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Flow Chemistry and Continuous Processing: More Mainstream than Ever!Click to copy article linkArticle link copied!
- Kevin P. Cole*Kevin P. Cole*Email: [email protected]Synthetic Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United StatesMore by Kevin P. Cole
- Jonathan N. JaworskiJonathan N. JaworskiProcess Chemistry Development, Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, Massachusetts 02139, United StatesMore by Jonathan N. Jaworski
- C. Oliver KappeC. Oliver KappeInstitute of Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, AustriaMore by C. Oliver Kappe
- Shu KobayashiShu KobayashiDepartment of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, JapanMore by Shu Kobayashi
- Anita R. MaguireAnita R. MaguireSchool of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, SSPC, the SFI Research Centre for Pharmaceuticals, University College Cork, Cork T12 K8AF, IrelandMore by Anita R. Maguire
- Anne O’Kearney-McMullanAnne O’Kearney-McMullanChemical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield SK10 2NA, United KingdomMore by Anne O’Kearney-McMullan
- Jaan A. PestiJaan A. PestiPharma Resource Group Inc., 880 Enterprise Drive, Royersford, Pennsylvania 19468, United StatesMore by Jaan A. Pesti
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SPECIAL ISSUE
This article is part of the
We are pleased to present the fifth OPR&D special issue focused on continuous processing and hope that it pays homage to the previous editions by inspiring further momentum in this exciting field! It is safe to say that continuous manufacturing (CM) can now be viewed as a mainstream technology that is widely implemented across fine chemicals, agrochemicals, and pharmaceuticals. It is now commonplace to meet (under)graduate students or postdocs who have experience performing reactions in flow, and the importance of academic research in flow chemistry has never been greater. This is key to supplying the workforce with fresh talent trained in CM, but companies must continue to invest in the training and education of their existing staff to keep a critical mass of CM know-how. While there is no arguing that industrial chemists have often provided leadership regarding a multitude of continuous flow concepts, they frequently rely on academia to pioneer new reaction or equipment types and to “lure” them into applying the new methods to industrial problems. With that can come important academic–industrial collaborations, which in addition to training students in CM has served to expedite much of the cutting-edge research coming out of universities. Of the pharmaceutical companies that possess their own manufacturing capabilities, many if not most have recently implemented divisions or personnel that specialize in flow processes. While this fact is encouraging, it may hide missed opportunities to push the limitations of CM. Many agrochemical and pharmaceutical manufacturers outsource the preparation of advanced intermediates and conduct only the final key steps, which are often less chemically complex, in-house. There are tremendous opportunities for CM upstream from the final sequence, where many of the most difficult chemical transformations are conducted, often by contract manufacturing organizations (CMOs).
It is obvious that CM capabilities are now increasing among CMOs in our industries. Many contract manufacturers in fine chemicals or pharmaceuticals offer various continuous processing capabilities. These range from simple plug-flow reactors (PFRs) or continuous stirred tank reactors (CSTRs) to more sophisticated equipment modalities such as photochemical or packed bed hydrogenation reactors and even the ability to conduct separations such as extraction or crystallization in continuous flow. What is perhaps most encouraging is that some CMOs now possess true competence in these areas and can develop and implement certain CM processes with minimal input from the customer. While this is not true for every case, none of it was true a decade ago when most CMOs had either not begun to implement CM or were only beginning to move in this direction; an IQ survey from ca. 2018 discusses this topic. (1) What caused such a rapid change in the level of adoption of CM technologies among CMOs? The answer is undoubtedly complex, but it certainly includes the manufacturers realizing the benefits of these technologies and increasing CM demand from their clients. The most important benefits of flow have not changed, but CMOs appear to have realized that they must offer CM capabilities or lose clients to competitors. We would be remiss as well to ignore the changes that have occurred in the regulatory space concerning the growing adaptation of CM. With the finalization of ICH Q13, (2) a framework for how CM processes can be developed and communicated to regulators is in place, and the fear of “how will regulators treat my CM submission?” is reduced.
