Christophe Allais, Aaron F. Baldwin, Hugh J. Clarke, Christina G. Connor, Michael Coutant, Cindy Duong, Michael Herr, Chintelle James, Maciej Kalinowski, Johnny W. Lee, Yizhou Liu, Jared L. Piper, John A. Ragan, John J. Salisbury, R. Matthew Weekly, Shu Yu, Mengtan Zhang
{"title":"Building and Evolving a Chiral Control Strategy for Accelerated COVID Programs","authors":"Christophe Allais, Aaron F. Baldwin, Hugh J. Clarke, Christina G. Connor, Michael Coutant, Cindy Duong, Michael Herr, Chintelle James, Maciej Kalinowski, Johnny W. Lee, Yizhou Liu, Jared L. Piper, John A. Ragan, John J. Salisbury, R. Matthew Weekly, Shu Yu, Mengtan Zhang","doi":"10.1021/acs.oprd.4c00392","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00392","url":null,"abstract":"The development of nirmatrelvir <b>1</b> (the active agent in PAXLOVID) was undertaken using a “lightspeed” paradigm to develop an oral antiviral treatment for SARS-CoV-2 (COVID-19). This paper describes our chiral control strategy to deliver high-quality drug substances from first in human studies to an ICH Q3A aligned commercial filing over a period of 17 months. We illustrate our approach to modeling, targeted synthetic efforts, and analytical method development to measure the only two observed stereoisomers instead of the potential 63 in the final drug substance. This paper also provides an overview of how we employed the knowledge gained on chiral control from nirmatrelvir and applied it to our second-generation oral inhibitor, ibuzatrelvir <b>2</b>.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"196 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597964","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}
Michael P. Carroll*, Aobha Hickey, Ava Rogers, Cáoimhe J. Niland, Rachel A. O’Sullivan, Nachimuthu Muniraj, Kevin F. O’Sullivan, Patrick J. Guiry and Michael M. Murray,
{"title":"Optimized Synthesis of an Abemaciclib Intermediate: Improved Conditions for a Miyaura Borylation/Suzuki Coupling Process","authors":"Michael P. Carroll*, Aobha Hickey, Ava Rogers, Cáoimhe J. Niland, Rachel A. O’Sullivan, Nachimuthu Muniraj, Kevin F. O’Sullivan, Patrick J. Guiry and Michael M. Murray, ","doi":"10.1021/acs.oprd.4c0038110.1021/acs.oprd.4c00381","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00381https://doi.org/10.1021/acs.oprd.4c00381","url":null,"abstract":"<p >Improved reaction conditions have been developed for a telescoped Miyaura borylation/Suzuki coupling process, which is utilized in the synthesis of an abemaciclib intermediate. Key improvements include the in situ generation of a lipophilic base and tailored ligand selection for each palladium-catalyzed step. Optimizing ligand choice significantly reduced aryl scrambling, a major source of impurities in the borylation step. Additionally, the process improvements led to shortened reaction times and lower palladium loadings, resulting in a more efficient, higher-yielding process.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 11","pages":"4127–4136 4127–4136"},"PeriodicalIF":3.1,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640898","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}
Michael P. Carroll, Aobha Hickey, Ava Rogers, Cáoimhe J. Niland, Rachel A. O’Sullivan, Nachimuthu Muniraj, Kevin F. O’Sullivan, Patrick J. Guiry, Michael M. Murray
{"title":"Optimized Synthesis of an Abemaciclib Intermediate: Improved Conditions for a Miyaura Borylation/Suzuki Coupling Process","authors":"Michael P. Carroll, Aobha Hickey, Ava Rogers, Cáoimhe J. Niland, Rachel A. O’Sullivan, Nachimuthu Muniraj, Kevin F. O’Sullivan, Patrick J. Guiry, Michael M. Murray","doi":"10.1021/acs.oprd.4c00381","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00381","url":null,"abstract":"Improved reaction conditions have been developed for a telescoped Miyaura borylation/Suzuki coupling process, which is utilized in the synthesis of an abemaciclib intermediate. Key improvements include the in situ generation of a lipophilic base and tailored ligand selection for each palladium-catalyzed step. Optimizing ligand choice significantly reduced aryl scrambling, a major source of impurities in the borylation step. Additionally, the process improvements led to shortened reaction times and lower palladium loadings, resulting in a more efficient, higher-yielding process.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"10 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594533","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}
