Nathaniel Kadunce, Olivier St-Jean, Amy Cagulada, Wen-Tau T. Chang, Alexander F. G. Goldberg, Zilin Huang, Jihun Kang, Jinsik Kim, Kyoungchan Kwon, Olga Lapina, Lennie Lin, Trevor J. Rainey, Lyubov Roever, Nisha P. Shah, Scott A. Wolckenhauer
{"title":"Synthetic Development and Scale-Up of a Complex Pyrazole Fragment of Lenacapavir","authors":"Nathaniel Kadunce, Olivier St-Jean, Amy Cagulada, Wen-Tau T. Chang, Alexander F. G. Goldberg, Zilin Huang, Jihun Kang, Jinsik Kim, Kyoungchan Kwon, Olga Lapina, Lennie Lin, Trevor J. Rainey, Lyubov Roever, Nisha P. Shah, Scott A. Wolckenhauer","doi":"10.1021/acs.oprd.4c00235","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00235","url":null,"abstract":"We describe herein the process development and scale-up of a complex cyclopropyl pyrazole fragment of lenacapavir, a drug recently approved for long-acting treatment of HIV (Sunlenca). A ten-step asymmetric synthesis was developed utilizing simple starting materials capable of supporting the commercial supply chain of lenacapavir. Key aspects of this development effort were the oxidation strategy to elaborate the core and optimization of the fluorination reaction to afford the final product.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yan Chen, Yongcheng Sun, Yufang Xu, Xuhong Qian and Weiping Zhu*,
{"title":"Fully Continuous Flow Synthesis of 2′-Deoxy-2′-fluoro-arabinoside: A Key Intermediate of Azvudine","authors":"Yan Chen, Yongcheng Sun, Yufang Xu, Xuhong Qian and Weiping Zhu*, ","doi":"10.1021/acs.oprd.4c0016610.1021/acs.oprd.4c00166","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00166https://doi.org/10.1021/acs.oprd.4c00166","url":null,"abstract":"<p >Azvudine was approved for the treatment of adult HIV-1 infection in China in 2021, and it was approved for conditional marketing for the treatment of SARS-CoV-2 in China in 2022. In this work, we describe a fully continuous flow synthesis of 2′-deoxy-2′-fluoroarabinoside, a key intermediate for azvudine. The process was accomplished via six chemical transformations, including chlorination, hydrolysis, fluorination, bromination, condensation, and deprotection in six sequential continuous flow devices. Under the optimized process conditions, the total yield was 32.3% with a total residence time of 156 min. Compared with batch conditions, the total yield was doubled, the total reaction time was shortened 16 times, and the E factor was reduced 1.63 times.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141990177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nathaniel Kadunce*, Olivier St-Jean*, Amy Cagulada, Wen-Tau T. Chang, Alexander F. G. Goldberg, Zilin Huang, Jihun Kang, Jinsik Kim, Kyoungchan Kwon, Olga Lapina, Lennie Lin, Trevor J. Rainey, Lyubov Roever, Nisha P. Shah and Scott A. Wolckenhauer,
{"title":"Synthetic Development and Scale-Up of a Complex Pyrazole Fragment of Lenacapavir","authors":"Nathaniel Kadunce*, Olivier St-Jean*, Amy Cagulada, Wen-Tau T. Chang, Alexander F. G. Goldberg, Zilin Huang, Jihun Kang, Jinsik Kim, Kyoungchan Kwon, Olga Lapina, Lennie Lin, Trevor J. Rainey, Lyubov Roever, Nisha P. Shah and Scott A. Wolckenhauer, ","doi":"10.1021/acs.oprd.4c0023510.1021/acs.oprd.4c00235","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00235https://doi.org/10.1021/acs.oprd.4c00235","url":null,"abstract":"<p >We describe herein the process development and scale-up of a complex cyclopropyl pyrazole fragment of lenacapavir, a drug recently approved for long-acting treatment of HIV (Sunlenca). A ten-step asymmetric synthesis was developed utilizing simple starting materials capable of supporting the commercial supply chain of lenacapavir. Key aspects of this development effort were the oxidation strategy to elaborate the core and optimization of the fluorination reaction to afford the final product.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141990231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cameron T. Armstrong*, Katharina Grohowalski, Grace Russell, Sara Mason, Kakasaheb Y. Nandiwale, DaQuawn Edwards, Jillian Sheeran, Talia J. Steiman, Douglas J. Critcher, Christopher P. Ashcroft, Angel R. Diaz and Steven M. Guinness*,
