CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)Knochel-Hauser bases, derived from 2,2,6,6-tetramethylpiperidinyl (TMP) metal amides, offered exceptional selectivity and functional group tolerance in the regioselective metalation of arenes and heteroarenes. The selectivity, stability and yield of these reactions were highly dependent on the nature of the base, additive and deprotonation temp. An automated micro-scale high throughput experimentation (HTE) approach to rapidly optimize base and temp. matrixes was developed and validated. The application of this approach to the regioselective functionalization of a variety of complex heterocycles and extension to the prepn. of organometallic reagents for transition metal catalyzed cross-coupling screens was described.(e) Brocklehurst, C. E.; Gallou, F.; Hartwieg, C. D.; Palmieri, M.; Rufle, D. Microtiter Plate (MTP) Reaction Screening and Optimization of Surfactant Chemistry: Examples of Suzuki–Miyaura and Buchwald–Hartwig Cross-Couplings in Water. Org. Process Res. Dev. 2018, 22, 1453– 1457, DOI: 10.1021/acs.oprd.8b002002ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVaqtL7J&md5=89f171d501c5bf310fb4a22eb875a9ebMicrotiter Plate (MTP) Reaction Screening and Optimization of Surfactant Chemistry: Examples of Suzuki-Miyaura and Buchwald-Hartwig Cross-Couplings in WaterBrocklehurst, Cara E.; Gallou, Fabrice; Hartwieg, J. Constanze D.; Palmieri, Marco; Rufle, DominikOrganic Process Research & Development (2018), 22 (10), 1453-1457CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A screening method to evaluate Suzuki-Miyaura and Buchwald-Hartwig coupling reactions performed using aq. surfactant mixts. as solvents; plastic microtiter plates were used to perform optimization reactions on micromolar scales at 40-50°. In the reactions screened, Buchwald-Hartwig third generation precatalysts were effective as catalysts for both Suzuki-Miyaura and Buchwald-Hartwig coupling reactions in aq. surfactant mixts. - 3Schmink, J. R.; Bellomo, A.; Berritt, S. Scientist-Led High-Throughput Experimentation (HTE) and Its Utility in Academia and Industry. Aldrichimica Acta 2013, 46, 71– 803https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlCnu7vI&md5=c4742905de4898264eeaf02476850a49Scientist-led High-Throughput Experimentation (HTE) and its utility in academia and industrySchmink, Jason R.; Bellomo, Ana; Berritt, SimonAldrichimica Acta (2013), 46 (3), 71-80, 10 pp.CODEN: ALACBI; ISSN:0002-5100. (Aldrich Chemical Co.)High-Throughput Experimentation is emerging, in both the academic and industrial settings, as a powerful tool for developing new synthetic methodologies. This approach has the advantage of being highly transferable from one reaction type to another. The numerous variables assocd. with transition-metal-catalyzed methodol. development complement HTE techniques perfectly. This report highlights recent (2009-2013) advances in the application of HTE in synthetic org. chem.
- 4
For applications of HTE in academia, see:
(a) Troshin, K.; Hartwig, J. F. Snap Deconvolution: An Informatics Approach to High-Throughput Discovery of Catalytic Reactions. Science 2017, 357, 175– 181, DOI: 10.1126/science.aan15684ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFOjs7rL&md5=f9b731ac0d8b99c2d0fa6f716cdb67f1Snap deconvolution: An informatics approach to high-throughput discovery of catalytic reactionsTroshin, Konstantin; Hartwig, John F.Science (Washington, DC, United States) (2017), 357 (6347), 175-181CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)We present an approach to multidimensional high-throughput discovery of catalytic coupling reactions that integrates mol. design with automated anal. and interpretation of mass spectral data. We simultaneously assessed the reactivity of three pools of compds. that shared the same functional groups (halides, boronic acids, alkenes, and alkynes, among other groups) but carried inactive substituents having specifically designed differences in masses. The substituents were chosen such that the products from any class of reaction in multiple reaction sets would have unique differences in masses, thus allowing simultaneous identification of the products of all transformations in a set of reactants. In this way, we easily distinguished the products of new reactions from noise and known couplings. Using this method, we discovered an alkyne hydroallylation and a nickel-catalyzed variant of alkyne diarylation.(b) McNally, A.; Prier, C. K.; MacMillan, D. W. C. Discovery of an α-Amino C–H Arylation Reaction Using the Strategy of Accelerated Serendipity. Science 2011, 334, 1114– 1117, DOI: 10.1126/science.12139204bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsV2mu7vP&md5=0c174902b9784e817801f5015c21566dDiscovery of an α-Amino C-H Arylation Reaction Using the Strategy of Accelerated SerendipityMcNally, Andrew; Prier, Christopher K.; MacMillan, David W. C.Science (Washington, DC, United States) (2011), 334 (6059), 1114-1117CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Serendipity has long been a welcome yet elusive phenomenon in the advancement of chem. We sought to exploit serendipity as a means of rapidly identifying unanticipated chem. transformations. By using a high-throughput, automated workflow and evaluating a large no. of random reactions, we have discovered a photoredox-catalyzed C-H arylation reaction for the construction of benzylic amines, an important structural motif within pharmaceutical compds. that is not readily accessed via simple substrates. The mechanism directly couples tertiary amines with cyano aroms. by using mild and operationally trivial conditions. - 5
For an example of the application of HTE in a collaboration between academia and industry, see:
Shevlin, M.; Friedfeld, M. R.; Sheng, H.; Pierson, N. A.; Hoyt, J. M.; Campeau, L.-C.; Chirik, P. J. Nickel-Catalyzed Asymmetric Alkene Hydrogenation of α,β-Unsaturated Esters: High-Throughput Experimentation-Enabled Reaction Discovery, Optimization, and Mechanistic Elucidation. J. Am. Chem. Soc. 2016, 138, 3562– 3569, DOI: 10.1021/jacs.6b005195https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XislOntr8%253D&md5=0fa0f704a79b5d039ff8d83e9ecb8a42Nickel-Catalyzed Asymmetric Alkene Hydrogenation of α,β-Unsaturated Esters: High-Throughput Experimentation-Enabled Reaction Discovery, Optimization, and Mechanistic ElucidationShevlin, Michael; Friedfeld, Max R.; Sheng, Huaming; Pierson, Nicholas A.; Hoyt, Jordan M.; Campeau, Louis-Charles; Chirik, Paul J.Journal of the American Chemical Society (2016), 138 (10), 3562-3569CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A highly active and enantioselective phosphine-nickel catalyst for the asym. hydrogenation of α,β-unsatd. esters has been discovered. The coordination chem. and catalytic behavior of nickel halide, acetate, and mixed halide-acetate with chiral bidentate phosphines have been explored and deuterium labeling studies, the method of continuous variation, nonlinear studies, and kinetic measurements have provided mechanistic understanding. Activation of mol. hydrogen by a trimeric (Me-DuPhos)3Ni3(OAc)5I complex was established as turnover limiting followed by rapid conjugate addn. of a nickel hydride and nonselective protonation to release the substrate. In addn. to reaction discovery and optimization, the previously unreported utility high-throughput experimentation for mechanistic elucidation is also described. - 6Selekman, J. A.; Tran, K.; Xu, Z.; Dummeldinger, M.; Kiau, S.; Nolfo, J.; Janey, J. High-Throughput Extractions: A New Paradigm for Workup Optimization in Pharmaceutical Process Development. Org. Process Res. Dev. 2016, 20, 1728– 1737, DOI: 10.1021/acs.oprd.6b002256https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVSkurbM&md5=31c85035f303b59613a01263958110a7High-Throughput Extractions: A New Paradigm for Workup Optimization in Pharmaceutical Process DevelopmentSelekman, Joshua A.; Tran, Kristy; Xu, Zhongmin; Dummeldinger, Michael; Kiau, Susanne; Nolfo, Joseph; Janey, JacobOrganic Process Research & Development (2016), 20 (10), 1728-1737CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)In the pharmaceutical industry, high throughput (HT) technol. is well developed and routinely utilized in chem. process development for reaction optimization and isolations via crystn. However, fewer HT technologies have been employed in the development of workup procedures, bridging optimized reaction and isolations. Frequently, extensive workups involving numerous unit operations are required to remove reaction stream components such as impurities, solvent and catalyst prior to isolation. Herein, we describe a systematic yet flexible approach using designed experimentation, lab. automation, and parallel experimentation to quickly and efficiently optimize unit operations that are required post reaction to remove reaction stream components (e.g. impurities, metal catalysts, solvent). This novel high throughput extn. (HTEx) platform has shown potential to broadly impact development by faster and more robustly improving process greenness, process mass intensity (PMI), cycle time, and ease of operation.
