Rapid Multikilogram Scale-Up of Di- and Trifluoromethoxy Proline Derivatives,Organic Process Research & Development

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Rapid Multikilogram Scale-Up of Di- and Trifluoromethoxy Proline Derivatives
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2024-03-11 , DOI: 10.1021/acs.oprd.3c00493
Pablo J. Cabrera ₁ , Christophe Allais ₁ , Joel T. Arcari ₂ , María González-Esguevillas ₁ , Emma L. McInturff ₁ , Matthew R. Reese ₂

Affiliation

This report describes the synthesis, development, and scale-up (up to 10 kg) of di- and trifluoromethoxy prolines, key fragments evaluated in the development of potential antiviral SARS-CoV2 M^pro inhibitors. We first demonstrate a scalable route to 1-tert-butyl 2-methyl (2S,4R)-4-(difluoromethoxy)pyrrolidine-1,2-dicarboxylate employing a Cu-catalyzed difluoromethylation of alcohols using 2,2-difluoro-2-(fluorosulfonyl)acetic acid. We then demonstrate the optimization and scale-up of challenging 1-tert-butyl 2-methyl (2S,4R)-4-(trifluoromethoxy)pyrrolidine-1,2-dicarboxylate through silver-mediated oxidative trifluoromethylation of the corresponding alcohol. Finally, we report on the oxidative fluoro-desulfurization of xanthates as a potentially scalable route to access chiral aliphatic trifluoromethoxy ethers.

中文翻译：

二氟甲氧基脯氨酸衍生物和三氟甲氧基脯氨酸衍生物的快速放大

本报告描述了二氟甲氧基脯氨酸和三氟甲氧基脯氨酸的合成、开发和放大（高达 10 千克），这是在潜在抗病毒 SARS-CoV2 M^前抑制剂开发过程中评估的关键片段。我们首先展示了利用 2,2-二氟-Cu 催化的醇二氟甲基化得到 1-叔丁基 2-甲基 (2 S ,4 R )-4-(二氟甲氧基)吡咯烷-1,2-二甲酸酯的可扩展路线。2-(氟磺酰基)乙酸。然后，我们展示了通过银介导的相应醇的氧化三氟甲基化来优化和放大具有挑战性的1-叔丁基2-甲基(2S , 4R ) -4-(三氟甲氧基)吡咯烷-1,2-二甲酸酯。最后，我们报告了黄原酸盐的氧化氟脱硫作为获得手性脂肪族三氟甲氧基醚的潜在可扩展途径。

更新日期：2024-03-11

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