Continuous Process for Preparing the Difluoromethylating Reagent [(DMPU)2Zn(CF2H)2] and Improved Synthesis of the ICHF2 Precursor,Organic Process Research & Development

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Continuous Process for Preparing the Difluoromethylating Reagent [(DMPU)2Zn(CF2H)2] and Improved Synthesis of the ICHF2 Precursor
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2020-05-05 , DOI: 10.1021/acs.oprd.0c00089
Sebastien Monfette ₁ , Yuan-Qing Fang ₂ , Matthew M. Bio ₂ , Adam R. Brown ₁ , Ian T. Crouch ₂ , Jean-Nicolas Desrosiers ₁ , Shengquan Duan ₁ , Joel M. Hawkins ₁ , Cheryl M. Hayward ₁ , Nikita Peperni ₁ , Joseph P. Rainville ₁

Affiliation

Complex [(DMPU)₂Zn(CF₂H)₂] 1 is a crystalline organometallic reagent with utility in various catalytic difluoromethylation reactions under mild conditions. Unfortunately, this reagent is not commercially available and the procedure for the preparation of this air- and moisture-sensitive zinc complex has only been reported on a small scale. Herein, we report the development of a continuous process for the preparation of reagent 1 on >100 g scale by using a continuous stirred-tank reactor. The key to success is the design of a continuous reactive crystallization process in which the precipitation of the zinc complex 1 is driven by its low solubility in the reaction solvent. The improved synthesis of the iododifluoromethane precursor 2 from readily available bromodifluoroacetic acid further enables the synthesis of complex 1 on a larger scale.

中文翻译：

连续制备二氟甲基化试剂[（DMPU）₂ Zn（CF ₂ H）₂ ]和改进ICHF ₂前体的合成

配合物[（DMPU）₂ Zn（CF ₂ H）₂ ] 1是一种结晶有机金属试剂，可在温和条件下用于各种催化二氟甲基化反应中。不幸的是，该试剂不是可商购的，并且仅对这种对空气和湿气敏感的锌络合物的制备方法进行了报道。在本文中，我们报告了通过使用连续搅拌釜反应器制备> 100 g规模试剂1的连续方法的发展。成功的关键是连续反应结晶过程的设计，其中锌络合物1的沉淀其在反应溶剂中的低溶解性驱动了该反应。由容易获得的溴二氟乙酸对碘二氟甲烷前体2的改进的合成进一步使得能够更大规模地合成配合物1。

更新日期：2020-06-19

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