- 7(a) Santanilla, A. B.; Regalado, E. L.; Pereira, T.; Shevlin, M.; Bateman, K.; Campeau, L.-C.; Schneeweis, J.; Berritt, S.; Shi, Z.-C.; Nantermet, P.; Liu, Y.; Helmy, R.; Welch, C. J.; Vachal, P.; Davies, I. W.; Cernak, T.; Dreher, S. D. Nanomole-Scale High-Throughput Chemistry for the Synthesis of Complex Molecules. Science 2015, 347, 49– 53, DOI: 10.1126/science.1259203There is no corresponding record for this reference.(b) Cernak, T.; Gesmundo, N. J.; Dykstra, K.; Yu, Y.; Wu, Z.; Shi, Z.-C.; Vachal, P.; Sperbeck, D.; He, S.; Murphy, B. A.; Sonatore, L.; Williams, S.; Madeira, M.; Verras, A.; Reiter, M.; Lee, C. H.; Cuff, J.; Sherer, E. C.; Kuethe, J.; Goble, S.; Perrotto, N.; Pinto, S.; Shen, D.-M.; Nargund, R.; Balkovec, J.; DeVita, R. J.; Dreher, S. D. Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinyl-1H-benzimidazole Diacylglycerol Acyltransferase 1 Inhibitors. J. Med. Chem. 2017, 60, 3594– 3605, DOI: 10.1021/acs.jmedchem.6b015437bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjsFKktrw%253D&md5=0ad43c076c3f9ea766c5f4c05b5b84a9Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinyl-1H-benzimidazole Diacylglycerol Acyltransferase 1 InhibitorsCernak, Tim; Gesmundo, Nathan J.; Dykstra, Kevin; Yu, Yang; Wu, Zhicai; Shi, Zhi-Cai; Vachal, Petr; Sperbeck, Donald; He, Shuwen; Murphy, Beth Ann; Sonatore, Lisa; Williams, Steven; Madeira, Maria; Verras, Andreas; Reiter, Maud; Lee, Claire Heechoon; Cuff, James; Sherer, Edward C.; Kuethe, Jeffrey; Goble, Stephen; Perrotto, Nicholas; Pinto, Shirly; Shen, Dong-Ming; Nargund, Ravi; Balkovec, James; DeVita, Robert J.; Dreher, Spencer D.Journal of Medicinal Chemistry (2017), 60 (9), 3594-3605CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chem. challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on ∼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging SNAr reaction. The availability of robust synthetic chem. conditions discovered in these miniaturized investigations enabled the development of structure-activity relationships that ultimately led to the discovery of sol., selective, and potent inhibitors of DGAT1.
- 8Sabatini, M. T.; Boulton, L. T.; Sheppard, T. D. Borate esters: Simple catalysts for the sustainable synthesis of complex amides. Sci. Adv. 2017, 3, e1701028, DOI: 10.1126/sciadv.17010288https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXls1Khur0%253D&md5=8c12cb2a64f45569123f0d1e419a1726Borate esters: Simple catalysts for the sustainable synthesis of complex amidesSabatini, Marco T.; Boulton, Lee T.; Sheppard, Tom D.Science Advances (2017), 3 (9), e1701028/1-e1701028/8CODEN: SACDAF; ISSN:2375-2548. (American Association for the Advancement of Science)Chem. reactions for the formation of amide bonds are among the most commonly used transformations in org. chem., yet they are often highly inefficient. A novel protocol for amidation using a simple borate ester catalyst is reported. The process presents significant improvements over other catalytic amidation methods in terms of efficiency and safety, with an unprecedented substrate scope including functionalized heterocycles and even unprotected amino acids. The method was used to access a wide range of functionalized amide derivs., including pharmaceutically relevant targets, important synthetic intermediates, a catalyst, and a natural product.
- 9Butters, M.; Catterick, D.; Craig, A.; Curzons, A.; Dale, D.; Gillmore, A.; Green, S. P.; Marziano, I.; Sherlock, J.-P.; White, W. Critical Assessment of Pharmaceutical Processes – A Rationale for Changing the Synthetic Route. Chem. Rev. 2006, 106, 3002– 3027, DOI: 10.1021/cr050982w9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XitVOjurY%253D&md5=9bfc73e0b64651b345d5231274084a81Critical Assessment of Pharmaceutical Processes-A Rationale for Changing the Synthetic RouteButters, Mike; Catterick, David; Craig, Andrew; Curzons, Alan; Dale, David; Gillmore, Adam; Green, Stuart P.; Marziano, Ivan; Sherlock, Jon-Paul; White, WesleyChemical Reviews (Washington, DC, United States) (2006), 106 (7), 3002-3027CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. The focus of this review is to identify and characterize criteria for rejecting a synthetic route and thus trigger the search for a viable alternative in pharmaceutical industry.
- 10Chirik, P.; Morris, R. Getting Down to Earth: The Renaissance of Catalysis with Abundant Metals. Acc. Chem. Res. 2015, 48, 2495– 2495, DOI: 10.1021/acs.accounts.5b0038510https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVKlsLrF&md5=72be4d92a8b18c0c99979d043c3a58b0Getting Down to Earth: The Renaissance of Catalysis with Abundant MetalsChirik, Paul; Morris, RobertAccounts of Chemical Research (2015), 48 (9), 2495CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)There is no expanded citation for this reference.
- 12(a) Darout, E.; McClure, K. F.; Piotrowski, D.; Raymer, B. CA 2907071 A1, 2016.There is no corresponding record for this reference.(b) McClure, K. F.; Piotrowski, D. W.; Petersen, D.; Wei, L.; Xiao, J.; Londregan, A. T.; Kamlet, A. S.; Dechert-Schmitt, A.-M.; Raymer, B.; Ruggeri, R. B.; Canterbury, D.; Limberakis, C.; Liras, S.; DaSilva-Jardine, P.; Dullea, R. G.; Loria, P. M.; Reidich, B.; Salatto, C. T.; Eng, H.; Kimoto, E.; Atkinson, K.; King-Ahmad, A.; Scott, D.; Beaumont, K.; Chabot, J. R.; Bolt, M. W.; Maresca, K.; Dahl, K.; Arakawa, R.; Takano, A.; Halldin, C. Liver-Targeted Small-Molecule Inhibitors of Proprotein Convertase Subtilisin/Kexin Type 9 Synthesis. Angew. Chem., Int. Ed. 2017, 56, 16218– 16222, DOI: 10.1002/anie.20170874412bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVKqtbjI&md5=42947e0019380b6056fec16b4f4c33c2Liver-Targeted Small-Molecule Inhibitors of Proprotein Convertase Subtilisin/Kexin Type 9 SynthesisMcClure, Kim F.; Piotrowski, David W.; Petersen, Donna; Wei, Liuqing; Xiao, Jun; Londregan, Allyn T.; Kamlet, Adam S.; Dechert-Schmitt, Anne-Marie; Raymer, Brian; Ruggeri, Roger B.; Canterbury, Daniel; Limberakis, Chris; Liras, Spiros; DaSilva-Jardine, Paul; Dullea, Robert G.; Loria, Paula M.; Reidich, Benjamin; Salatto, Christopher T.; Eng, Heather; Kimoto, Emi; Atkinson, Karen; King-Ahmad, Amanda; Scott, Dennis; Beaumont, Kevin; Chabot, Jeffrey R.; Bolt, Michael W.; Maresca, Kevin; Dahl, Kenneth; Arakawa, Ryosuke; Takano, Akihiro; Halldin, ChristerAngewandte Chemie, International Edition (2017), 56 (51), 16218-16222CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Targeting of the human ribosome is an unprecedented therapeutic modality with a genome-wide selectivity challenge. A liver-targeted drug candidate is described that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small mols. Key to the concept was the identification of pharmacol. active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesterase 1. The synthesis of select tetrazole prodrugs was crucial. A cell-free in vitro translation assay contg. human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. In vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomog. 18F-isotopologue validated our liver-targeting approach.