Looking to the future, the merits of conducting so-called “end-to-end continuous manufacturing” can be argued (and are!). End-to-end processes, and even merely linked and simultaneously operating CM processes (e.g., a PFR and a linked separation unit operation) are still relatively uncommon in our industries. We often select a batch–flow hybrid model, where a standalone flow unit operation (normally a reaction) is conducted and the subsequent workup is performed in batch mode. When adjacent flow unit operations are linked, the complexity and challenge of conducting these operations greatly increases, especially if the processes are conducted under rigorous quality constraints such as current Good Manufacturing Practices (cGMPs). It is important to note, however, that there is tremendous unrealized potential in continuous separation unit operations. Separations that are run continuously such as countercurrent extraction, thin-film evaporation, or kinetically controlled crystallization can offer miraculous benefits over the batch analog in terms of yield, safety, impurity rejection, resource usage, etc. While many chemists and engineers are now trained to look for opportunities to implement flow reactions, we should also search for what beneficial flow separations might exist when designing and commercializing new syntheses. It is our belief that the next CM special issue will possess articles highlighting increased numbers of separations performed in flow. These capabilities will become as widespread as flow reaction unit operations.
We sincerely thank all the authors who have contributed to this issue with their time and talent. There are many noteworthy articles in the 2024 special issue, but three particularly caught our attention. Many teams have described their development approaches toward covalent KRAS G12C inhibitors, (3) and this previously undruggable target has become popular throughout oncology drug development. (4) Many small-molecule inhibitors feature a densely functionalized biaryl ring system, some of which are atropisomeric. A team from Genentech and Roche (DOI: 10.1021/acs.oprd.3c00164) describe an excellent application of continuous flow technology in the Grignard exchange and subsequent transmetalation to the arylzinc reagent needed to forge the biaryl bond (Scheme 1). The continuous process enabled operation at higher temperature (−20 vs −70 °C), which was cited by the authors as being an important factor in the ability to scale the process to commercial volumes in available equipment. The continuous process was demonstrated at kilogram scale and gave a 72% isolated yield after the subsequent Negishi coupling.
Scheme 1
The formation of N–N bonds can be a powerful method for the synthesis of aromatic heterocycles. A team from TCG GreenChem Inc. (DOI: 10.1021/acs.oprd.3c00184) demonstrated the use of multistep continuous processing to form 2-cyanopyrrole from pyrrole (Scheme 2). In the next step, pyrrole N-amination is achieved in flow using in situ-generated chloramine. The previously reported base for the amination, sodium hydride, was replaced with safer t-BuOK in the flow process. Finally, the 1-aminopyrrole intermediate is treated with formamidine acetate in batch mode to afford desired pyrrolotriazine target. Several process safety improvements were noted as driving factors in this work, and the yield of the three-step sequence was 52% with high purity and assay. This work is impressive from the perspective that multiple simultaneous unit operations were connected, including separations, to enable multiple challenging chemical transformation to be achieved at once.
Scheme 2
Finally, an interesting example of continuous reactor design has been disclosed by Jiang and co-workers (DOI: 10.1021/acs.oprd.3c00328). A series of eight mini-CSTRs capable of vertical or horizontal flow was constructed with a built-in LED array, stirring, and cooling capabilities (Figure 1). This reactor design was demonstrated to tolerate use of a solid-supported catalyst, uranyl-doped glass wool, in addition to more standard catalysts. In the case of the glass-wool-supported catalyst, catalyst recycling of at least 12 cycles was demonstrated without loss of activity. The reactor was tested with a handful of photochemical applications, including oxidations and ketone carboxylation. This stands as an example of how improved reactor design can further enable specialized conditions for applications in CM.
Figure 1
Figure 1. Eight CSTRs in series reactor for heterogeneous photocatalytic processes. Reproduced from 10.1021/acs.oprd.3c00328. Copyright 2023 American Chemical Society.
We hope that you will enjoy this issue and take the time to read many of the articles in-depth. It was certainly a fun challenge to pull all these articles together for this issue, and we hope that the passion, dedication, and engagement of the authors is evident and infectious. Happy reading!
