Bromodomains (BRDs) and extra-terminal domain (BET) family proteins (BRD2, BRD3, BRD4 and BRDT) are epigenetic reader proteins. The BRDT protein is found at the highest levels in meiotic prophase spermatocytes, differing in expression from the other BET family members. The first bromodomain of BRDT, BRDT-1, is essential for male germ cell differentiation, and homozygous knockout mice were shown to be viable but sterile, making this an attractive target for the development of novel male contraceptives. Triazolothienodiazepine (+)-JQ1 has been utilized as chemical probe to validate testis-specific BRDT as a promising male contraceptive target. As part of our collaborative drug discovery toward a non-hormonal male contraceptive, we prepared (+)-JQ1 for further bioevaluation based on reported routes (Filippakopoulos et al. Nature, 2010, 468, 1067-1073). We envisioned a scalable synthesis of racemic JQ1 by developing a one-pot method for the synthesis of the triazole moiety. The conversion of an amide to an amidrazone via a thioamide using Lawesson’s reagent avoided the use of excess P2S5, which is problematic during work-up (gas development and sulfur-related smell). This method significantly improved the purification process and product yield. For the synthesis of enantiomerically enriched (+)-JQ1, we replaced highly toxic diethyl chlorophosphate used in the literature procedure with the less toxic diphenyl chlorophosphate in the three-step one-pot triazole formation without effecting yields and enantiomeric purity.

Improved syntheses of BET inhibitor JQ1

249th National Meeting (2015)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.