- 13(a) Bruno, N. C.; Buchwald, S. L. Synthesis and Application of Palladium Precatalysts that Accommodate Extremely Bulky Di-tert-butylphosphino Biaryl Ligands. Org. Lett. 2013, 15, 2876– 2879, DOI: 10.1021/ol401208t13ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnslWmsLo%253D&md5=665c7c1949a64a975ba2bc88b5358ac7Synthesis and Application of Palladium Precatalysts that Accommodate Extremely Bulky Di-tert-butylphosphino Biaryl LigandsBruno, Nicholas C.; Buchwald, Stephen L.Organic Letters (2013), 15 (11), 2876-2879CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A series of palladacyclic precatalysts, e.g. I (L = TBuBrettPhos), that incorporate electron-rich di-tert-butylphosphino biaryl ligands is reported. These precatalysts are easily prepd., and their use provides a general means of employing bulky ligands in palladium-catalyzed cross-coupling reactions. The application of these palladium sources to various C-N and C-O bond-forming processes is also described. E.g., in presence of I (L = TBuBrettPhos), arylation of PhCONH2 with 1-chloro-2,5-dimethoxybenzene gave 97% arylated amide (II).(b) Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Design and Preparation of New Palladium Precatalysts for C–C and C–N Cross-Coupling Reactions. Chem. Sci. 2013, 4, 916– 920, DOI: 10.1039/C2SC20903A13bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFKjtr0%253D&md5=5b50ac18cb67251e5439199c6746dba8Design and preparation of new palladium precatalysts for C-C and C-N cross-coupling reactionsBruno, Nicholas C.; Tudge, Matthew T.; Buchwald, Stephen L.Chemical Science (2013), 4 (3), 916-920CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)A series of easily prepd., phosphine-ligated palladium precatalysts based on the 2-aminobiphenyl scaffold have been prepd. The role of the precatalyst-assocd. labile halide (or pseudohalide) in the formation and stability of the palladacycle has been examd. It was found that replacing the chloride in the previous version of the precatalyst with a mesylate leads to a new class of precatalysts with improved soln. stability and that are readily prepd. from a wider range of phosphine ligands. The differences between the previous version of precatalyst and that reported here are explored. In addn., the reactivity of the latter is examd. in a range of C-C and C-N bond forming reactions.
- 14(a) https://matthey.com/products-and-services/pharmaceutical-and-medical/catalysts/phosphine-pi-allyl-catalyst-kit (accessed June 28, 2018).There is no corresponding record for this reference.(b) DeAngelis, A. J.; Gildner, P. G.; Chow, R.; Colacot, T. J. Generating Active “L-Pd(0)” via Neutral or Cationic π-Allylpalladium Complexes Featuring Biaryl/Bipyrazolylphosphines: Synthetic, Mechanistic, and Structure–Activity Studies in Challenging Cross-Coupling Reactions. J. Org. Chem. 2015, 80, 6794– 6813, DOI: 10.1021/acs.joc.5b0100514bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpsFaltb0%253D&md5=2ea299fdd0c2f08a3398d1cd7b5f29d2Generating Active "L-Pd(0)" via Neutral or Cationic π-Allylpalladium Complexes Featuring Biaryl/Bipyrazolylphosphines: Synthetic, Mechanistic, and Structure-Activity Studies in Challenging Cross-Coupling ReactionsDeAngelis, A. J.; Gildner, Peter G.; Chow, Ruishan; Colacot, Thomas J.Journal of Organic Chemistry (2015), 80 (13), 6794-6813CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Two new classes of highly active yet air- and moisture-stable π-R-allylpalladium complexes contg. bulky biaryl- and bipyrazolylphosphines with extremely broad ligand scope were developed. Neutral π-allylpalladium complexes incorporated a range of biaryl/bipyrazolylphosphine ligands, while extremely bulky ligands were accommodated by a cationic scaffold. These complexes are easily activated under mild conditions and are efficient for a wide array of challenging C-C and C-X (X = heteroatom) cross-coupling reactions. Their high activity is correlated to their facile activation to a 12-electron-based L-Pd(0) catalyst under commonly employed conditions for cross-coupling reactions, noninhibitory byproduct release upon activation, and suppression of the off-cycle pathway to form dinuclear (μ-allyl)(μ-Cl)Pd2(L)2 species, supported by structural (single crystal x-ray) and kinetic studies. A broad scope of C-C and C-X coupling reactions with low catalyst loadings and short reaction times highlight the versatility and practicality of these catalysts in org. synthesis.
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An electronic positive displacement repeater pipet is employed when the compound to be dispensed is in solution; if a slurry is obtained, the source is dispensed using a basic manual pipet one well at a time.
There is no corresponding record for this reference. - 16https://www.biodot.com (accessed May 19, 2018). However, the manufacturer has confirmed that this item has been discontinued and is no longer commercially available.There is no corresponding record for this reference.
- 17(a) Adamo, C.; Amatore, C.; Ciofini, I.; Jutand, A.; Lakmini, H. Mechanism of the Palladium-Catalyzed Homocoupling of Arylboronic Acids: Key Involvement of a Palladium Peroxo Complex. J. Am. Chem. Soc. 2006, 128, 6829– 6836, DOI: 10.1021/ja056995917ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xkt1Ogtrs%253D&md5=5c22a31342395f19be52a876eb414187Mechanism of the Palladium-Catalyzed Homocoupling of Arylboronic Acids: Key Involvement of a Palladium Peroxo ComplexAdamo, Carlo; Amatore, Christian; Ciofini, Ilaria; Jutand, Anny; Lakmini, HakimJournal of the American Chemical Society (2006), 128 (21), 6829-6836CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The mechanism of the palladium-catalyzed homocoupling of arylboronic acids ArB(OH)2 (Ar = 4-Z-C6H4 with Z = MeO, H, CN) in the presence of dioxygen, leading to sym. biaryls, has been fully elucidated. The peroxo complex (η2-O2)PdL2 (L = PPh3), generated in the reaction of dioxygen with the Pd(0) catalyst, was found to play a crucial role. Indeed, it reacts with the arylboronic acid to generate an adduct (coordination of one oxygen atom of the peroxo complex to the oxophilic boron atom of the arylboronic acid) characterized by 31P NMR spectroscopy and ab initio calcns. This adduct reacts with a second mol. of arylboronic acid to generate trans-ArPd(OH)L2 complexes. A transmetalation by the arylboronic acid gives trans-ArPdArL2 complexes. The biaryl is then released in a reductive elimination. This reaction is at the origin of the formation of biaryls as byproducts in palladium-catalyzed Suzuki-Miyaura reactions when they are not conducted under oxygen-free atm.(b) Kirai, N.; Yamamoto, Y. Homocoupling of Arylboronic Acids Catalyzed by 1,10-Phenanthroline-Ligated Copper Complexes in Air. Eur. J. Org. Chem. 2009, 2009, 1864– 1867, DOI: 10.1002/ejoc.200900173There is no corresponding record for this reference.
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The results from these studies will be included in a future article covering the complete synthesis of compound 1 on a large scale.
