Simon Wagschal*, Diego Broggini*, Trung D.C. Cao, Pascal Schleiss, Kristian Paun, Jessica Steiner, Anna-Lena Merk, Joachim Harsdorf, Winfried Fiedler, Stefan Schirling, Sven Hock, Tobias Strittmatter, Jan Dijkmans, Ivan Vervest, Tim Van Hoegaerden, Brecht Egle, Matthew P. Mower, Zhi Liu, Zhiyong Cao, Xiaoning He, Lei Chen, Lei Qin, Hongyu Tan, Jun Yan, Nicolas Lucien Cunière, Carolyn S. Wei, Venkata Vuyyuru, Rajaram Ayothiraman, Sundaramurthy Rangaswamy, Mohamed Jaleel, Rajappa Vaidyanathan, Martin D. Eastgate, Richard Klep, Cyril Benhaïm, Ilse Vogels, Koen Peeters and Sébastien Lemaire,
{"title":"Toward the Development of a Manufacturing Process for Milvexian: Scale-Up Synthesis of the Side Chain","authors":"Simon Wagschal*, Diego Broggini*, Trung D.C. Cao, Pascal Schleiss, Kristian Paun, Jessica Steiner, Anna-Lena Merk, Joachim Harsdorf, Winfried Fiedler, Stefan Schirling, Sven Hock, Tobias Strittmatter, Jan Dijkmans, Ivan Vervest, Tim Van Hoegaerden, Brecht Egle, Matthew P. Mower, Zhi Liu, Zhiyong Cao, Xiaoning He, Lei Chen, Lei Qin, Hongyu Tan, Jun Yan, Nicolas Lucien Cunière, Carolyn S. Wei, Venkata Vuyyuru, Rajaram Ayothiraman, Sundaramurthy Rangaswamy, Mohamed Jaleel, Rajappa Vaidyanathan, Martin D. Eastgate, Richard Klep, Cyril Benhaïm, Ilse Vogels, Koen Peeters and Sébastien Lemaire, ","doi":"10.1021/acs.oprd.2c00399","DOIUrl":null,"url":null,"abstract":"<p >Anticoagulants play a critical role in the prevention and treatment of thrombotic-driven cardiovascular diseases. Factor XIa (FXIa) inhibitors have the potential to improve the benefit/risk profile of existing anticoagulants through a safer bleeding profile in a variety of conditions where patients are predisposed to a high risk of thrombotic or bleeding events. To support the clinical development program of milvexian (BMS-986177/JNJ-70033093), a FXIa inhibitor that recently completed phase II clinical trials, we improved the discovery route to deliver the suitable quantity of key intermediate <b>1</b> for clinical supply. This paper describes our optimization of the Suzuki cross-coupling and how we simplified and improved the isolation of 4-trimethylsilyl-1,2,3-triazole <b>6</b> after the azidation–click sequence. On top of streamlining the processes for the chlorination and demethylation steps, we demonstrated that the recrystallization of the penultimate intermediate <b>7</b> was key to control the purity and the color of the desired 4-chloro-1,2,3-triazole <b>1</b>, which could be obtained in a 70% yield over five steps.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"27 4","pages":"680–691"},"PeriodicalIF":3.1000,"publicationDate":"2023-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Organic Process Research & Development","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.oprd.2c00399","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
引用次数: 0
Abstract
Anticoagulants play a critical role in the prevention and treatment of thrombotic-driven cardiovascular diseases. Factor XIa (FXIa) inhibitors have the potential to improve the benefit/risk profile of existing anticoagulants through a safer bleeding profile in a variety of conditions where patients are predisposed to a high risk of thrombotic or bleeding events. To support the clinical development program of milvexian (BMS-986177/JNJ-70033093), a FXIa inhibitor that recently completed phase II clinical trials, we improved the discovery route to deliver the suitable quantity of key intermediate 1 for clinical supply. This paper describes our optimization of the Suzuki cross-coupling and how we simplified and improved the isolation of 4-trimethylsilyl-1,2,3-triazole 6 after the azidation–click sequence. On top of streamlining the processes for the chlorination and demethylation steps, we demonstrated that the recrystallization of the penultimate intermediate 7 was key to control the purity and the color of the desired 4-chloro-1,2,3-triazole 1, which could be obtained in a 70% yield over five steps.
期刊介绍：
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.
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