{"title":"Thermodynamically Controlled and Industrially Viable Telescopic Process for the Synthesis of Fluazuron","authors":"Dattatray Patil, Rakesh R. Ganorkar, Ramakant Kardile, Madhavrao Bhoite, Amol Jadhav, Rutuja Gundal, Garbapu Suresh","doi":"10.1021/acs.oprd.4c00345","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00345","url":null,"abstract":"Fluazuron <i>N</i>-[(4-chloro-3-[3-chloro-5-(trifluoromethyl)pyridine-2-yl]oxy phenyl]carbamoyl]-2,6-difluorobenzamide (<b>14</b>) is a noteworthy antiparasitic veterinary medicine belonging to the class of benzoyl phenyl urea derivatives, a class of chitin synthesis inhibitors. The commercial-scale synthesis, which is compliant with current regulatory requirements, particularly purity and impurity profiles, is not well established. Therefore, a robust and sustainable manufacturing process is essential to manufacture and supply fluazuron or any drug substance, for that matter, meeting all criteria. In this work, a safe, scalable, economic, and sustainable process was described through a robust in situ protocol for the bottleneck isocyanate intermediate (<b>20</b>) to manufacture a substantially pure fluazuron active pharmaceutical ingredient (API) with >99.5% HPLC purity and a yield of >78% overall. This large-scale GMP manufacturing process was established by implementing DoE tools and principles of green chemistry like process mass intensity assessment (PMI) and the “3Rs” principle (reduce/reuse/recycle) to attain the “3Ps” sustainability target (profit/people/planet). The developed process technology was successfully validated under cGMP plant conditions on a scale of 600 kg batch size to supply the fluazuron API (<b>14</b>) across the globe for veterinary use. This process is commercially friendly and environmentally benign. Furthermore, several process-related impurities were identified, synthesized, characterized, and studied for their purging capability. According to the SciFinder database, there are two new impurities (<b>23</b> and <b>24</b>), which are structurally similar to the fluazuron API, that could lead to the discovery of new biological applications in both animal and human drug development.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"5 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596789","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}
Dattatray Patil, Rakesh R. Ganorkar, Ramakant Kardile, Madhavrao Bhoite, Amol Jadhav, Rutuja Gundal and Garbapu Suresh*,
{"title":"Thermodynamically Controlled and Industrially Viable Telescopic Process for the Synthesis of Fluazuron","authors":"Dattatray Patil, Rakesh R. Ganorkar, Ramakant Kardile, Madhavrao Bhoite, Amol Jadhav, Rutuja Gundal and Garbapu Suresh*, ","doi":"10.1021/acs.oprd.4c0034510.1021/acs.oprd.4c00345","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00345https://doi.org/10.1021/acs.oprd.4c00345","url":null,"abstract":"<p >Fluazuron <i>N</i>-[(4-chloro-3-[3-chloro-5-(trifluoromethyl)pyridine-2-yl]oxy phenyl]carbamoyl]-2,6-difluorobenzamide (<b>14</b>) is a noteworthy antiparasitic veterinary medicine belonging to the class of benzoyl phenyl urea derivatives, a class of chitin synthesis inhibitors. The commercial-scale synthesis, which is compliant with current regulatory requirements, particularly purity and impurity profiles, is not well established. Therefore, a robust and sustainable manufacturing process is essential to manufacture and supply fluazuron or any drug substance, for that matter, meeting all criteria. In