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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| Published in | Organic process research & development Vol. 20; no. 8; pp. 1476 - 1481 |
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| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
WASHINGTON
American Chemical Society
19.08.2016
Amer Chemical Soc |
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| 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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| AbstractList | 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 similar to 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. 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. |
| Author | Campeau, Louis-Charles Maligres, Peter Zhou, Guoyue Belyk, Kevin Zhang, Wei Chen, Qinghao Gu, Chaozhan O’Shea, Paul D Gauvreau, Danny Girardin, Mélina Tan, Lushi |
| AuthorAffiliation | Merck Frosst Center for Therapeutic Research Merck Research Laboratories Process Research and Development WuXi AppTec Co., Ltd |
| AuthorAffiliation_xml | – name: Process Research and Development – name: Merck Research Laboratories – name: WuXi AppTec Co., Ltd – name: Merck Frosst Center for Therapeutic Research |
| Author_xml | – sequence: 1 givenname: Louis-Charles surname: Campeau fullname: Campeau, Louis-Charles email: louis-charles_campeau@merck.com – sequence: 2 givenname: Qinghao surname: Chen fullname: Chen, Qinghao – sequence: 3 givenname: Danny surname: Gauvreau fullname: Gauvreau, Danny – sequence: 4 givenname: Mélina surname: Girardin fullname: Girardin, Mélina – sequence: 5 givenname: Kevin surname: Belyk fullname: Belyk, Kevin – sequence: 6 givenname: Peter surname: Maligres fullname: Maligres, Peter – sequence: 7 givenname: Guoyue surname: Zhou fullname: Zhou, Guoyue – sequence: 8 givenname: Chaozhan surname: Gu fullname: Gu, Chaozhan – sequence: 9 givenname: Wei surname: Zhang fullname: Zhang, Wei – sequence: 10 givenname: Lushi surname: Tan fullname: Tan, Lushi – sequence: 11 givenname: Paul D surname: O’Shea fullname: O’Shea, Paul D |
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| Keywords | ROOM-TEMPERATURE POTENT HIV NONNUCLEOSIDE REVERSE-TRANSCRIPTASE CYANATION ANTIRETROVIRAL THERAPY INHIBITOR BORYLATION |
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| Title | A Robust Kilo-Scale Synthesis of Doravirine |
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