Author Information
- Kevin P. Cole, Synthetic Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States,
https://orcid.org/0000-0002-2333-6557,
- Jonathan N. Jaworski, Process Chemistry Development, Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, Massachusetts 02139, United States,https://orcid.org/0000-0002-9509-3769
- C. Oliver Kappe, Institute of Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria,https://orcid.org/0000-0003-2983-6007
- Shu Kobayashi, Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan,https://orcid.org/0000-0002-8235-4368
- Anita R. Maguire, School of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, SSPC, the SFI Research Centre for Pharmaceuticals, University College Cork, Cork T12 K8AF, Ireland,https://orcid.org/0000-0001-8306-1893
References
This article references 4 other publications.
- 1McWilliams, J. C.; Allian, A. D.; Opalka, S. M.; May, S. A.; Journet, M.; Braden, T. M. The Evolving State of Continuous Processing in Pharmaceutical API Manufacturing: A Survey of Pharmaceutical Companies and Contract Manufacturing Organizations. Org. Process Res. Dev. 2018, 22, 1143– 1166, DOI: 10.1021/acs.oprd.8b00160Google Scholar1The Evolving State of Continuous Processing in Pharmaceutical API Manufacturing: A Survey of Pharmaceutical Companies and Contract Manufacturing OrganizationsMcWilliams, J. Christopher; Allian, Ayman D.; Opalka, Suzanne M.; May, Scott A.; Journet, Michel; Braden, Timothy M.Organic Process Research & Development (2018), 22 (9), 1143-1166CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)This manuscript provides the results of an in-depth survey assessment of the capabilities, experience, and perspectives on continuous processing in the pharmaceutical sector, with respondents from both pharmaceutical companies and Contract Manufg. Organizations (CMOs). The survey includes staffing (personnel), chem., reaction platforms, postreaction processing, anal., regulatory, and factors that influence the adoption of continuous manufg. The results of the survey demonstrate that the industry has been increasing, and will continue to increase, the portion of total manufg. executed as continuous processes with a decrease in batch processing. In general, most of the experience with continuous processing on scale have been enabling reaction chem., while postprocessing and anal. remain in the very early stages of development and implementation.
- 2Q13 Continuous Manufacturing of Drug Substances and Drug Products: Guidance for Industry. U.S. Food and Drug Administration, March 2023. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q13-continuous-manufacturing-drug-substances-and-drug-products (accessed 2023-11-18).Google ScholarThere is no corresponding record for this reference.
- 3
For recent selected references related to KRAS inhibitor synthesis, see:
(a) Feng, W.-D. Process Research for ZG1077, a KRAS G12C Inhibitor. Org. Process Res. Dev 2022, 26, 2986– 2996, DOI: 10.1021/acs.oprd.2c00284Google ScholarThere is no corresponding record for this reference.(b) Allison, B. D.; Deng, X.; Li, L.-S.; Liang, J.; Mani, N. S.; Ren, P.; Sales, Z. S. Selective Metalation of Functionalized Quinazolines to Enable Discovery and Advancement of Covalent KRAS Inhibitors. Org. Process Res. Dev 2022, 26, 2926– 2936, DOI: 10.1021/acs.oprd.2c00242Google Scholar3bSelective Metalation of Functionalized Quinazolines to Enable Discovery and Advancement of Covalent KRAS InhibitorsAllison, Brett D.; Deng, Xiaohu; Li, Lian-Sheng; Liang, Jimmy; Mani, Neelakandha S.; Ren, Pingda; Sales, Zachary S.Organic Process Research & Development (2022), 26 (10), 2926-2936CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The quinazoline compd. I ARS-1620 is a recently discovered, mutant-specific covalent inhibitor of KRASG12C. Route scouting in support of multigram ARS-1620 batches led to a new synthetic approach that relies on metalation of substituted quinazolines at C7 II (X = H, Cl). The exquisite selectivity seen in this metalation formed the basis for a scalable route to kilogram quantities of compds. in this family. It also accelerated medicinal chem. efforts as crit. intermediates became readily available in large quantities.