{"title":"Early-Stage Flow Process Development of a Key Intermediate toward PF-07265807, an AXL-MER Inhibitor Oncology Candidate","authors":"Cameron T. Armstrong*, Katharina Grohowalski, Grace Russell, Sara Mason, Kakasaheb Y. Nandiwale, DaQuawn Edwards, Jillian Sheeran, Talia J. Steiman, Douglas J. Critcher, Christopher P. Ashcroft, Angel R. Diaz and Steven M. Guinness*, ","doi":"10.1021/acs.oprd.4c0011210.1021/acs.oprd.4c00112","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00112https://doi.org/10.1021/acs.oprd.4c00112","url":null,"abstract":"<p >The application of continuous processing can afford certain advantages during development and scale-up, such as enhanced risk mitigation of hazardous compounds and reducing both manufacturing cycle time and solvent waste through telescoping steps and avoiding intermediate isolations. While telescoping is not unique to flow, the operating windows enabled by the process intensification only possible in flow are notable, and they often possess the additional benefit of accessing chemistries not feasible in a batch. In this work, we highlight efforts to translate an early-stage batch route for the AXL-MER inhibitor oncology candidate PF-07265807 into a viable continuous flow process. The route to the key intermediate of interest features two S<sub>N</sub>Ar reactions, the latter utilizing aqueous hydrazine to enable an intramolecular cascade reaction, followed by a Boc deprotection. Efforts were made to assess and demonstrate the suitability of the process for telescoping steps in flow by finding a solvent/base system that maintained the solubility of all species and led to efficacious reactions. Additional studies were performed to reduce the concentration of aqueous hydrazine solution used as a feed in the continuous process to 5 wt % hydrazine, adding to the various safety advantages not amenable to a traditional batch process. Furthermore, an automated D-optimal design of experiment study was carried out for the aqueous hydrazine step to increase process understanding and screen effects during this early stage of development.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141990268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cameron T. Armstrong, Katharina Grohowalski, Grace Russell, Sara Mason, Kakasaheb Y. Nandiwale, DaQuawn Edwards, Jillian Sheeran, Talia J. Steiman, Douglas J. Critcher, Christopher P. Ashcroft, Angel R. Diaz, Steven M. Guinness
{"title":"Early-Stage Flow Process Development of a Key Intermediate toward PF-07265807, an AXL-MER Inhibitor Oncology Candidate","authors":"Cameron T. Armstrong, Katharina Grohowalski, Grace Russell, Sara Mason, Kakasaheb Y. Nandiwale, DaQuawn Edwards, Jillian Sheeran, Talia J. Steiman, Douglas J. Critcher, Christopher P. Ashcroft, Angel R. Diaz, Steven M. Guinness","doi":"10.1021/acs.oprd.4c00112","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00112","url":null,"abstract":"The application of continuous processing can afford certain advantages during development and scale-up, such as enhanced risk mitigation of hazardous compounds and reducing both manufacturing cycle time and solvent waste through telescoping steps and avoiding intermediate isolations. While telescoping is not unique to flow, the operating windows enabled by the process intensification only possible in flow are notable, and they often possess the additional benefit of accessing chemistries not feasible in a batch. In this work, we highlight efforts to translate an early-stage batch route for the AXL-MER inhibitor oncology candidate PF-07265807 into a viable continuous flow process. The route to the key intermediate of interest features two S<sub>N</sub>Ar reactions, the latter utilizing aqueous hydrazine to enable an intramolecular cascade reaction, followed by a Boc deprotection. Efforts were made to