This report describes the research and development of a practical, efficient, and cost-effective process for manufacturing the selective USP1 inhibitor TNG348. This developed process made it possible to overcome a major challenge of the original medicinal chemistry route, namely, the poor regioselectivity of alkylation of 11 on the 8-iminopurine core, which led to a very low overall yield (1.6% from intermediate 8). A new route was designed where intermediate 8 was treated with benzoyl thioisocyanate, and the resulting thio-urea was cyclized to intermediate 15. Alkylation of Bz-protected 15 gave only the desired regioisomer 16. A Suzuki reaction and deprotection afforded TNG348. Further process development was conducted, such as the direct cyclization of intermediate 13 to 15 with DIC, isolation of the crude API as the TsOH salt to reject the urea impurity, and salt breaking. These improvements led to the second-eneration process, which successfully delivered the first GMP batch of TNG348 with 5.5 kg of material at 99.8% purity and a 37% overall yield from intermediate 8.
Liang et al. (Wed,) studied this question.