(c) Zhang, L. Development of a Commercial Manufacturing Process for Sotorasib, a First-in-Class KRASG12C Inhibitor. Org. Process Res. Dev 2022, 26, 3115– 3125, DOI: 10.1021/acs.oprd.2c00249Google Scholar3cDevelopment of a Commercial Manufacturing Process for Sotorasib, a First-in-Class KRASG12C InhibitorZhang, Liang; Griffin, Daniel J.; Beaver, Matthew G.; Blue, Laura E.; Borths, Christopher J.; Brown, Derek B.; Caille, Seb; Chen, Ying; Cherney, Alan H.; Cochran, Brian M.; Colyer, John T.; Corbett, Michael T.; Correll, Tiffany L.; Crockett, Richard D.; Dai, Xi-Jie; Dornan, Peter K.; Farrell, Robert P.; Hedley, Simon J.; Hsieh, Hsiao-Wu; Huang, Liang; Huggins, Seth; Liu, Min; Lovette, Michael A.; Quasdorf, Kyle; Powazinik, William; Reifman, Jonathan; Robinson, Jo Anna; Sangodkar, Rahul P.; Sharma, Sonika; Kumar, Srividya Sharvan; Smith, Austin G.; St-Pierre, Gabrielle; Tedrow, Jason S.; Thiel, Oliver R.; Truong, Jonathan V.; Walker, Shawn D.; Wei, Carolyn S.; Wilsily, Ashraf; Xie, Yong; Yang, Ning; Parsons, Andrew T.Organic Process Research & Development (2022), 26 (11), 3115-3125CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A com. process to manuf. sotorasib (AMG 510), a first-in-class KRASG12C inhibitor, was described. Development efforts focused on rendering a fit-for-purpose early-phase route into a viable long-term com. process through the redn. of side reactions to improve yield and product quality, as well as reducing cycle times of crystn. processes by improving particle properties and filtration times. These improvements were key to ensuring clin. supply and com. launch. The final route consists of five synthetic operations from starting material M-1, including a telescoped two-step sequence, and a final form-setting crystn.(d) Yang, X. Hindered Biaryl Bond Construction and Subsequent Diastereomeric Crystallization to Produce an Atropisomeric Covalent KRASG12C Inhibitor ARS-2102. Org. Process Res. Dev 2023, 27, 206– 216, DOI: 10.1021/acs.oprd.2c00335Google Scholar3dHindered Biaryl Bond Construction and Subsequent Diastereomeric Crystallization to Produce an Atropisomeric Covalent KRASG12C Inhibitor ARS-2102Yang, Xiaogen; Li, Zhiwen; Xu, Wenwen; Zhu, Guanming; Feng, Xiantong; Zhang, Jun; Zhao, Hongbin; Chen, Yuyin; Kong, Jianshe; Mai, Wanping; Li, Lian-Sheng; Pippel, Daniel J.; Ren, Pingda; Deng, XiaohuOrganic Process Research & Development (2023), 27 (1), 206-216CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A scaleup route for a first-generation covalent KRASG12C inhibitor ARS-2102 was devised, featuring an "early cross-coupling" strategy to construct the tetra-substituted atropisomeric biaryl scaffold. An iterative diastereomeric recrystn. enabled an effective chiral resoln. of key intermediate Bu (2R,5S)-4-(2,6-dichloro-8-fluoro-7-(S-2-fluoro-6-methoxyphenyl)quinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate. A global deprotection followed by chemoselective functionalization afforded ARS-2102 in excellent yield and diastereomeric enrichment. This chromatog.-free sequence was successfully executed on kilogram scale.(e) Nikitidis, G. Synthetic and Chromatographic Challenges and Strategies for Multigram Manufacture of KRASG12C Inhibitors. Org. Process Res. Dev 2022, 26, 710– 729, DOI: 10.1021/acs.oprd.1c00179Google Scholar3eSynthetic and Chromatographic Challenges and Strategies for Multigram Manufacture of KRASG12C InhibitorsNikitidis, Grigorios; Carlsson, Anna-Carin C.; Karlsson, Staffan; Campbell, Andrew D.; Cook, Calum; Dai, Kuangchu; Emtenaes, Hans; Jonson, Anna C.; Leek, Hanna; Malmgren, Marcus; Moravcik, Stefan; Pithani, Subhash; Tatton, Matthew R.; Zhao, Hucheng; Oehlen, KristinaOrganic Process Research & Development (2022), 26 (3), 