A Robust Kilo-Scale Synthesis of Doravirine

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2016-07-05 DOI:10.1021/acs.oprd.6b00163

Louis-Charles Campeau*, Qinghao Chen, Danny Gauvreau, Mélina Girardin, Kevin Belyk, Peter Maligres, Guoyue Zhou, Chaozhan Gu, Wei Zhang, Lushi Tan, Paul D. O’Shea

引用次数: 46

Abstract

Doravirine is non-nucleoside reverse transcriptase inhibitor (NNRTI) currently in phase III clinical trials for the treatment of HIV infection. Herein we describe a robust kilo-scale synthesis for its manufacture. The structure and origin of major impurities were determined and their downstream fate-and-purge studied. This resulted in a redesign of the route to introduce the key nitrile functionality via a copper mediated cyanation which allowed all impurities to be controlled to an acceptable level. The improved synthesis was scaled to prepare ～100 kg batches of doravirine to supply all preclinical and clinical studies up to phase III. The synthesis affords high-quality material in a longest linear sequence of six steps and 37% overall yield.

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一种稳健的千尺度合成多拉韦林的方法

Doravirine是一种非核苷类逆转录酶抑制剂(NNRTI)，目前正处于治疗HIV感染的III期临床试验中。本文描述了一种鲁棒的千尺度合成方法。确定了主要杂质的结构和来源，并对其下游命运和净化进行了研究。这导致了对路线的重新设计，通过铜介导的氰化反应引入关键的腈功能，从而使所有杂质控制在可接受的水平。改进后的合成可批量制备约100公斤的多拉韦林，以供临床前和临床研究直至第三期。在六个步骤的最长线性序列中，合成提供了高质量的材料，总收率为37%。

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.