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Continuous GMP Manufacturing for Grignard Reagent/Zincate Synthesis and Negishi Coupling Reaction
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2024-01-22 , DOI: 10.1021/acs.oprd.3c00361
Joel R. Calvin 1 , Raymond Boyse 2 , Timothy M. Braden 1 , Alison C. Brewer 1 , Shujauddin Changi 1 , Donal Harrold 2 , Martin Johnson 1 , Mark S. Kerr 1 , Gordon R. Lambertus 1 , Carla V. Luciani 1 , Scott A. May 1 , Harold Moloney 2 , John D. Murphy 2 , Jeffrey C. Roberts 1 , John P. Schafer 1, 3 , Richard D. Spencer 2 , Luke P. Webster 1
Affiliation  

A synthetic route to API was designed containing a Negishi cross-coupling reaction, where the zincate reagent was generated by transmetalation of a Grignard reagent. In order to manage the poor stability of the Grignard reagent, as well as safety concerns, the chemistry was developed as a flow process. Here we will disclose the flow process for the generation of the Grignard/zincate and subsequent Negishi reaction as well as the workup steps that were funneled into the continuous crystallization process. This process was developed to operate at 10+ kg/day in a GMP manufacturing fume hood facility that won an International Society for Pharmaceutical Engineering 2019 Facility of the Year Award for Innovation. Tools, techniques, models, and equipment that were used to overcome challenges during the development of this safe and reliable manufacturing process are also described herein.

中文翻译:

格氏试剂/锌酸盐合成和根岸偶联反应的连续 GMP 制造

API 的合成路线被设计为包含根岸交叉偶联反应,其中锌酸盐试剂是通过格氏试剂的金属转移生成的。为了解决格氏试剂稳定性差以及安全问题,该化学过程被开发为流动过程。在这里,我们将公开格氏/锌酸盐的生成和随后的根岸反应的流程,以及进入连续结晶过程的后处理步骤。该工艺是在 GMP 制造通风柜设施中以 10+ 公斤/天的速度运行而开发的,该设施荣获国际制药工程学会 2019 年度创新设施奖。本文还描述了在开发这种安全可靠的制造工艺期间用于克服挑战的工具、技术、模型和设备。
更新日期:2024-01-22
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