There is no corresponding record for this reference. - 19Wright, S. W.; Hageman, D. L.; McClure, L. D. Fluoride-Mediated Boronic Acid Coupling Reactions. J. Org. Chem. 1994, 59, 6095– 6097, DOI: 10.1021/jo00099a04919https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXmtlSntrk%253D&md5=32a4ec1c4d7ea069b5cf163b3caa2567Fluoride-Mediated Boronic Acid Coupling ReactionsWright, Stephen W.; Hageman, David L.; McClure, Lester D.Journal of Organic Chemistry (1994), 59 (20), 6095-7CODEN: JOCEAH; ISSN:0022-3263.Fluoride salts are effective in promoting boron to palladium transmetalation in the coupling of arylboronic and vinylboronic acids with aryl bromides and aryl triflates. The reactions may be carried out in a variety of aq., protic or aprotic media. The use of cesium fluoride in aprotic solvents is compatible with a variety of base- and nucleophile-sensitive functional groups. E.g., treating PhB(OH)2 with Me 4-bromophenylacetate in DME contg. 2 equiv CsF and 3 mol % Pd(PPh)4 gave 98% 4-PhC6H4CH2CO2Me.
- 20Akin, A.; Barrila, M. T.; Brandt, T. A.; Dechert-Schmitt, A.-M. R.; Dube, P.; Ford, D. D.; Kamlet, A. S.; Limberakis, C.; Pearsall, A.; Piotrowski, D. W.; Quinn, B.; Rothstein, S.; Salan, J.; Wei, L.; Xiao, J. A Scalable Route for the Regio- and Enantioselective Preparation of a Tetrazole Prodrug: Application to the Multi-Gram-Scale Synthesis of a PCSK9 Inhibitor. Org. Process Res. Dev. 2017, 21, 1990– 2000, DOI: 10.1021/acs.oprd.7b0030420https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslOnsL3K&md5=67b0f5f390214681d725d4859944fd81A Scalable Route for the Regio- and Enantioselective Preparation of a Tetrazole Prodrug: Application to the Multi-Gram-Scale Synthesis of a PCSK9 InhibitorAkin, Anne; Barrila, Mark T.; Brandt, Thomas A.; Dechert-Schmitt, Anne-Marie R.; Dube, Pascal; Ford, David D.; Kamlet, Adam S.; Limberakis, Chris; Pearsall, Andrew; Piotrowski, David W.; Quinn, Brian; Rothstein, Sarah; Salan, Jerry; Wei, Liuqing; Xiao, JunOrganic Process Research & Development (2017), 21 (12), 1990-2000CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The synthesis of multigram quantities of small mol. PCSK9 inhibitor (R,S)-I is described. The route features a safe, multikilogram method to prep. 5-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2H-tetrazole (II). A three-component dynamic kinetic resoln. between tetrazole II, acetaldehyde, and isobutyric anhydride was catalyzed by a chiral DMAP catalyst to afford enantiomerically enriched hemiaminal ester (S)-III on multikilogram scale. Magnesiation, transmetalation, and Negishi coupling provided access to Boc-intermediate (R,S)-IV, which was deprotected to provide (R,S)-I in multigram quantities.
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Ligand abbreviations: DCyPF, dicyclohexylphosphinoferrocene; dppf, diphenylphosphinoferrocene; Cy, cyclohexyl.
There is no corresponding record for this reference. - 22
1,4-Dioxane was not included in this screen due to its toxicity.
There is no corresponding record for this reference. - 23
For papers on the discovery of 11, see:
(a) Watterson, S. H.; De Lucca, G. V.; Shi, Q.; Langevine, C. M.; Liu, Q.; Batt, D. G.; Bertrand, M. B.; Gong, H.; Dai, J.; Yip, S.; Li, P.; Sun, D.; Wu, D.-R.; Wang, C.; Zhang, Y.; Traeger, S. C.; Pattoli, M. A.; Skala, S.; Cheng, L.; Obermeier, M. T.; Vickery, R.; Discenza, L. N.; D’Arienzo, C. J.; Zhang, Y.; Heimrich, E.; Gillooly, K. M.; Taylor, T. L.; Pulicicchio, C.; McIntyre, K. W.; Galella, M. A.; Tebben, A. J.; Muckelbauer, J. K.; Chang, C.; Rampulla, R.; Mathur, A.; Salter-Cid, L.; Barrish, J. C.; Carter, P. H.; Fura, A.; Burke, J. R.; Tino, J. A. Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton’s Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers. J. Med. Chem. 2016, 59, 9173– 9200, DOI: 10.1021/acs.jmedchem.6b0108823ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVKjsrfF&md5=91098abc802521b9ad91563d20ac5893Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton's Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked AtropisomersWatterson, Scott H.; De Lucca, George V.; Shi, Qing; Langevine, Charles M.; Liu, Qingjie; Batt, Douglas G.; Beaudoin Bertrand, Myra; Gong, Hua; Dai, Jun; Yip, Shiuhang; Li, Peng; Sun, Dawn; Wu, Dauh-Rurng; Wang, Chunlei; Zhang, Yingru; Traeger, Sarah C.; Pattoli, Mark A.; Skala, Stacey; Cheng, Lihong; Obermeier, Mary T.; Vickery, Rodney; Discenza, Lorell N.; D'Arienzo, Celia J.; Zhang, Yifan; Heimrich, Elizabeth; Gillooly, Kathleen M.; Taylor, Tracy L.; Pulicicchio, Claudine; McIntyre, Kim W.; Galella, Michael A.; Tebben, Andy J.; Muckelbauer, Jodi K.; Chang, ChiehYing; Rampulla, Richard; Mathur, Arvind; Salter-Cid, Luisa; Barrish, Joel C.; Carter, Percy H.; Fura, Aberra; Burke, James R.; Tino, Joseph A.Journal of Medicinal Chemistry (2016), 59 (19), 9173-9200CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiol. of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clin. treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a redn. in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clin. studies.(b) De Lucca, G. V.; Shi, Q.; Liu, Q.; Batt, D. G.; Bertrand, M. B.; Rampulla, R.; Mathur, A.; Discenza, L.; D’Arienzo, C.; Dai, J.; Obermeier, M.; Vickery, R.; Zhang, Y.; Yang, Z.; Marathe, P.; Tebben, A. J.; Muckelbauer, J. K.; Chang, C. J.; Zhang, H.; Gillooly, K.; Taylor, T.; Pattoli, M. A.; Skala, S.; Kukral, D. W.; McIntyre, K. W.; Salter-Cid, L.; Fura, A.; Burke, J. R.; Barrish, J. C.; Carter, P. H.; Tino, J. A. Small Molecule Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK): Structure–Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide (BMS-935177). J. Med. Chem. 2016, 59, 7915– 7935, DOI: 10.1021/acs.jmedchem.6b0072223bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlCrsL3M&md5=7c7ec1a52121c541753c045c1cbf758bSmall Molecule Reversible Inhibitors of Bruton's Tyrosine Kinase (BTK): Structure-Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide (BMS-935177)De Lucca, George V.; Shi, Qing; Liu, Qingjie; Batt, Douglas G.; Beaudoin Bertrand, Myra; Rampulla, Rick; Mathur, Arvind; Discenza, Lorell; D'Arienzo, Celia; Dai, Jun; Obermeier, Mary; Vickery, Rodney; Zhang, Yingru; Yang, Zheng; Marathe, Punit; Tebben, Andrew J.; Muckelbauer, Jodi K.; Chang, ChiehYing J.; Zhang, Huiping; Gillooly, Kathleen; Taylor, Tracy; Pattoli, Mark A.; Skala, Stacey; Kukral, Daniel W.; McIntyre, Kim W.; Salter-Cid, Luisa; Fura, Aberra; Burke, James R.; Barrish, Joel C.; Carter, Percy H.; Tino, Joseph A.Journal of Medicinal Chemistry (2016), 59 (17), 7915-7935CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bruton's tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a crit. role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure-activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clin. development. - 24Garber, K. Principia Biopharma. Nat. Biotechnol. 2013, 31, 377, DOI: 10.1038/nbt0513-37724https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntF2qtrc%253D&md5=75d9a15a69967849f1137126f74f4f44Principia BiopharmaGarber, KenNature Biotechnology (2013), 31 (5), 377CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)A University of California, San Francisco, startup offers a reversible twist on covalent drugs.
