Jianqing Li*, Daniel Smith, Lyndon Cornelius, Subramaniam Krishnananthan, Peng Li, Dauh-Rurng Wu, Chetan Padmakar Darne, Ning Li, James Kempson, Shun Su, Roshan Y. Nimje, Yoganand Shanmugam, Dyamanna Doddalingappa, Rajesh Krishnan, Anuradha Gupta and Arvind Mathur,
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引用次数: 0
摘要
本文介绍了(−)-(1R,2S,3R,4R，Z)-7-（溴基乙烯）- n -（4-氟-3-（三氟甲基）苯基）-3-（2,2,2-三氟乙酰氨基）双环[2.2.1]庚烷-2-羧酰胺（(−)-14,BMT-395173）的复合合成路线的发展，这是一种用于发散药物发现合成的多功能支架。这个新工艺从现成的商业原料开始，包括在(Z)-4-（苯氧基）-4-氧丁-2-烯酸（21）和六氟磷酸二茂铁（15）之间进行高度可扩展的立体选择性diols - alder反应，从而形成醇rac-20。此外，酮rac-10与（溴乙基）三苯基溴化磷的立体选择性Wittig反应引入了(−)-14的溴乙烯基团。该工艺被应用于制备超过100 g光学纯BMS-395173的多批次，用于临床前化学型优化。
Development of a Multigram Preparation of Optically Pure (−)-7-(Bromomethylene)-3-amidobicyclo[2.2.1]heptane-2-carboxamide BMT-395137, a Versatile Scaffold for Divergent Drug Discovery Synthesis
This paper describes the development of a synthetic route for the multigram synthesis of (−)-(1R,2S,3R,4R,Z)-7-(bromomethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2,2,2-trifluoroacetamido)bicyclo[2.2.1]heptane-2-carboxamide ((−)-14, BMT-395173), a versatile scaffold for divergent drug discovery synthesis. This new process begins with readily available commercial starting materials and includes a highly scalable stereoselective Diels–Alder reaction between (Z)-4-(benzyloxy)-4-oxobut-2-enoic acid (21) and ferrocenium hexafluorophosphate (15), resulting in the formation of alcohol rac-20. Additionally, a stereoselective Wittig reaction of ketone rac-10 with (bromomethyl)triphenylphosphonium bromide introduces the bromomethylene group of (−)-14. The process was applied to the preparation of over 100 g of optically pure BMS-395173 via multiple batches for preclinical chemotype optimization.
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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