Multikilogram Synthesis of a Potent Dual Bcl-2/Bcl-xL Antagonist. 2. Manufacture of the 1,3-Diamine Moiety and Improvement of the Final Coupling Reaction,Organic Process Research & Development

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Multikilogram Synthesis of a Potent Dual Bcl-2/Bcl-xL Antagonist. 2. Manufacture of the 1,3-Diamine Moiety and Improvement of the Final Coupling Reaction
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2019-11-19 , DOI: 10.1021/acs.oprd.9b00367
Christophe Hardouin ₁ , Sandrine Baillard ₁ , François Barière ₁ , Anthony Craquelin ₁ , Mathieu Grandjean ₁ , Solenn Janvier ₁ , Stéphane Le Roux ₁ , Christine Penloup ₁ , Olivier Russo ₁

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This paper describes the synthesis of kilogram quantities of the sulfonamide moiety 3 involved in a coupling reaction with acid moiety 2 to provide batches of drug candidate 1 for preclinical studies and first-in-human clinical trials. A first approach relying on a chiral separation furnished the desired enantiomer of 1,3-diamine 20, precursor of sulfonamide 3. An enantiomeric synthesis of 20 using the Ellman’s chiral auxiliary coupled with an aza-Reformatsky reaction to control the stereochemistry is also discussed. Coupling conditions of the final step involving EDCI to provide 1 under a cGMP process are detailed. An alternative approach using N-(1-methanesulfonyl)benzotriazole is also presented.

中文翻译：

强大的双重Bcl-2 / Bcl-x _L拮抗剂的多千克合成。2. 1,3-二胺部分的制造和最终偶联反应的改进

本文描述了与酸部分2偶联反应中涉及的千克量磺酰胺部分3的合成，以提供批次的候选药物1用于临床前研究和首次人类临床试验。依靠手性分离的第一种方法提供了所需的1,3-二胺20（磺酰胺3的前体）对映体。还讨论了使用Ellman手性助剂与aza-Reformatsky反应耦合以控制立体化学的对映体合成20。详细介绍了EDCI在cGMP流程中提供1的最终步骤的耦合条件。另一种使用方法还提出了N-（1-甲磺酰基）苯并三唑。

更新日期：2019-11-19

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