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.
Bibliographical noteFunding 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.
- BET inhibitors
- Male contraceptive
- One-pot method
- Triazolothienodiazepine (+)-JQ1