this work, a safe, scalable, economic, and sustainable process was described through a robust in situ protocol for the bottleneck isocyanate intermediate (<b>20</b>) to manufacture a substantially pure fluazuron active pharmaceutical ingredient (API) with >99.5% HPLC purity and a yield of >78% overall. This large-scale GMP manufacturing process was established by implementing DoE tools and principles of green chemistry like process mass intensity assessment (PMI) and the “3Rs” principle (reduce/reuse/recycle) to attain the “3Ps” sustainability target (profit/people/planet). The developed process technology was successfully validated under cGMP plant conditions on a scale of 600 kg batch size to supply the fluazuron API (<b>14</b>) across the globe for veterinary use. This process is commercially friendly and environmentally benign. Furthermore, several process-related impurities were identified, synthesized, characterized, and studied for their purging capability. According to the SciFinder database, there are two new impurities (<b>23</b> and <b>24</b>), which are structurally similar to the fluazuron API, that could lead to the discovery of new biological applications in both animal and human drug development.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 12","pages":"4348–4373 4348–4373"},"PeriodicalIF":3.1,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858577","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, Anna M. Wagner, Jeromy Cottell, Kathy Dao, Darryl D. Dixon, Blanka M. Hodur, Dane Holte, Michael A. Ischay, Jihun Kang, Seongtaek Kim, Young Ho Kim, Seung Moh Koo, Willard Lew, Lucas Man, Kashi Reddy Methuku, Henry Morrison, Patrick D. Parker, David A. Siler, Chloe Y. Wong
{"title":"Early Process Development of an LPAR1 Antagonist, GS-2278","authors":"Nathaniel Kadunce, Anna M. Wagner, Jeromy Cottell, Kathy Dao, Darryl D. Dixon, Blanka M. Hodur, Dane Holte, Michael A. Ischay, Jihun Kang, Seongtaek Kim, Young Ho Kim, Seung Moh Koo, Willard Lew, Lucas Man, Kashi Reddy Methuku, Henry Morrison, Patrick D. Parker, David A. Siler, Chloe Y. Wong","doi":"10.1021/acs.oprd.4c00369","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00369","url":null,"abstract":"(<i>R</i>)-1-(2,5-Difluoropyridin-3-yl)ethyl(1-methyl-4-(5-(2-(trifluoromethyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1<i>H</i>-1,2,3-triazol-5-yl)carbamate (GS-2278) is a lysophosphatidic acid receptor 1 antagonist under development for the treatment of idiopathic pulmonary fibrosis. GS-2278 is assembled in a 9-step sequence. Initially, 2-bromo-5-fluoropyridine is metalated and trapped with ethyl difluoroacetate. Then, after condensation with tosyl hydrazide, Sakai cyclization with methylamine, and carboxylation with carbon dioxide, the triazole carboxylic acid core is generated. For the final assembly, the core is elaborated through a two-step hydroxamic acid formation and Lossen rearrangement to form an isocyanate which is trapped in situ by a chiral alcohol. The resulting carbamate is Boc-deprotected and subjected to amide coupling with a pyrimidine carboxylic acid to yield the active pharmaceutical ingredient. Process development was conducted to determine reaction and isolation conditions to enable scale-ups to support preclinical and early clinical studies. This paper focuses on the development of conditions from the medicinal chemistry route to the Ph 1 manufacturing route.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"61 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580637","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*, Anna M. Wagner*, Jeromy Cottell, Kathy Dao, Darryl D. Dixon, Blanka M. Hodur, Dane Holte, Michael A. Ischay, Jihun Kang, Seongtaek Kim, Young Ho Kim, Seung Moh Koo, Willard Lew, Lucas Man, Kashi Reddy Methuku, Henry Morrison, Patrick D. Parker, David A. Siler and Chloe Y. Wong,