- 25
For the commercial synthesis of BMS-986142, see:
Beutner, G.; Carrasquillo, R.; Geng, P.; Hsiao, Y.; Huang, E. C.; Janey, J.; Katipally, K.; Kolotuchin, S.; La Porte, T.; Lee, A.; Lobben, P.; Lora-Gonzalez, F.; Mack, B.; Mudryk, B.; Qiu, Y.; Qian, X.; Ramirez, A.; Razler, T. M.; Rosner, T.; Shi, Z.; Simmons, E.; Stevens, J.; Wang, J.; Wei, C.; Wisniewski, S. R.; Zhu, Y. Adventures in Atropisomerism: Total Synthesis of a Complex Active Pharmaceutical Ingredient with Two Chirality Axes. Org. Lett. 2018, 20, 3736– 3740, DOI: 10.1021/acs.orglett.8b0121825https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFeltrbE&md5=ab925c9f4992d77915b18d3140e28948Adventures in Atropisomerism: Total Synthesis of a Complex Active Pharmaceutical Ingredient with Two Chirality AxesBeutner, Gregory; Carrasquillo, Ronald; Geng, Peng; Hsiao, Yi; Huang, Eric C.; Janey, Jacob; Katipally, Kishta; Kolotuchin, Sergei; La Porte, Thomas; Lee, Andrew; Lobben, Paul; Lora-Gonzalez, Federico; Mack, Brendan; Mudryk, Boguslaw; Qiu, Yuping; Qian, Xinhua; Ramirez, Antonio; Razler, Thomas M.; Rosner, Thorsten; Shi, Zhongping; Simmons, Eric; Stevens, Jason; Wang, Jianji; Wei, Carolyn; Wisniewski, Steven R.; Zhu, YeOrganic Letters (2018), 20 (13), 3736-3740CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A strategy to prep. compds. with multiple chirality axes, which has led to a concise total synthesis of compd. I with complete stereocontrol, is reported. - 26
For a recent reference regarding the preparation of aryldiazonium salts, see:
Oger, N.; Le Grognec, E.; Felpin, F.-X. Handling Diazonium Salts in Flow for Organic and Material Chemistry. Org. Chem. Front. 2015, 2, 590– 614, DOI: 10.1039/C5QO00037H26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXksFWmsr4%253D&md5=5ddf50967098bf22ace7503011c9200eHandling diazonium salts in flow for organic and material chemistryOger, Nicolas; Le Grognec, Erwan; Felpin, Francois-XavierOrganic Chemistry Frontiers (2015), 2 (5), 590-614CODEN: OCFRA8; ISSN:2052-4129. (Royal Society of Chemistry)This review gives an overview of transformations involving the use of diazonium salts in flow. The efficiency of the strategies is critically discussed with a special emphasis on the design of the flow devices. If comparative studies with batch chem. is provided, the input of flow chem. with regard to the reaction yields and safety issues is discussed as well. - 27(a) Hamilton, P.; Sanganee, M. J.; Graham, J. P.; Hartwig, T.; Ironmonger, A.; Priestley, C.; Senior, L. A.; Thompson, D. R.; Webb, M. R. Using PAT to Understand, Control, and Rapidly Scale Up the Production of a Hydrogenation Reaction and Isolation of Pharmaceutical Intermediate. Org. Process Res. Dev. 2015, 19, 236– 243, DOI: 10.1021/op500285x27ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVegu7rI&md5=fa3d5dfa3c071f8d208fca0098a7f645Using PAT To Understand, Control, and Rapidly Scale Up the Production of a Hydrogenation Reaction and Isolation of Pharmaceutical IntermediateHamilton, Peter; Sanganee, Mahesh Jayantilal; Graham, Jonathan P.; Hartwig, Thoralf; Ironmonger, Alan; Priestley, Catherine; Senior, Lesley A.; Thompson, Duncan R.; Webb, Michael R.Organic Process Research & Development (2015), 19 (1), 236-243CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The development of a hydrogenation process and subsequent isolation for an intermediate in the manuf. of an active pharmaceutical ingredient is described. In-line process anal. technol. (PAT) approaches were applied to gain process understanding and control. First, a calibration-free, qual., scale-independent approach using in situ mid-IR (MIR) spectrometry to det. the end point of a hydrogenation reaction in real time is described. A curve-fitting algorithm was developed using MATLAB software to allow the reaction rate to be calcd. at any given time during the reaction on the basis of the consumption of an intermediate species. The algorithm, coupled with understanding of the process, allowed the end point to be correctly identified in triplicate during scale-up of the process from 0.2-20 L scale. Second, a quant. partial least-squares (PLS) regression model was developed using near-IR (NIR) spectrometry to det. the solvent compn. during the subsequent const.-vol. distn. process prior to the crystn. of the hydrogenated product. Here the application of in-line NIR spectroscopy allowed the correct crystn. seed point to be detd., enhancing the control of quality and manufacturability.(b) Leitch, D. C.; Greene, T. F.; O’Keeffe, R. O.; Lovelace, T. C.; Powers, J. D.; Searle, A. D. A Combined High-Throughput Screening and Reaction Profiling Approach toward Development of a Tandem Catalytic Hydrogenation for the Synthesis of Salbutamol. Org. Process Res. Dev. 2017, 21, 1806– 1814, DOI: 10.1021/acs.oprd.7b0026127bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1yhtrrM&md5=e50f0dab8b02253e35611acfd0879049A Combined High-Throughput Screening and Reaction Profiling Approach toward Development of a Tandem Catalytic Hydrogenation for the Synthesis of SalbutamolLeitch, David C.; Greene, Thomas F.; O'Keeffe, Roisin; Lovelace, Thomas C.; Powers, Jeremiah D.; Searle, Andrew D.Organic Process Research & Development (2017), 21 (11), 1806-1814CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A combined high-throughput screening and reaction profiling approach to the telescoping of two redns. in the synthesis of Salbutamol is described. Optimization studies revealed the beneficial effect of mildly acidic conditions, and the use of water as a cosolvent. Persistent formation of deoxygenated impurities using a Pd/C catalyst led to the initiation of reaction profiling studies, which revealed that the ketone intermediate formed after rapid debenzylation is the sole source of deoxygenated impurities, indicating that more rapid ketone hydrogenation should minimize this deoxygenation. A dual catalyst approach based on these insights has been developed, with both Pd/Pt and Ru/Pt catalyst systems as more selective than Pd-only systems. Based on reaction profiles that indicate the deoxygenation side reaction is first-order in the concn. of debenzylated ketone intermediate, Pt catalysts for rapid and selective ketone hydrogenation were paired with Pd and Ru catalysts known to perform selective debenzylation. Optimization of these dual catalyst processes led to conditions that were demonstrated on 20 g scale to prep. Salbutamol in 49% isolated yield after recrystn.
