A Robust Kilo-Scale Synthesis of Doravirine

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...

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Bibliographic Details
Published inOrganic process research & development Vol. 20; no. 8; pp. 1476 - 1481
Main Authors Campeau, Louis-Charles, Chen, Qinghao, Gauvreau, Danny, Girardin, Mélina, Belyk, Kevin, Maligres, Peter, Zhou, Guoyue, Gu, Chaozhan, Zhang, Wei, Tan, Lushi, O’Shea, Paul D
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 19.08.2016
Amer Chemical Soc
Subjects
Chemistry
Chemistry, Applied
Chemistry, Organic
Physical Sciences
Science & Technology
ROOM-TEMPERATURE
POTENT
HIV
NONNUCLEOSIDE REVERSE-TRANSCRIPTASE
CYANATION
ANTIRETROVIRAL THERAPY
INHIBITOR
BORYLATION
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Summary: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.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.6b00163