Scalable syntheses of the BET bromodomain inhibitor JQ1

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Abstract

We have developed methods involving the use of alternate, safer reagents for the scalable syntheses of the potent BET bromodomain inhibitor JQ1. A one-pot three step method, involving the conversion of a benzodiazepine to a thioamide using Lawesson's reagent, followed by amidrazone formation and installation of the triazole moiety furnished JQ1. This method provides good yields and a facile purification process. For the synthesis of enantiomerically enriched (+)-JQ1, the highly toxic reagent diethyl chlorophosphate, used in a previous synthesis, was replaced with the safer reagent diphenyl chlorophosphate in the three-step one-pot triazole formation without effecting yields and enantiomeric purity of (+)-JQ1.

Original languageEnglish (US)
Pages (from-to)3454-3457
Number of pages4
JournalTetrahedron Letters
Volume56
Issue number23
DOIs
StatePublished - May 25 2015

Bibliographical note

Funding Information:
Financial support for this project is gratefully acknowledged from the NIH/NICHD : 1U01HD076542 and HHSN275201300017C . The determination of the enantiomeric purity of (+)-JQ1 was carried out by Shanghai ChemPartner Co., Ltd China.

Publisher Copyright:
© 2015 The Authors. Published by Elsevier Ltd.

Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.

Keywords

  • BET inhibitors
  • Bromodomains
  • Male contraceptive
  • One-pot method
  • Thionation
  • Triazolothienodiazepine (+)-JQ1

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