- 28(a) Boros, E. E.; Burova, S. A.; Erickson, G. A.; Johns, B. A.; Koble, C. S.; Kurose, N.; Sharp, M. J.; Tabet, E. A.; Thompson, J. B.; Toczko, M. A. A Scaleable Synthesis of Methyl 3-Amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate. Org. Process Res. Dev. 2007, 11, 899– 902, DOI: 10.1021/op700132628ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpvVaksLY%253D&md5=50bb690cf065a568e1eb9bb54a71e75cA Scalable Synthesis of Methyl 3-Amino-5-(4-fluorobenzyl)-2-pyridinecarboxylateBoros, Eric E.; Burova, Svetlana A.; Erickson, Greg A.; Johns, Brian A.; Koble, Cecilia S.; Kurose, Noriyuki; Sharp, Matthew J.; Tabet, Elie A.; Thompson, James B.; Toczko, Matthew A.Organic Process Research & Development (2007), 11 (5), 899-902CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A scalable synthesis of Me 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (I, R = Me), starting from 5-bromo-2-methoxypyridine and 4-fluorobenzaldehyde, is described. Key steps in the process include lithium-bromine exchange of 5-bromo-2-methoxypyridine, addn. of the resulting lithiate to 4-fluorobenzaldehyde, regioselective nitration of pyridone II, and Pd-catalyzed alkoxycarbonylation of bromopyridine III. Overall yield of the five-stage synthesis was 23%; intermediates and final product I·HCl were isolated as filterable solids. Compds. I (R = Me, Et) are important intermediates in the synthesis of 7-benzylnaphthyridinones and related HIV-1 integrase inhibitors.(b) Crump, B. R.; Goss, C.; Lovelace, T.; Lewis, R.; Peterson, J. Influence of Reaction Parameters on the First Principles Reaction Rate Modeling of a Platinum and Vanadium Catalyzed Nitro Reduction. Org. Process Res. Dev. 2013, 17, 1277– 1286, DOI: 10.1021/op400116k28bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVSitL%252FO&md5=c900de4b5ab4231bde21024ef5203b2bInfluence of Reaction Parameters on the First Principles Reaction Rate Modeling of a Platinum and Vanadium Catalyzed Nitro ReductionCrump, Brian R.; Goss, Charles; Lovelace, Tom; Lewis, Rick; Peterson, JohnOrganic Process Research & Development (2013), 17 (10), 1277-1286CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)This paper describes the influence of key reaction parameters on the development of a rate model which can be used to forecast starting material conversion independent of scale. A nitro redn. was examd. via first principles reaction progress modeling. The reaction parameters, most notably hydrogen partial pressure and agitation rate, influenced the choice of rate model. At lower hydrogen partial pressures, the reaction rate was influenced by gas to liq. mass transfer, hydrogen pore diffusion, and the rate of the surface reaction during the overall reaction. No single model could be generated to explain the rate observations at lower hydrogen partial pressures. At higher hydrogen partial pressures, a kinetic reaction model was used to generate an equation to forecast the substrate concn. as a function of time and reaction parameters. This reaction model is independent of scale provided that the mass transfer coeff. exceeded a min. threshold value. The model can be used to set an appropriate design space for key reaction parameters and negates the need to validate the design space at scale.(c) Bowman, R. K.; Bullock, K. M.; Copley, R. C. B.; Deschamps, N. M.; McClure, M. S.; Powers, J. D.; Wolters, A. M.; Wu, Lianming; Xie, S. Conversion of a Benzofuran Ester to an Amide through an Enamine Lactone Pathway: Synthesis of HCV Polymerase Inhibitor GSK852A. J. Org. Chem. 2015, 80, 9610– 9619, DOI: 10.1021/acs.joc.5b0159828chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVygsr%252FJ&md5=1d9aad81e54f3030ccaa5d9deca7a56dConversion of a Benzofuran Ester to an Amide through an Enamine Lactone Pathway: Synthesis of HCV Polymerase Inhibitor GSK852ABowman, Roy K.; Bullock, Kae M.; Copley, Royston C. B.; Deschamps, Nicole M.; McClure, Michael S.; Powers, Jeremiah D.; Wolters, Andy M.; Wu, Lianming; Xie, ShipingJournal of Organic Chemistry (2015), 80 (19), 9610-9619CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)HCV NS5B polymerase inhibitor GSK852A (IV) was synthesized in only five steps from Et 4-fluorobenzoylacetate in 46% overall yield. Key to the efficient route was the synthesis of the highly functionalized benzofuran core I (X = Br) from the β-keto ester in one pot and the efficient conversion of ester I (X = c-Pr) to amide II via enamine lactone III. Serendipitous events led to identification of the isolable enamine lactone intermediate III. Single crystal X-ray diffraction and NMR studies supported the intramol. hydrogen bond in enamine lactone III. The hydrogen bond was considered an enabler in the proposed pathway from ester 6 to enamine lactone III and its rearrangement to amide II. GSK852A (IV) was obtained after reductive amination and mesylation with conditions amenable to the presence of the boronic acid moiety which was considered important for the desirable pharmacokinetics of IV. The overall yield of 46% in five steps was a significant improvement to the previous synthesis from the same β-keto ester in 5% yield over 13 steps.
- 29Hazlet, S. E.; Dornfeld, C. A. The Reduction of Aromatic Nitro Compounds with Activated Iron. J. Am. Chem. Soc. 1944, 66, 1781– 1782, DOI: 10.1021/ja01238a04929https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaH2MXhslKi&md5=791c8b8fad14b32e9781b4634151f77eReduction of aromatic nitro compounds with activated FeHazlet, Stewart E.; Dornfeld, Clinton A.Journal of the American Chemical Society (1944), 66 (), 1781-2CODEN: JACSAT; ISSN:0002-7863.Activated Fe was prepd. by adding 10 ml. concd. HCl to 50 g. 40-mesh granulated Fe. Reduction was carried out by adding the Fe to 5 g. of the NO2 compds. in 200 ml. C6H6 on the water bath, refluxing 0.5 hr., adding 1 ml. H2O and refluxing 7 hrs., during which 20 ml. of H2O were added. The amines were isolated as the HCl salts or as the free base. The yields (%) of amines were: PhNO2 82, o- and p-O2NC6H4Me 61 and 91, 4-O2NC6H4Ph 93, 1-C10H7NO2 96, o-ClC6H4NO2 92, o-BrC6H4NO2 97, 2,4-Cl(O2N)C6H3Me 89, o-, m- and p-O2NC6H4NH2 33, 32 and 14, 6,2-O2NC10H6NH2 28, o- and p-O2NC6H4OH 28, small, p-O2NC6H4OAc 9, p-O2NC6H4CO2Bu 72; p-O2NC6H4O3SPh gives 90% of p-aminophenyl benzenesulfonate, m. 100-1°.
- 30(a) Kadam, H. K.; Tilve, S. G. Advancement in methodologies for reduction of nitroarenes. RSC Adv. 2015, 5, 83391– 83407, DOI: 10.1039/C5RA10076C30ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFWhurfF&md5=a91364ff6d1faf7eda190af93f4b75dbAdvancement in methodologies for reduction of nitroarenesKadam, Hari K.; Tilve, Santosh G.RSC Advances (2015), 5 (101), 83391-83407CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)The importance of aryl amines as raw materials for various applications has spurred extensive research in developing economic processes for the redn. of nitroarenes. Developing green methodologies is now a compelling discipline for synthetic org. chemists. The recent surge in nanochem. has led to the development of some interesting applications in nitro redn. processes. This review discusses some recent examples of reports in this field. The different methods are classified based on the source of hydrogen utilized during redn. and the mechanism involved in the redn. process.(b) Loos, P.; Alex, H.; Hassfeld, J.; Lovis, K.; Platzek, J.; Steinfeldt, N.; Hübner, S. Selective Hydrogenation of Halogenated Nitroaromatics to Haloanilines in Batch and Flow. Org. Process Res. Dev. 2016, 20, 452– 464, DOI: 10.1021/acs.oprd.5b0017030bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1Gnu77F&md5=c4f0af965f12364c3c37b3d2e3f4400dSelective Hydrogenation of Halogenated Nitroaromatics to Haloanilines in Batch and FlowLoos, Patrick; Alex, Hannes; Hassfeld, Jorma; Lovis, Kai; Platzek, Johannes; Steinfeldt, Norbert; Huebner, SandraOrganic Process Research & Development (2016), 20 (2), 452-464CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The selective hydrogenation of functionalized nitroaroms. poses a major challenge from both academic as well as industrial viewpoints. As part of the CHEM21 initiative (www.chem21.eu), we are interested in highly selective, catalytic hydrogenations of halogenated nitroaroms. Initially, the catalytic redn. of 1-iodo-4-nitrobenzene to 4-iodoaniline served as a model system to investigate com. heterogeneous catalysts. After detg. optimal hydrogenation conditions and profiling performances of the best catalysts, hydrogenations were transferred from batch to continuous flow. Finally, the optimized flow conditions were applied to transformations which represent important steps in the syntheses of the active pharmaceutical ingredients clofazimine and vismodegib.
