A Robust Kilo-Scale Synthesis of Doravirine

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• 作者：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
• 刊名：Organic Process Research & Development
• 出版年：2016
• 出版时间：August 19, 2016
• 年：2016
• 卷：20
• 期：8
• 页码：1476-1481
• 全文大小：325K
• 年卷期：0
• ISSN：1520-586X

文摘

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.