The development of a scalable process for a complex intermediate featuring a chiral, quaternary cyclopropane moiety presented significant challenges. We report two generations of synthetic strategies appropriate for the respective stages of development. The initial approach utilized a stereoselective Simmons–Smith cyclopropanation of (R)-pyroglutamic acid ester, which predominantly yielded the undesired stereoisomer. To circumvent this issue, we implemented a strategy that combined isomerization, recycling of the undesired isomer, and selective crystallization to improve the yield of the desired product. An important insight was that the Simmons–Smith cyclopropanation exhibited opposite stereoselectivity with a benzoyl ester of a prolinol substrate, resulting in the desired stereoisomer as the major product. This understanding enabled the development of a second-generation process that facilitated the large-scale production of the targeted intermediate, thus supporting the advancement of clinical trials.

中文翻译：

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开发具有复杂立体化学的环丙基-甲基-脯氨酸合成可扩展工艺：因子 D 抑制剂的关键组成部分


为具有手性季铵盐环丙烷部分的复杂中间体开发可扩展工艺提出了重大挑战。我们报告了适用于各自发展阶段的两代合成策略。最初的方法利用了 （R）-焦谷氨酸酯的立体选择性 Simmons-Smith 环丙烷化，主要产生不需要的立体异构体。为了规避这个问题，我们实施了一项策略，将异构化、不需要的异构体回收和选择性结晶相结合，以提高所需产品的产量。一个重要的见解是，Simmons-Smith 环丙烷化反应与脯氨酸底物的苯甲酰酯表现出相反的立体选择性，导致所需的立体异构体作为主要产物。这种理解促成了第二代工艺的开发，促进了目标中间体的大规模生产，从而支持了临床试验的推进。