710-729CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)In one of our drug development projects, we identified potent KRASG12C inhibitors for treatment of cancer. For our early preclin. studies, we needed a strategy to enable supply of two candidates in a cost-effective and productive manner. The active pharmaceutical ingredients (APIs) were structurally complex and were initially obtained via long linear sequences resulting in time-consuming manufs. In addn., both two candidates comprised a biaryl fragment with hindered rotation along the chiral axis. As a result, a pair of stable atropisomers was generated for each candidate. With special attention to the chromatog. challenges for the atropisomer sepn. and for the API purifn., this article describes our initial efforts to develop synthetic routes that were amenable for multigram synthesis of our two drug candidates. In particular, the consequences of implementing a key Suzuki reaction late or early in the sequence are discussed. - 4Gabizon, R.; London, N. Hitting KRAS When It’s Down. J. Med. Chem. 2020, 63, 6677– 6678, DOI: 10.1021/acs.jmedchem.0c00785Google Scholar4Hitting KRAS When It's DownGabizon, Ronen; London, NirJournal of Medicinal Chemistry (2020), 63 (13), 6677-6678CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A polemic in answer to Fell et al., J. Med. Chem. 2020, DOI: 10.1021/acs.jmedchem.9b02052. KRAS, one of the most prevalent oncogenes and sought-after anticancer targets, has eluded chemists for decades until an irreversible covalent strategy targeting a specific mutation (G12C) paved the way for the first KRAS inhibitors to reach the clinic. MRTX849 is one such clin. candidate with promising initial results in patients harboring the mutation. The impressive optimization story of MRTX849 highlights challenges and solns. in the development of covalent drugs, including the use of an α-fluoroacrylamide electrophile.
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Scheme 1
Scheme 1. Grignard Exchange and Transmetalation Steps Developed in Flow En Route to KRAS G12C Inhibitor DivarasibScheme 2
Scheme 2. Synthesis of Triazine 9 Using Multiple Flow Unit Operations with Enabled Hazardous ChemistryFigure 1
Figure 1. Eight CSTRs in series reactor for heterogeneous photocatalytic processes. Reproduced from 10.1021/acs.oprd.3c00328. Copyright 2023 American Chemical Society.
References
This article references 4 other publications.
- 1McWilliams, J. C.; Allian, A. D.; Opalka, S. M.; May, S. A.; Journet, M.; Braden, T. M. The Evolving State of Continuous Processing in Pharmaceutical API Manufacturing: A Survey of Pharmaceutical Companies and Contract Manufacturing Organizations. Org. Process Res. Dev. 2018, 22, 1143– 1166, DOI: 10.1021/acs.oprd.8b001601The Evolving State of Continuous Processing in Pharmaceutical API Manufacturing: A Survey of Pharmaceutical Companies and Contract Manufacturing OrganizationsMcWilliams, J. Christopher; Allian, Ayman D.; Opalka, Suzanne M.; May, Scott A.; Journet, Michel; Braden, Timothy M.Organic Process Research & Development (2018), 22 (9), 1143-1166CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)This manuscript provides the results of an in-depth survey assessment of the capabilities, experience, and perspectives on continuous processing in the pharmaceutical sector, with respondents from both pharmaceutical companies and Contract Manufg. Organizations (CMOs). The survey includes staffing (personnel), chem., reaction platforms, postreaction processing, anal., regulatory, and factors that influence the adoption of continuous manufg. The results of the survey demonstrate that the industry has been increasing, and will continue to increase, the portion of total manufg. executed as continuous processes with a decrease in batch processing. In general, most of the experience with continuous processing on scale have been enabling reaction chem., while postprocessing and anal. remain in the very early stages of development and implementation.
