Process Development and Scale Up of a Selective JAK3 Covalent Inhibitor PF-06651600

IF 3.5 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2019-07-19 DOI:10.1021/acs.oprd.9b00198

Yong Tao*, J. Christopher McWilliams, Kristin E. Wiglesworth, Kevin P. Girard, Teresa M. Makowski, Neal W. Sach, Jason G. Mustakis, Ruchi Mehta, John I. Trujillo, Xiaofeng Chen, Tangqing Li, Feng Shi, Chengfu Xie, Qing Zhang

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引用次数: 3

Abstract

A scalable process for PF-06651600 (1) has been developed through successful enabling of the first generation syntheis. The synthesis highlights include the following: (1) replacement of costly PtO₂ with a less expensive 5% Rh/C catalyst for a pyridine hydrogenation, (2) identification of a diasteroemeric salt crystallization to isolate the enantiomerically pure cis-isomer directly from a racemic mixture of cis/trans isomers, (3) a high yielding amidation via Schotten–Baumann conditions, and (4) critical development of a reproducible crystallization procedure for a stable crystalline salt (1·TsOH), which is suitable for long-term storage and tablet formulation. All chromatographic purifications, including two chiral SFC chromatographic separations, were eliminated. Combined with other improvements in each step of the synthesis, the overall yield was increased from 5% to 14%. Several multikilogram batches of the API have been delivered to support clinical studies.

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选择性JAK3共价抑制剂PF-06651600的工艺开发和规模化研究

通过成功实现第一代合成，已经开发出可扩展的PF-06651600(1)工艺。综合要点包括以下几点:(1)用更便宜的5% Rh/C催化剂取代昂贵的PtO2进行吡啶加氢;(2)鉴定非对映异构体盐结晶，直接从顺反异构体的外消旋混合物中分离出对映异构的纯顺式异构体;(3)通过schotton - baumann条件进行高产酰胺化;(4)开发可重复结晶过程，获得稳定结晶盐(1·TsOH)。适合长期储存和片剂配制。所有色谱纯化，包括两个手性SFC色谱分离，都被取消。结合合成各步骤的其他改进，总收率从5%提高到14%。已经交付了几批多公斤的原料药以支持临床研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

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.