Negishi偶联反应
锌酸盐
试剂
化学
偶联反应
格氏试剂
联轴节(管道)
组合化学
格氏反应
有机化学
材料科学
冶金
锌
催化作用
作者
Joel R. Calvin,Raymond A. Boyse,Timothy M. Braden,Alison Campbell Brewer,Shujauddin M. Changi,Donal Harrold,Martin D. Johnson,Mark S. Kerr,Gordon R. Lambertus,Carla V. Luciani,Scott A. May,Harold Moloney,John D. Murphy,Jeffrey C. Roberts,J.P. Schafer,Richard D. Spencer,Luke P. Webster
标识
DOI:10.1021/acs.oprd.3c00361
摘要
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.
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