- 2Q13 Continuous Manufacturing of Drug Substances and Drug Products: Guidance for Industry. U.S. Food and Drug Administration, March 2023. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q13-continuous-manufacturing-drug-substances-and-drug-products (accessed 2023-11-18).There is no corresponding record for this reference.
- 3
For recent selected references related to KRAS inhibitor synthesis, see:
(a) Feng, W.-D. Process Research for ZG1077, a KRAS G12C Inhibitor. Org. Process Res. Dev 2022, 26, 2986– 2996, DOI: 10.1021/acs.oprd.2c00284There is no corresponding record for this reference.(b) Allison, B. D.; Deng, X.; Li, L.-S.; Liang, J.; Mani, N. S.; Ren, P.; Sales, Z. S. Selective Metalation of Functionalized Quinazolines to Enable Discovery and Advancement of Covalent KRAS Inhibitors. Org. Process Res. Dev 2022, 26, 2926– 2936, DOI: 10.1021/acs.oprd.2c002423bSelective Metalation of Functionalized Quinazolines to Enable Discovery and Advancement of Covalent KRAS InhibitorsAllison, Brett D.; Deng, Xiaohu; Li, Lian-Sheng; Liang, Jimmy; Mani, Neelakandha S.; Ren, Pingda; Sales, Zachary S.Organic Process Research & Development (2022), 26 (10), 2926-2936CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The quinazoline compd. I ARS-1620 is a recently discovered, mutant-specific covalent inhibitor of KRASG12C. Route scouting in support of multigram ARS-1620 batches led to a new synthetic approach that relies on metalation of substituted quinazolines at C7 II (X = H, Cl). The exquisite selectivity seen in this metalation formed the basis for a scalable route to kilogram quantities of compds. in this family. It also accelerated medicinal chem. efforts as crit. intermediates became readily available in large quantities.(c) Zhang, L. Development of a Commercial Manufacturing Process for Sotorasib, a First-in-Class KRASG12C Inhibitor. Org. Process Res. Dev 2022, 26, 3115– 3125, DOI: 10.1021/acs.oprd.2c002493cDevelopment of a Commercial Manufacturing Process for Sotorasib, a First-in-Class KRASG12C InhibitorZhang, Liang; Griffin, Daniel J.; Beaver, Matthew G.; Blue, Laura E.; Borths, Christopher J.; Brown, Derek B.; Caille, Seb; Chen, Ying; Cherney, Alan H.; Cochran, Brian M.; Colyer, John T.; Corbett, Michael T.; Correll, Tiffany L.; Crockett, Richard D.; Dai, Xi-Jie; Dornan, Peter K.; Farrell, Robert P.; Hedley, Simon J.; Hsieh, Hsiao-Wu; Huang, Liang; Huggins, Seth; Liu, Min; Lovette, Michael A.; Quasdorf, Kyle; Powazinik, William; Reifman, Jonathan; Robinson, Jo Anna; Sangodkar, Rahul P.; Sharma, Sonika; Kumar, Srividya Sharvan; Smith, Austin G.; St-Pierre, Gabrielle; Tedrow, Jason S.; Thiel, Oliver R.; Truong, Jonathan V.; Walker, Shawn D.; Wei, Carolyn S.; Wilsily, Ashraf; Xie, Yong; Yang, Ning; Parsons, Andrew T.Organic Process Research & Development (2022), 26 (11), 3115-3125CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A com. process to manuf. sotorasib (AMG 510), a first-in-class KRASG12C inhibitor, was described. Development efforts focused on rendering a fit-for-purpose early-phase route into a viable long-term com. process through the redn. of side reactions to improve yield and product quality, as well as reducing cycle times of crystn. processes by improving particle properties and filtration times. These improvements were key to ensuring clin. supply and com. launch. The final route consists of five synthetic operations from starting material M-1, including a telescoped two-step sequence, and a final form-setting crystn.