Highlights from the Literature
Mark McLaughlin, Antonio Ramirez, Magnus Widegren, Paul Richardson, Soumrendu Paul, Andrei Zlota, and Trevor Laird*
Highlights from the Patents
José R. Ochoa-Gómez* , Olga Gómez-Jiménez-Aberasturi, Camilo Ramírez-López, and Mikel Belsué
Glycerol carbonate is one the glycerol derivatives which attracts attention for industrial applications. This review compares strategies for its synthesis, and their analyses lead to the conclusion that (indirect) procedures starting from glycerol- and/or CO2-derivatives are the most attractive. These are described and compared, taking criteria of industrial feasibility into account. As a result, the transesterification of dimethyl carbonate or ethylene carbonate with glycerol using uncalcined CaO as catalyst appears to be currently the most suitable industrial process. Finally, potential applications of glycerol carbonate as a multifunctional compound are exemplified.
Hans Heeres, Adri J. Minnaard, Bart Hessen, and Hero J. Heeres*
The effect of process conditions (temperature, partial pressures of CO and H2) on the product selectivity and ee of the palladium-catalysed asymmetric hydro-acylation of 1-pentene in dichloromethane with the chiral Josiphos ligand (SL-J008-1, L1) was investigated. The highest ee value (73%) for the desired product 4-methyl-5-decanone (1) was obtained at the lowest temperature in the range (30 °C). The selectivity for 1 was between 12 and 20 mol % at 30 °C, though considerably higher at 90 °C (59 mol %). Statistical modeling was applied to quantify the influence of the process conditions on the product selectivity and ee.
Danny Lafrance* and Stéphane Caron
A new synthetic route to a dipeptidyl peptidase-4 (DPP4) inhibitor was developed and demonstrated on a multigram scale. This approach takes advantage of the cheap and readily available Boc-trans-4-hydroxy-l-proline methyl ester as starting material which was derivatized through an SN2 reaction. Several leaving groups were studied, and the nosylate group showed superiority over other derivatives. Formation of an amide using the most costly starting material, 3,3-difluoropyrrolidine, was performed late in the synthesis to minimize its economical impact on the overall cost of the API.
Ronald B. Leng* , Mark V. M. Emonds, Christopher T. Hamilton, and James W. Ringer
New agrochemical, fine chemical, and pharmaceutical products often require the development and selection of economical and effective chemical routes to enable commercial success. Atom economy and reaction step minimization are key drivers for low-cost routes. In addition, capital requirements, process operability and robustness, environmental health and safety, supply chain, quality, and intellectual property factors should be considered in the selection process. A holistic evaluation of process route options by a multidiscipline team of chemists and engineers early in the route-selection phase can result in the selection of a better route with a more focused process development research plan. Examples from three Dow AgroSciences projects illustrate route selection criteria.
Claire S. MacLeod* and Frans L. Muller
Pharmaceutical compounds often crystallise as particles with high aspect ratio, typically as needle-shaped particles. These particles must be isolated from the crystallisation liquors before further secondary processing to form the drug product. A common isolation method in the fine chemical and pharmaceutical industries is pressure filtration. Previous experience has shown that, on scale-up from lab to pilot plant, the particle size distribution can change quite significantly. This has typically been associated with agitation of the filter cake. To test this assumption a number of industrial case studies were conducted. The particle size distribution of various needle-shaped particles of different pharmaceutical and model compounds have been tracked through the filtration and drying process. The work here shows that, for the needle-shaped particles tested, particle breakage occurs during both pressure filtration and agitated drying. This is a previously unreported observation and is contrary to the previously held assumption that breakage is only observed during agitated drying. A mechanistic understanding of the breakage has been built up using particle dimensions, applied pressure, and bed density. The estimated stresses on the needle-shaped particles are of the same order of magnitude as typical tensile strengths of pharmaceutical materials, thus explaining why breakage is observed. A small-scale test has been developed to help identify potentially fragile compounds where breakage during pressure filtration is likely.
