Development and Scale-Up of an Asymmetric Synthesis of AZD8186 Using the Fukuyama Modification of the Mitsunobu Reaction,Organic Process Research & Development

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Development and Scale-Up of an Asymmetric Synthesis of AZD8186 Using the Fukuyama Modification of the Mitsunobu Reaction
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2021-07-15 , DOI: 10.1021/acs.oprd.1c00133
Peter R. Moore ₁ , James C. Muir ₂ , Jerome Dubiez ₁ , Kevin W. Leslie ₂ , Paula Tomlin ₂ , Marc McCormick ₁ , Sophie L. Janbon ₁ , Philip Cornwall ₁ , Per Ryberg ₃ , Robert Berg ₃

Affiliation

A large-scale asymmetric synthesis has been developed for the kilo-lab manufacture of AZD8186. The process initially employs a regioselective Heck coupling in water to provide the starting aromatic ketone. This ketone is reduced asymmetrically under ruthenium-catalyzed transfer hydrogenation conditions to provide a chiral alcohol in high enantiomeric purity. The key synthetic step then requires the reaction of this chiral alcohol with the activated derivative of 3,5-difluoroaniline under the Mitsunobu reaction conditions. The common issues associated with the use of the Mitsunobu reaction, such as removal of triphenylphosphine oxide and reduced diisopropyl azodicarboxylate (DIAD) by-products, have been eliminated through crystallization of the relevant intermediates.

中文翻译：

AZD8186 不对称合成的开发和放大使用光信反应的福山改性

为 AZD8186 的公斤实验室制造开发了大规模不对称合成。该方法最初在水中采用区域选择性 Heck 偶联来提供起始芳香酮。该酮在钌催化的转移氢化条件下不对称还原，以提供高对映体纯度的手性醇。然后，关键的合成步骤需要这种手性醇与 3,5-二氟苯胺的活化衍生物在光信反应条件下反应。与使用 Mitsunobu 反应相关的常见问题，例如去除氧化三苯基膦和还原偶氮二羧酸二异丙酯 (DIAD) 副产物，已通过相关中间体的结晶消除。

更新日期：2021-08-20

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