(d) Yang, X. Hindered Biaryl Bond Construction and Subsequent Diastereomeric Crystallization to Produce an Atropisomeric Covalent KRASG12C Inhibitor ARS-2102. Org. Process Res. Dev 2023, 27, 206– 216, DOI: 10.1021/acs.oprd.2c003353dHindered Biaryl Bond Construction and Subsequent Diastereomeric Crystallization to Produce an Atropisomeric Covalent KRASG12C Inhibitor ARS-2102Yang, Xiaogen; Li, Zhiwen; Xu, Wenwen; Zhu, Guanming; Feng, Xiantong; Zhang, Jun; Zhao, Hongbin; Chen, Yuyin; Kong, Jianshe; Mai, Wanping; Li, Lian-Sheng; Pippel, Daniel J.; Ren, Pingda; Deng, XiaohuOrganic Process Research & Development (2023), 27 (1), 206-216CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A scaleup route for a first-generation covalent KRASG12C inhibitor ARS-2102 was devised, featuring an "early cross-coupling" strategy to construct the tetra-substituted atropisomeric biaryl scaffold. An iterative diastereomeric recrystn. enabled an effective chiral resoln. of key intermediate Bu (2R,5S)-4-(2,6-dichloro-8-fluoro-7-(S-2-fluoro-6-methoxyphenyl)quinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate. A global deprotection followed by chemoselective functionalization afforded ARS-2102 in excellent yield and diastereomeric enrichment. This chromatog.-free sequence was successfully executed on kilogram scale.(e) Nikitidis, G. Synthetic and Chromatographic Challenges and Strategies for Multigram Manufacture of KRASG12C Inhibitors. Org. Process Res. Dev 2022, 26, 710– 729, DOI: 10.1021/acs.oprd.1c001793eSynthetic and Chromatographic Challenges and Strategies for Multigram Manufacture of KRASG12C InhibitorsNikitidis, Grigorios; Carlsson, Anna-Carin C.; Karlsson, Staffan; Campbell, Andrew D.; Cook, Calum; Dai, Kuangchu; Emtenaes, Hans; Jonson, Anna C.; Leek, Hanna; Malmgren, Marcus; Moravcik, Stefan; Pithani, Subhash; Tatton, Matthew R.; Zhao, Hucheng; Oehlen, KristinaOrganic Process Research & Development (2022), 26 (3), 710-729CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)In one of our drug development projects, we identified potent KRASG12C inhibitors for treatment of cancer. For our early preclin. studies, we needed a strategy to enable supply of two candidates in a cost-effective and productive manner. The active pharmaceutical ingredients (APIs) were structurally complex and were initially obtained via long linear sequences resulting in time-consuming manufs. In addn., both two candidates comprised a biaryl fragment with hindered rotation along the chiral axis. As a result, a pair of stable atropisomers was generated for each candidate. With special attention to the chromatog. challenges for the atropisomer sepn. and for the API purifn., this article describes our initial efforts to develop synthetic routes that were amenable for multigram synthesis of our two drug candidates. In particular, the consequences of implementing a key Suzuki reaction late or early in the sequence are discussed. - 4Gabizon, R.; London, N. Hitting KRAS When It’s Down. J. Med. Chem. 2020, 63, 6677– 6678, DOI: 10.1021/acs.jmedchem.0c007854Hitting KRAS When It's DownGabizon, Ronen; London, NirJournal of Medicinal Chemistry (2020), 63 (13), 6677-6678CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A polemic in answer to Fell et al., J. Med. Chem. 2020, DOI: 10.1021/acs.jmedchem.9b02052. KRAS, one of the most prevalent oncogenes and sought-after anticancer targets, has eluded chemists for decades until an irreversible covalent strategy targeting a specific mutation (G12C) paved the way for the first KRAS inhibitors to reach the clinic. MRTX849 is one such clin. candidate with promising initial results in patients harboring the mutation. The impressive optimization story of MRTX849 highlights challenges and solns. in the development of covalent drugs, including the use of an α-fluoroacrylamide electrophile.