- 31(a) Nishimura, S.. Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis; Wiley: New York, 2001.There is no corresponding record for this reference.
- 32Orlandi, M.; Brenna, D.; Harms, R.; Jost, S.; Benaglia, M. Recent Developments in the Reduction of Aromatic and Aliphatic Nitro Compounds to Amines. Org. Process Res. Dev. 2018, 22, 430– 445, DOI: 10.1021/acs.oprd.6b0020532https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1SktLjI&md5=d3d977219544e37be5dd25aa35385b06Recent Developments in the Reduction of Aromatic and Aliphatic Nitro Compounds to AminesOrlandi, Manuel; Brenna, Davide; Harms, Reentje; Jost, Sonja; Benaglia, MaurizioOrganic Process Research & Development (2018), 22 (4), 430-445CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A review. The redn. of the nitro group represents a powerful and widely used transformation that allows to introducing an amino group in the mol. New synthetic strategies for complex functionalized mol. architectures are deeply needed, including highly efficient and selective nitro redn. methods, tolerant of a diverse array of functional moieties and protecting groups. Since chiral amino groups are ubiquitous in a variety of bioactive mols. such as alkaloids, natural products, drugs and medical agents, the development of reliable catalytic methodologies for the nitro group redn. is attracting an increasing interest also in the prepn. of enantiomerically pure amines. In this context, the modern redn. methods should be chemoselective and respectful of the stereochem. integrity of the stereogenic elements of the mol. The review will offer an overview of the different possible methodologies available for this fundamental transformation, with a special attention on the most recent contributions in the field: hydrogenations, metal dissolving and hydride transfer redns., catalytic transfer hydrogenations and metal-free redns. The main advantages or limitations for the proposed methods will be briefly discussed, highlighting in some cases the most important features of the presented redn. methodologies from an industrial point of view.
- 33Blaser, H.-U.; Steiner, H.; Studer, M. Selective Catalytic Hydrogenation of Functionalized Nitroarenes: An Update. ChemCatChem 2009, 1, 210– 221, DOI: 10.1002/cctc.20090012933https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1amt7nM&md5=1044185cf70d0c5bd48031a26a62c437Selective Catalytic Hydrogenation of Functionalized Nitroarenes: An UpdateBlaser, Hans-Ulrich; Steiner, Heinz; Studer, MartinChemCatChem (2009), 1 (2), 210-221CODEN: CHEMK3; ISSN:1867-3880. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Progress made in the last decade for the selective catalytic hydrogenation of nitroarenes in the presence of other reducible functions is reviewed. The main focus is on catalytic systems capable of reducing nitro groups with very high chemoselectivity in substrates contg. carbon-carbon or carbon-nitrogen double or triple bonds, carbonyl or benzyl groups, and multiple Cl, Br, or I substituents. The performance of new catalyst types is described, most notably of gold-based catalysts, but also of modified classical Pt, Pd, and Ni catalysts, as well as homogeneous catalysts. The best results for the various chemoselectivity problems are compiled and assessed with regard to their versatility and synthetic viability. In addn., progress in understanding mechanistic aspects are briefly described.
- 34Kasparian, A. J.; Savarin, C.; Allgeier, A. M.; Walker, S. D. Selective Catalytic Hydrogenation of Nitro Groups in the Presence of Activated Heteroaryl Halides. J. Org. Chem. 2011, 76, 9841– 9844, DOI: 10.1021/jo201566434https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht12jsb7J&md5=71ffb05ba937463faa12e5fb39efcc19Selective catalytic hydrogenation of nitro groups in the presence of activated heteroaryl halidesKasparian, Annie J.; Savarin, Cecile; Allgeier, Alan M.; Walker, Shawn D.Journal of Organic Chemistry (2011), 76 (23), 9841-9844CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Chemoselective redn. of nitro groups in the presence of activated heteroaryl halides was achieved via catalytic hydrogenation with a com. available sulfided platinum catalyst. The optimized conditions employ low temp., pressure, and catalyst loading (<0.1 mol % Pt) to afford heteroarom. amines with minimal hydrodehalogenation byproducts.
- 35(a) Haber, F. Gradual electrolytic reduction of nitrobenzene with limited cathode potential. Z. Elektrochem. Angew. Phys. Chem. 1898, 4, 506, DOI: 10.1002/bbpc.1898004220435ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaD28XltFWmsQ%253D%253D&md5=d7e497a060e89cd7dc71c2b7ee57d6d2On successive reductions of nitrobenzene under definite potential differencesHaber, F.Zeitschrift fuer Elektrochemie und Angewandte Physikalische Chemie (1898), 4 (), 506CODEN: ZEAPAA ISSN:.The author considers that oxidation and reduction processes depend chiefly on the potential difference between the solution and the electrode at which the reaction takes place. A platinum electrode in a solution consisting of 25 g nitrobenzene, 40 g sodium hydroxid, 50 g water and 350 g alcohol gave a value of 0.72 volt against a decinormal calomel electrode. If polarized until bubbles of hydrogen appeared the value rose to 1.29 volts. In the first experiment the current density was regulated so that the potential difference between the platinum electrode and the decinormal calomel electrode never exceeded 0.93 volt. The reaction products consisted almost exclusively of azoxybenzene, only traces of azobenzene, hydrazobenzene and anilin being present. Special experiments showed that the anilin was not formed by reduction of the hydrazobenzene. It appears that the primary reduction product is nitrosobenzene, C6H5NO, then β-phenylhydroxylamin. For the most part these two react, as observed by Bamberger, forming azoxybenzene; a small portion of the β-phenylhydroxylamin is however reduced to anilin. The hydrazobenzene comes from the partial reduction of the azoxybenzene, while the cause for the appearance of the azobenzene has not been worked out. In acid solutions the main products are azoxybenzene, p-amidophenol, p-phenetidin, benzidin and anilin. The first two stages are the same as in the alkaline reduction, nitrosobenzene and then phenylhydroxylamin. The two substances do not react rapidly in acid solution and therefore there is not so much azoxybenzene formed as in alkaline solutions. On the other hand in acid solutions β-phenylhydroxylamin changes readily to p-amidophenol and to p-phenetidin, while the hydrazobenzene formed from the azoxybenzene changes to benzidin. To show the formation of β-phenylhydroxylamin the author reduced nitrobenzene in aqueous acetic acid, with a high current density.(b) Corma, A.; Concepcion, P.; Serna, P. A Different Reaction Pathway for the Reduction of Aromatic Nitro Compounds on Gold Catalysts. Angew. Chem., Int. Ed. 2007, 46, 7266– 7269, DOI: 10.1002/anie.20070082335bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFCqtr3M&md5=f8ca1d821c8f4f581d9c2cc9954db44eA different reaction pathway for the reduction of aromatic nitro compounds on gold catalystsCorma, Avelino; Concepcion, Patricia; Serna, PedroAngewandte Chemie, International Edition (2007), 46 (38), 7266-7269CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)With an Au/TiO2 catalyst, the formation of condensation products during the hydrogenation of arom. nitro compds. is avoided. Macrokinetic expts. and in situ IR measurements, which showed that nitrosobenzene is generated in only small amts. and that hydroxylamine and nitrosobenzene interact strongly with the catalyst surface, led to the proposal of a novel reaction sequence.