assess and demonstrate the suitability of the process for telescoping steps in flow by finding a solvent/base system that maintained the solubility of all species and led to efficacious reactions. Additional studies were performed to reduce the concentration of aqueous hydrazine solution used as a feed in the continuous process to 5 wt % hydrazine, adding to the various safety advantages not amenable to a traditional batch process. Furthermore, an automated D-optimal design of experiment study was carried out for the aqueous hydrazine step to increase process understanding and screen effects during this early stage of development.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Russell F. Algera, Christophe Allais, Pablo J. Cabrera, María González-Esguevillas, Yanfei Guan, Chintelle James, Johnny W. Lee, Jeffrey M. Massicott, Emma L. McInturff, Robert J. Pearson, Hud Risley, Rebecca B. Watson
{"title":"Sustainable Manufacturing of trans-4-Trifluoromethyl-l-proline via Stereochemical Editing: A Combined In Silico and Experimental Approach","authors":"Russell F. Algera, Christophe Allais, Pablo J. Cabrera, María González-Esguevillas, Yanfei Guan, Chintelle James, Johnny W. Lee, Jeffrey M. Massicott, Emma L. McInturff, Robert J. Pearson, Hud Risley, Rebecca B. Watson","doi":"10.1021/acs.oprd.4c00202","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00202","url":null,"abstract":"Ibuzatrelvir (<b>1</b>) is a second-generation, orally bioavailable, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease inhibitor clinical candidate. Herein, we report the implementation of an in silico and high-throughput experimentation strategy leading to the identification of a rapid, efficient, and sustainable route to <i>trans</i>-4-trifluoromethyl-<span>l</span>-proline (<b>2</b>), a key building block for ibuzatrelvir. This novel synthetic route features a key stereochemical editing step to enable an efficient and scalable protocol that operates under mild conditions with high stereoselectivity, providing effective access to more than 235 kg of <i>trans</i>-4-trifluoromethyl-<span>l</span>-proline <b>2</b> in a five-step synthetic sequence from readily available starting materials.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yan Chen, Yongcheng Sun, Yufang Xu, Xuhong Qian, Weiping Zhu
{"title":"Fully Continuous Flow Synthesis of 2′-Deoxy-2′-fluoro-arabinoside: A Key Intermediate of Azvudine","authors":"Yan Chen, Yongcheng Sun, Yufang Xu, Xuhong Qian, Weiping Zhu","doi":"10.1021/acs.oprd.4c00166","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00166","url":null,"abstract":"Azvudine was approved for the treatment of adult HIV-1 infection in China in 2021, and it was approved for conditional marketing for the treatment of SARS-CoV-2 in China in 2022. In this work, we describe a fully continuous flow synthesis of 2′-deoxy-2′-fluoroarabinoside, a key intermediate for azvudine. The process was accomplished via six chemical transformations, including chlorination, hydrolysis, fluorination, bromination, condensation, and deprotection in six sequential continuous flow devices. Under the optimized process conditions, the total yield was 32.3% with a total residence time of 156 min. Compared with batch conditions, the total yield was doubled, the total reaction time was shortened 16 times, and the E factor was reduced 1.63 times.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anna M. Wagner, Sara A. Bonderoff, Stanley Chang, Jeffrey Deignan, Michelle M. Esanu, Huy Van Huynh, Tianmin Niu, Vinh Ngo, B. Michael O’Keefe, Jenny Phoenix, Trevor J. Rainey, Benjamin J. Roberts, Jinyu Shen, Craig Stewart, Amanda L. Vandehey, Scott A. Wolckenhauer, Chloe Y. Wong, Brian H. Yarmuch
