Development of a Scalable Synthesis of Mevidalen (LY3154207), an Orally Available Positive Allosteric Modulator of the Human Dopamine D1 Receptor

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED Organic Process Research & Development Pub Date : 2020-09-22 DOI:10.1021/acs.oprd.0c00229

Jeffery Richardson*, Kevin P. Cole, Amy C. DeBaillie, Junliang Hao, Jared Piper, Peter Houghton, John Rizzo, Mo Jia, Peng Liu, Ping Huang, Katarina Kadlecikova, Conchita F. Garcia, Daniel S. Richards

引用次数: 6

Abstract

The evolution from early medicinal chemistry to large-scale production of the chemical synthesis of Lilly D1-positive allosteric modulator (PAM) mevidalen (LY3154207) and its hydroxybenzoate co-crystal is outlined. The issues and steps taken to resolve them are outlined across several generations of synthesis, including unexpected issues that arose during cryogenic addition of MeLi to a key imine intermediate and the use of flow chemistry to enable large-scale production. Ultimately, a process that was used to deliver >100 kg of API to support ongoing clinical trials is described.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

可扩展合成人多巴胺D1受体口服正变构调节剂Mevidalen (LY3154207)的研究

概述了Lilly d1阳性变构调节剂(PAM) mevidalen (LY3154207)及其羟基苯甲酸盐共晶的化学合成从早期药物化学到大规模生产的演变过程。本文概述了几代合成中存在的问题和解决这些问题的步骤，包括在低温添加MeLi到关键亚胺中间体过程中出现的意想不到的问题，以及使用流动化学来实现大规模生产。最后，描述了用于提供100公斤原料药以支持正在进行的临床试验的过程。

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分钟内获得全文去求助

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.