Process Development for the Manufacture of a Topical Pan-Trk Inhibitor Incorporating Decarboxylative sp2–sp3 Cross-Coupling

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-11-12 DOI:10.1021/acs.oprd.4c0032510.1021/acs.oprd.4c00325

Michael S. Ashwood, Edward I. Balmond, David Fengas, Jane McGuffog, Jonathan Moore, Nicola M. Robas, Neil G. Stevenson* and Lisa Wise,

{"title":"Process Development for the Manufacture of a Topical Pan-Trk Inhibitor Incorporating Decarboxylative sp2–sp3 Cross-Coupling","authors":"Michael S. Ashwood, Edward I. Balmond, David Fengas, Jane McGuffog, Jonathan Moore, Nicola M. Robas, Neil G. Stevenson* and Lisa Wise, ","doi":"10.1021/acs.oprd.4c0032510.1021/acs.oprd.4c00325","DOIUrl":null,"url":null,"abstract":"The development of a synthetic route toward topical pan-Trk inhibitor 1 is described as an eight-stage synthesis from available starting materials. Process improvements include the development of a decarboxylative sp2–sp3 cross-coupling which had not previously been demonstrated on scale. Parameters were explored, balancing the safety aspects with conversion and selectivity, scaling up in a stepwise fashion to multiple successful 0.7 kg batches. The cross-coupling showed high diastereoselectivity, with the opposite diastereomer not observed in the crude 19F NMR. Selectivity was further improved by crystallizing the downstream pyrrolidine salt after Boc deprotection, to give a diastereomer ratio of 99.5:0.5 by UPLC. This route has been reproducibly demonstrated in two GMP campaigns delivering API on kilogram scale, in >98% area purity by HPLC. The route design, solid-form screening, process research, and manufacture have enabled crucial first-in-human (FIH) clinical studies, through focus on speed of delivery.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 12","pages":"4317–4327 4317–4327"},"PeriodicalIF":3.1000,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Organic Process Research & Development","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.oprd.4c00325","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}

引用次数: 0

Abstract

The development of a synthetic route toward topical pan-Trk inhibitor 1 is described as an eight-stage synthesis from available starting materials. Process improvements include the development of a decarboxylative sp²–sp³ cross-coupling which had not previously been demonstrated on scale. Parameters were explored, balancing the safety aspects with conversion and selectivity, scaling up in a stepwise fashion to multiple successful 0.7 kg batches. The cross-coupling showed high diastereoselectivity, with the opposite diastereomer not observed in the crude ¹⁹F NMR. Selectivity was further improved by crystallizing the downstream pyrrolidine salt after Boc deprotection, to give a diastereomer ratio of 99.5:0.5 by UPLC. This route has been reproducibly demonstrated in two GMP campaigns delivering API on kilogram scale, in >98% area purity by HPLC. The route design, solid-form screening, process research, and manufacture have enabled crucial first-in-human (FIH) clinical studies, through focus on speed of delivery.

Abstract Image

查看原文本刊更多论文

结合脱羧sp2-sp3交叉偶联的局部Pan-Trk抑制剂的生产工艺开发

局部泛trk抑制剂1的合成路线的发展被描述为从可用的起始材料合成的八个阶段。工艺改进包括开发脱羧sp2-sp3交叉偶联，这在以前没有被大规模证明。对参数进行了探索，平衡了安全性方面的转化和选择性，逐步扩大到多个成功的0.7公斤批次。交叉偶联表现出高的非对映选择性，在粗19F NMR中未观察到相反的非对映体。Boc脱保护后，通过对下游吡啶盐的结晶进一步提高了选择性，UPLC得到的非对映体比为99.5:0.5。该路线已在两次GMP活动中得到重复性证明，以公斤为单位，HPLC纯度为98%。路线设计、固体形式筛选、工艺研究和制造，通过关注递送速度，实现了关键的首次人体临床研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

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.