- 36May, P. C.; Willis, B. A.; Lowe, S. L.; Dean, R. A.; Monk, S. A.; Cocke, P. J.; Audia, J. E.; Boggs, L. N.; Borders, A. R.; Brier, R. A.; Calligaro, D. O.; Day, T. A.; Ereshefsky, L.; Erickson, J. A.; Gevorkyan, H.; Gonzales, C. R.; James, D. E.; Jhee, S.; Komjathy, S. F.; Li, L.; Lindstrom, T. D.; Mathes, B. M.; Martényi, F.; Sheehan, S. M.; Stout, S. L.; Timm, D. E.; Vaught, G. M.; Watson, B. M.; Winneroski, L. L.; Yang, Z.; Mergott, D. J. The Potent BACE1 Inhibitor LY2886721 Elicits Robust Central Aβ Pharmacodynamic Responses in Mice, Dogs, and Humans. J. Neurosci. 2015, 35, 1199– 1210, DOI: 10.1523/JNEUROSCI.4129-14.201536https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXit1Oit78%253D&md5=7e16cc00767a8af4da7dd17b6e40e8f5The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humansMay, Patrick C.; Willis, Brian A.; Lowe, Stephen L.; Dean, Robert A.; Monk, Scott A.; Cocke, Patrick J.; Audia, James E.; Boggs, Leonard N.; Borders, Anthony R.; Brier, Richard A.; Calligaro, David O.; Day, Theresa A.; Ereshefsky, Larry; Erickso, Jon A.; Gevorkyan, Hykop; Gonzales, Celedon R.; James, Douglas E.; Jhee, Stanford S.; Komjathy, Steven F.; Li, Linglin; Lindstrom, Terry D.; Mathe, Brian M.; Martenyi, Ferenc; Sheehan, Scott M.; Stout, Stephanie L.; Timm, David E.; Vaught, Grant M.; Watson, Brian M.; Winneroski, Leonard L.; Yang, Zhixiang; Mergott, Dustin J.Journal of Neuroscience (2015), 35 (3), 1199-1210, 12 pp.CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclin. and early clin. development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clin. trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid β lowering in nonclin. animal models. Similar potent and persistent amyloid β lowering was obsd. in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.
- 37Mergott, D. J.; Green, S. J.; Shi, Y.; Watson, B. M.; Leonard, L. L.; Hembre, E. J. US Patent 20140371212, 2014.There is no corresponding record for this reference.
- 38(a) Kolis, S. P.; Hansen, M. M.; Arslantas, E.; Brändli, L.; Buser, J.; DeBaillie, A. C.; Frederick, A. L.; Hoard, D. W.; Hollister, A.; Huber, D.; Kull, T.; Linder, R. J.; Martin, T. J.; Richey, R. N.; Stutz, A.; Waibel, M.; Ward, J. A.; Zamfir, A. Synthesis of BACE Inhibitor LY2886721. Part I. An Asymmetric Nitrone Cycloaddition Strategy. Org. Process Res. Dev. 2015, 19, 1203– 1213, DOI: 10.1021/op500351q38ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVKit7nI&md5=6b3d37701117c1b5b5efe381d6d27939Synthesis of BACE Inhibitor LY2886721. Part I. An Asymmetric Nitrone Cycloaddition StrategyKolis, Stanley P.; Hansen, Marvin M.; Arslantas, Enver; Brandli, Lukas; Buser, Jonas; DeBaillie, Amy C.; Frederick, Andrea L.; Hoard, David W.; Hollister, Adrienne; Huber, Dominique; Kull, Thomas; Linder, Ryan J.; Martin, Thomas J.; Richey, Rachel N.; Stutz, Alfred; Waibel, Michael; Ward, Jeffrey A.; Zamfir, AlexandruOrganic Process Research & Development (2015), 19 (9), 1203-1213CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A scalable, asym. synthesis of (3aS,6aS)-6a-(5-bromo-2-fluorophenyl)-1-((R)-1-phenylpropyl)tetrahydro-1H,3H-furo[3,4-c]isoxazole, I, a key intermediate in the synthesis of LY2886721, is reported. Highlights of the synthesis include the development of an asym. [3 + 2] intramol. cycloaddn. facilitated by trifluoroethanol, and the development of a new synthesis of (R)-N-(1-phenylpropyl)hydroxylamine tosylate which proceeds through a p-anisaldehyde imine and avoids the formation of toxic hydrogen cyanide gas as a byproduct. The synthesis proceeds over four steps and provides the product in 36% overall yield.(b) Zaborenko, N.; Linder, R. J.; Braden, T. M.; Campbell, B. M.; Hansen, M. M.; Johnson, M. D. Org. Process Res. Dev. 2015, 19, 1231– 1243, DOI: 10.1021/op500317738bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlOjurvL&md5=0d0aab2b52ed037f943326ecd46c835cDevelopment of Pilot-Scale Continuous Production of an LY2886721 Starting Material by Packed-Bed HydrogenolysisZaborenko, Nikolay; Linder, Ryan J.; Braden, Timothy M.; Campbell, Bradley M.; Hansen, Marvin M.; Johnson, Martin D.Organic Process Research & Development (2015), 19 (9), 1231-1243CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The design, development, and implementation of a pilot-scale continuous hydrogenolysis in a catalytic packed bed to generate a starting material is described. Control of a crit. defluorination impurity under the reaction conditions was achieved by reducing residence time inside the catalyst bed to 15-30 min. A reactor vol. throughput of 206 kg/h·m3 was attained in a 3 L reactor (1.5 kg of 5% Pd/C catalyst) over a 9 h demonstration period, superior to the 1.3 kg/h·m3 vol. throughput obtained in batch. The reaction was successfully scaled up from 9 g/h to 550 g/h in packed beds ranging from 20 to 1500 g catalyst, demonstrating heat/mass transfer sufficiency at all examd. scales. The process was monitored by online HPLC, providing real-time reaction information, using an internally developed automation cart coupled to a std. HPLC. Significant tech. and business drivers for running the process in continuous flow mode were proposed and examd. during development, demonstrating superior control of crit. impurities and catalyst utilization with minimized risk to product and increased safety due to reduced handling of hydrogen and of palladium catalyst relative to equiv. substrate throughputs in a typical batch process.
- 39Marigo, M.; Fielenbach, D.; Braunton, A.; Kjaersgaard, A.; Jørgensen, K. A. Enantioselective Formation of Stereogenic Carbon–Fluorine Centers by a Simple Catalytic Method. Angew. Chem., Int. Ed. 2005, 44, 3703– 3706, DOI: 10.1002/anie.20050039539https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlslelsLg%253D&md5=059636ce65a1a33ae0c7cde25f0e342eEnantioselective formation of stereogenic carbon-fluorine centers by a simple catalytic methodMarigo, Mauro; Fielenbach, Doris; Braunton, Alan; Kjoersgaard, Anne; Jorgensen, Karl AnkerAngewandte Chemie, International Edition (2005), 44 (24), 3703-3706CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)An easy protocol has been developed for the formation of stereogenic carbon-fluorine centers by the organocatalytic asym. α-fluorination of aldehydes RCH2CHO (R = Bn, Pr, Bu, hexyl, cyclohexyl, etc.). The 2-fluoroaldehydes are formed with (PhSO2)2NF as the fluorinating agent and only 1 mol% of a sterically demanding silylated prolinol I as catalyst. The 2-fluoroaldehydes are subsequently reduced to the corresponding alcs. without loss of enantiomeric excess.
- 40(a) Beeson, T. D.; MacMillan, D. W. C. Enantioselective Organocatalytic α-Fluorination of Aldehydes. J. Am. Chem. Soc. 2005, 127, 8826– 8828, DOI: 10.1021/ja051805f40ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXkt1WrtbY%253D&md5=a1bc3958c426a2cd1dbeecad6fec2e40Enantioselective Organocatalytic α-Fluorination of AldehydesBeeson, Teresa D.; MacMillan, David W. C.Journal of the American Chemical Society (2005), 127 (24), 8826-8828CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The direct enantioselective catalytic α-fluorination of aldehydes has been accomplished. The use of enamine catalysis has provided a new organocatalytic strategy for the enantioselective fluorination of aldehydes to generate α-fluoro aldehydes, an important chiral synthon for medicinal agent synthesis. The use of imidazolidinone I as the asym. catalyst mediates the fluorination of a large variety of aldehyde substrates with N-fluorobenzenesulfonimide as the electrophilic source of fluorine. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. While catalyst quantities of 20 mol % were generally employed in this study, successful halogenation can be accomplished using catalyst loadings as low as 2.5 mol %.(b) Pihko, P. M. Angew. Chem., Int. Ed. 2006, 45, 544– 547, DOI: 10.1002/anie.20050242540b