Mahbub Alam* , Christopher Wise* , Carl A. Baxter, Ed Cleator, and Andrew Walkinshaw
A general procedure for the copper-catalyzed regioselective ring-opening of epoxides with Grignard reagents is described. The procedure developed provides robust reaction conditions which limit the formation of impurities and has been applied successfully using a series of epoxides and Grignard reagents to provide the desired products in >90% yield with excellent regioselectivity and purity.
Jie Lu* , Yi-Ping Li, Jing Wang, Zhen Li, Sohrab Rohani, and Chi-Bun Ching
Oiling-out, also termed as demixing or liquid–liquid phase separation (LLPS), frequently occurs in the crystallization process of pharmaceuticals and normally results in slow crystal growth, uncontrollable crystal morphology, and low purity of products. In this work, the oiling-out and cooling crystallization of idebenone were investigated. The cooling crystallization and the purity of its products were found to depend upon whether an oiling-out occurred in the course of cooling. At low initial concentrations (e.g., 12 mg/mL), oiling-out did not take place, and the crystallization products possessed higher purity. At moderate initial concentrations (e.g., 25 mg/mL) small quantities of oil droplets formed and then coalesced into larger droplets, which subsequently crystallized into products with lower purity. When high initial concentrations (e.g., 31 mg/mL) were employed, large quantities of oil droplets formed a stable oil phase, and thus no products could be harvested. In addition to initial concentration, other parameters such as solvent, cooling rate, and seeding also affected the occurrence of oiling-out. On the basis of the above results, the approach to purifying idebenone through cooling crystallization will be found.
Bharti Patel, Catherine R. Firkin, Evan W. Snape, Shelley L. Jenkin, David Brown, Julian G. K. Chaffey, Philip A. Hopes, Carl D. Reens, Mike Butters, and Jonathan D. Moseley*
A brief comparison of the early manufacturing routes to AZD7545 is given. Process development of the preferred long-term manufacturing route is reported in detail, and changes from the initial kilogram-scale route are discussed. Scale-up experience from the pilot-plant manufacture is included in the discussion of each stage. Noteworthy aspects throughout the development of AZD7545 concerned chemical hazards, mechanisms, analysis, and impurities, upon which this case study will focus.
William P. Hems, William P. Jackson, Peter Nightingale, and Rob Bryant*
A highly enantioselective and cost efficient process for the synthesis of (+)-erythro mefloquine has been developed. The key step is an enantioselective reduction of pyridyl ketone KI using transfer hydrogenation with formic acid as the hydrogen source. The ratio of formic acid to NEt3 was found to be very important to achieving a highly efficient process.
William L. Parker, Ronald L. Hanson* , Steven L. Goldberg, Thomas P. Tully, and Animesh Goswami
(S)-1-Cyclopropyl-2-methoxyethanamine is a key chiral intermediate for the synthesis of a corticotropin-releasing factor-1(CRF-1) receptor antagonist. Resolution of the racemic amine by transaminase from Vibrio fluvalis gave a 38% yield of the S-amine with 53% ee. Resolution by lipase-catalyzed acylation provided the S-amine in 35% yield with 91% ee. With limited success of these resolution approaches, an efficient chemo-enzymatic route to (S)-1-cyclopropyl-2-methoxyethanamine was devised starting from methylcyclopropyl ketone. Permanganate oxidation of the ketone gave cyclopropylglyoxylic acid, which was converted to (S)-cyclopropylglycine by reductive amination using leucine dehydrogenase from Thermoactinomyces intermedius with NADH cofactor recycling by formate dehydrogenase from Pichia pastoris. Both enzymes were cloned and expressed in recombinant E. coli. (S)-Cyclopropylglycine obtained from enzymatic reductive amination was isolated as the N-Boc derivative and converted to the desired amine by reduction, methylation, and deprotection to give (S)-1-cyclopropyl-2-methoxyethanamine in 62% overall yield from cyclopropylglyoxylic acid, with no detectable R-enantiomer.