{"title":"Early Process Development of an LPAR1 Antagonist, GS-2278","authors":"Nathaniel Kadunce*, Anna M. Wagner*, Jeromy Cottell, Kathy Dao, Darryl D. Dixon, Blanka M. Hodur, Dane Holte, Michael A. Ischay, Jihun Kang, Seongtaek Kim, Young Ho Kim, Seung Moh Koo, Willard Lew, Lucas Man, Kashi Reddy Methuku, Henry Morrison, Patrick D. Parker, David A. Siler and Chloe Y. Wong, ","doi":"10.1021/acs.oprd.4c0036910.1021/acs.oprd.4c00369","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00369https://doi.org/10.1021/acs.oprd.4c00369","url":null,"abstract":"<p >(<i>R</i>)-1-(2,5-Difluoropyridin-3-yl)ethyl(1-methyl-4-(5-(2-(trifluoromethyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1<i>H</i>-1,2,3-triazol-5-yl)carbamate (GS-2278) is a lysophosphatidic acid receptor 1 antagonist under development for the treatment of idiopathic pulmonary fibrosis. GS-2278 is assembled in a 9-step sequence. Initially, 2-bromo-5-fluoropyridine is metalated and trapped with ethyl difluoroacetate. Then, after condensation with tosyl hydrazide, Sakai cyclization with methylamine, and carboxylation with carbon dioxide, the triazole carboxylic acid core is generated. For the final assembly, the core is elaborated through a two-step hydroxamic acid formation and Lossen rearrangement to form an isocyanate which is trapped in situ by a chiral alcohol. The resulting carbamate is Boc-deprotected and subjected to amide coupling with a pyrimidine carboxylic acid to yield the active pharmaceutical ingredient. Process development was conducted to determine reaction and isolation conditions to enable scale-ups to support preclinical and early clinical studies. This paper focuses on the development of conditions from the medicinal chemistry route to the Ph 1 manufacturing route.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 11","pages":"4099–4113 4099–4113"},"PeriodicalIF":3.1,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142641108","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}
Steve Avery, Jamie M. Buske, Doris Chen, Herman Chen, Xin Chen, Andrew R. Davidson, Jean-Nicolas Desrosiers, Hanqing Dong, Noalle Fellah, David F. Fernández, John Grosso, Lu Han, Teri Hochdorfer, Amber M. Johnson, Brian P. Jones, Maciej Kalinowski, Katherine D. Launer-Felty, Jorge Lopez, Teresa Makowski, Carolyn Mastriano, Truong N. Nguyen, Nitinchandra D. Patel, Zhihui Peng, Tyler Potter, Robert P. Pritchard, Anil M. Rane, Max Reeve, Margaret C. Richins, Chase A. Salazar, John J. Salisbury, Robert Simpson, Liza Tabshey, Erin J. Tweed, Paul G. Wahome, Nancy Walsh-Sayles, Jordan A. Willie, Ethan Wood
{"title":"Development of a Commercial Manufacturing Process for Vepdegestrant, an Orally Bioavailable PROTAC Estrogen Receptor Degrader for the Treatment of Breast Cancer","authors":"Steve Avery, Jamie M. Buske, Doris Chen, Herman Chen, Xin Chen, Andrew R. Davidson, Jean-Nicolas Desrosiers, Hanqing Dong, Noalle Fellah, David F. Fernández, John Grosso, Lu Han, Teri Hochdorfer, Amber M. Johnson, Brian P. Jones, Maciej Kalinowski, Katherine D. Launer-Felty, Jorge Lopez, Teresa Makowski, Carolyn Mastriano, Truong N. Nguyen, Nitinchandra D. Patel, Zhihui Peng, Tyler Potter, Robert P. Pritchard, Anil M. Rane, Max Reeve, Margaret C. Richins, Chase A. Salazar, John J. Salisbury, Robert Simpson, Liza Tabshey, Erin J. Tweed, Paul G. Wahome, Nancy Walsh-Sayles, Jordan A. Willie, Ethan Wood","doi":"10.1021/acs.oprd.4c00362","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00362","url":null,"abstract":"A commercial process for vepdegestrant (<b>1</b>), the most advanced PROTAC protein degrader in human clinical trials, has been developed to support clinical and commercial needs. The process features an efficient convergent synthetic strategy through the final reductive amination of two advanced chiral intermediates, as well as several highly efficient telescoped processes and robust crystallization for purity control. The final commercial process of vepdegestrant (<b>1</b>) consists of seven proposed regulatory GMP steps with five isolations in an overall yield of 29%.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"144 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580692","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}
