Multikilogram Synthesis of a Potent Dual Bcl-2/Bcl-x<sub>L</sub> Antagonist. 1. Manufacture of the Acid Moiety and Development of Some Key Reactions
作者:Christophe Hardouin、Sandrine Baillard、François Barière、Chloé Copin、Anthony Craquelin、Solenn Janvier、Sylvain Lemaitre、Stéphane Le Roux、Olivier Russo、Sébastien Samson
DOI:10.1021/acs.oprd.9b00364
日期:2020.5.15
Our efforts toward the process development of drug candidate 1 are described in a series of two papers. This manuscript focuses on the synthesis of kilogram quantities of acid precursor 2 to provide batches of material for preclinical studies and first-in-human clinical trials. Our approach relies on a chiral resolution to furnish the desired stereocenter, a cryogenic carboxylation, and N-alkylation
我们在两篇论文中描述了我们对候选药物1的开发过程。该手稿侧重于千克量的酸前体2的合成,以提供批次的材料用于临床前研究和首次人体临床试验。我们的方法依赖于手性拆分以提供所需的立体中心,低温羧化和通过Suzuki偶联制备的氯化物衍生物26的N-烷基化。还讨论了进一步的努力,以改进那些可能成为更大规模问题的关键步骤。