Christopher P. Ashcroft, Yann Dessi, David A. Entwistle* , Lynsey C. Hesmondhalgh, Adrian Longstaff, and Julian D Smith*
This article describes the selection, process development, and scale-up of a synthetic route to a complex nucleoside analogue, the A2a agonist UK-432,097 (1), that culminated in the manufacture of over 25 kg of the API. The key steps in the process were (1) a stereoselective glycosidation reaction; (2) a scalable bleach–TEMPO oxidation; and (3) an unusual elevated temperature crystallization process for the final API. The problems that were encountered with the scale-up of the route together with how they were overcome are also presented.
Sithamalli V. Chandramouli, Timothy A. Ayers* , Xiao-Dong Wu, Loc T. Tran, James H. Peers, Rocco Disanto, Frederick Roberts, Narendra Kumar, Ying Jiang, Nakyen Choy, Clive Pemberton, Matthew R. Powers, Anthony J. Gardetto, Geoffrey A. D’Netto, Xuemin Chen, Juan Gamboa, Duc Ngo, Warren Copeland, Duane E. Rudisill, Andrew W. Bridge, Benoit J. Vanasse, and David J. Lythgoe
An enantioselective Overman 3,3-sigmatropic rearrangement on a quinuclidine skeleton was developed for the pilot-plant synthesis of a glycine transporter 1 inhibitor. The first stereocenter was produced by a Ru-catalyzed asymmetric transfer hydrogenation process followed by chirality transfer using the Overman rearrangement. The second stereocenter was generated by a diastereoselective hydrogenation reaction.
Yasushi Kawase, Takehiro Yamagishi, Teruo Kutsuma, Huo Zhibao, Yoshinori Yamamoto, Tomohiro Kimura, Tadashi Nakata, Tadashi Kataoka, and Tsutomu Yokomatsu*
Sodium monobenzoxyborohydride, which is easily prepared from sodium borohydride and benzoic acid in THF in situ, is treated with α-picoline in THF under mild conditions to give α-picoline–borane in an excellent yield. This method can be a practical preparation for α-picoline–borane.
Qiang Yang* , Luckner G. Ulysse, Mark D. McLaws, Daniel K. Keefe, Brian P. Haney, Congxiang Zha, Peter R. Guzzo, and Shuang Liu
Early process development toward a triple reuptake inhibitor is described. Three different routes were evaluated; one of them was optimized and scaled up to generate 470 g of API as this route minimized the formation of undesired side products. The selected route featured Eaton’s reagent-mediated cyclization of a phenyl acetamide, copper-mediated Buchwald–Hartwig coupling to install a morpholine moiety, and palladium-catalyzed α-arylation of a dihydroisoquinolinone to construct the core structure.
Chinmoy Pramanik* , Rahul Bhumkar, Ganesh Karhade, Pravinkumar Khairnar, Narendra Kumar Tripathy, and Mukund K. Gurjar
During the commercial manufacturing of antimigraine drug Rizatriptan benzoate, several impurities are reported to be formed. This present work demonstrates a convergent and short synthesis of the most critical impurity (C) of Rizatriptan, [2-(5-((1H-1,2,4-triazol-1-yl)methyl)-1H-indole-2-yl)-N,N-dimethylethanamine (1)], recently reported in U.S. Pharmacopeia.
Nicholas A. Straessler* , Michael W. Lesley, and Louis F. Cannizzo
An efficient process for synthesizing and isolating a new investigative anticancer agent, 1-bromoacetyl-3,3-dinitroazetidine, is described. The reaction entails a sequence of oxidative nitration followed by acylative dealkylation. The methods reported give 50–60-g batches of high-purity product without a designated purification step. The reaction conditions have been designed to mitigate the safety concerns associated with gem-dinitroazetidines. Some observations on the acylative dealkylation mechanism are discussed.
Darren M. Caine, Ian L. Paternoster, Simon Sedehizadeh, and Peter D. P. Shapland*
The sequential treatment of an intermediate in the synthesis of GSK159797 with a protic acid and sodium chloride was developed to control the stoichiometry of the hydrochloric acid salt of the API. This offered significant advantages over addition of hydrochloric acid, thus avoiding decomposition of an acid-sensitive formamide group. A range of acids were investigated to determine the optimum pKa range in which to use the acid. The optimum process, using acetic acid, was performed on >100 kg input scale.