Steve Avery, Jamie M. Buske, Doris Chen, Herman Chen, Xin Chen, Andrew R. Davidson, Jean-Nicolas Desrosiers, Hanqing Dong*, Noalle Fellah, David F. Fernández*, John Grosso, Lu Han, Teri Hochdorfer, Amber M. Johnson, Brian P. Jones, Maciej Kalinowski, Katherine D. Launer-Felty, Jorge Lopez, Teresa Makowski, Carolyn Mastriano, Truong N. Nguyen, Nitinchandra D. Patel, Zhihui Peng*, Tyler Potter, Robert P. Pritchard, Anil M. Rane, Max Reeve, Margaret C. Richins, Chase A. Salazar, John J. Salisbury, Robert Simpson*, Liza Tabshey, Erin J. Tweed, Paul G. Wahome, Nancy Walsh-Sayles, Jordan A. Willie and Ethan Wood,
{"title":"Development of a Commercial Manufacturing Process for Vepdegestrant, an Orally Bioavailable PROTAC Estrogen Receptor Degrader for the Treatment of Breast Cancer","authors":"Steve Avery, Jamie M. Buske, Doris Chen, Herman Chen, Xin Chen, Andrew R. Davidson, Jean-Nicolas Desrosiers, Hanqing Dong*, Noalle Fellah, David F. Fernández*, John Grosso, Lu Han, Teri Hochdorfer, Amber M. Johnson, Brian P. Jones, Maciej Kalinowski, Katherine D. Launer-Felty, Jorge Lopez, Teresa Makowski, Carolyn Mastriano, Truong N. Nguyen, Nitinchandra D. Patel, Zhihui Peng*, Tyler Potter, Robert P. Pritchard, Anil M. Rane, Max Reeve, Margaret C. Richins, Chase A. Salazar, John J. Salisbury, Robert Simpson*, Liza Tabshey, Erin J. Tweed, Paul G. Wahome, Nancy Walsh-Sayles, Jordan A. Willie and Ethan Wood, ","doi":"10.1021/acs.oprd.4c0036210.1021/acs.oprd.4c00362","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00362https://doi.org/10.1021/acs.oprd.4c00362","url":null,"abstract":"<p >A commercial process for vepdegestrant (<b>1</b>), the most advanced PROTAC protein degrader in human clinical trials, has been developed to support clinical and commercial needs. The process features an efficient convergent synthetic strategy through the final reductive amination of two advanced chiral intermediates, as well as several highly efficient telescoped processes and robust crystallization for purity control. The final commercial process of vepdegestrant (<b>1</b>) consists of seven proposed regulatory GMP steps with five isolations in an overall yield of 29%.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 11","pages":"4079–4090 4079–4090"},"PeriodicalIF":3.1,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142641055","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}
{"title":"Continuous Flow Enabled Synthesis of Multiresistant Drug Clofazimine","authors":"Rajat Pandey, Faith Akwi and Paul Watts*, ","doi":"10.1021/acs.oprd.4c0042010.1021/acs.oprd.4c00420","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00420https://doi.org/10.1021/acs.oprd.4c00420","url":null,"abstract":"<p >Drug resistance to tuberculosis is still one of the major challenges worldwide. Clofazimine, which belongs to the riminophenazine (antibiotic) class, is still one of the active drugs that are efficient against drug-resistant <i>Mycobacterium tuberculosis</i>. Apart from this, it is also a WHO-approved drug for the treatment of leprosy and, at present, is under phase 2 clinical trial for its activity against the SARS-CoV-2 virus. Owing to its vast importance in clinical research, we have developed a semicontinuous flow-mediated synthesis of Clofazimine using readily available <i>p</i>-chloroaniline and 1-fluoro-2-nitrobenzene. The target drug molecule was obtained from four consecutive chemical transformations with nominal residence time, improved purity, and yields when compared to the batch process. Moreover, the first two steps were also successfully telescoped under the optimized reaction conditions.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 11","pages":"4163–4172 4163–4172"},"PeriodicalIF":3.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.oprd.4c00420","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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