{"title":"Synthesis of Lenacapavir Sodium: Active Pharmaceutical Ingredient Process Development and Scale-up","authors":"Anna M. Wagner, Sara A. Bonderoff, Stanley Chang, Jeffrey Deignan, Michelle M. Esanu, Huy Van Huynh, Tianmin Niu, Vinh Ngo, B. Michael O’Keefe, Jenny Phoenix, Trevor J. Rainey, Benjamin J. Roberts, Jinyu Shen, Craig Stewart, Amanda L. Vandehey, Scott A. Wolckenhauer, Chloe Y. Wong, Brian H. Yarmuch","doi":"10.1021/acs.oprd.4c00242","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00242","url":null,"abstract":"Lenacapavir sodium (GS-6207-02) is a first-in-class HIV capsid inhibitor. Process development of the four-step final assembly of lenacapavir sodium from four synthetic intermediates is described here. A bis-bromopyridine core is sequentially subjected to an alkynylation, an amide coupling with a chiral pyrazole carboxylic acid, and a Suzuki cross-coupling with an indazole boronic ester. The final step is a telescoped bis-methanesulfonylation and hydrolysis to yield the API. This report highlights experimental work on the final assembly sequence to establish robust processing conditions, minimize process mass intensity, control impurity formation, understand impurity purge, and enable large-scale manufacturing of lenacapavir sodium.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anna M. Wagner*, Sara A. Bonderoff, Stanley Chang, Jeffrey Deignan, Michelle M. Esanu, Huy Van Huynh, Tianmin Niu, Vinh Ngo, B. Michael O’Keefe, Jenny Phoenix, Trevor J. Rainey, Benjamin J. Roberts, Jinyu Shen, Craig Stewart, Amanda L. Vandehey, Scott A. Wolckenhauer, Chloe Y. Wong and Brian H. Yarmuch,
{"title":"Synthesis of Lenacapavir Sodium: Active Pharmaceutical Ingredient Process Development and Scale-up","authors":"Anna M. Wagner*, Sara A. Bonderoff, Stanley Chang, Jeffrey Deignan, Michelle M. Esanu, Huy Van Huynh, Tianmin Niu, Vinh Ngo, B. Michael O’Keefe, Jenny Phoenix, Trevor J. Rainey, Benjamin J. Roberts, Jinyu Shen, Craig Stewart, Amanda L. Vandehey, Scott A. Wolckenhauer, Chloe Y. Wong and Brian H. Yarmuch, ","doi":"10.1021/acs.oprd.4c0024210.1021/acs.oprd.4c00242","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00242https://doi.org/10.1021/acs.oprd.4c00242","url":null,"abstract":"<p >Lenacapavir sodium (GS-6207-02) is a first-in-class HIV capsid inhibitor. Process development of the four-step final assembly of lenacapavir sodium from four synthetic intermediates is described here. A bis-bromopyridine core is sequentially subjected to an alkynylation, an amide coupling with a chiral pyrazole carboxylic acid, and a Suzuki cross-coupling with an indazole boronic ester. The final step is a telescoped bis-methanesulfonylation and hydrolysis to yield the API. This report highlights experimental work on the final assembly sequence to establish robust processing conditions, minimize process mass intensity, control impurity formation, understand impurity purge, and enable large-scale manufacturing of lenacapavir sodium.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141990184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rosaria Ciriminna, Cristina Della Pina, Rafael Luque, Mario Pagliaro
{"title":"Reshoring Fine Chemical and Pharmaceutical Productions","authors":"Rosaria Ciriminna, Cristina Della Pina, Rafael Luque, Mario Pagliaro","doi":"10.1021/acs.oprd.4c00219","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00219","url":null,"abstract":"Prolonged shortage of active pharmaceutical ingredients (APIs) in many countries that do not produce critically important APIs requires urgent reshoring of the said fine chemical productions. The situation is even worsened by frequent disruption of the global supply chains, first during the COVID-19 crisis and subsequently with the ongoing Red Sea crisis. In this study, we first outline the main economic and policy aspects emerging from selected cases of reshoring of API production to Europe. Hence, broadening the analysis to include selected cases in China and India, we investigate the industrial uptake of continuous manufacturing in fine chemicals production. Following said concrete analysis of the concrete situation, the study concludes with three main findings.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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