Development and Execution of an Ni(II)-Catalyzed Reductive Cross-Coupling of Substituted 2-Chloropyridine and Ethyl 3-Chloropropanoate,Organic Process Research & Development

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Development and Execution of an Ni(II)-Catalyzed Reductive Cross-Coupling of Substituted 2-Chloropyridine and Ethyl 3-Chloropropanoate
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2020-05-18 , DOI: 10.1021/acs.oprd.0c00134
Sri Krishna Nimmagadda ₁ , Satish Korapati ₁ , Debottam Dasgupta ₁ , Noormohamed Abdul Malik ₁ , Arun Vinodini ₁ , Aravind S. Gangu ₁ , Srinivas Kalidindi ₁ , Prantik Maity ₁ , Siva Sankar Bondigela ₁ , Alla Venu ₁ , William P. Gallagher ₂ , Selin Aytar ₂ , Francisco González-Bobes ₂ , Rajappa Vaidyanathan ₁

Affiliation

We describe the development and scale-up of a nickel-catalyzed reductive cross-electrophile coupling reaction between a substituted 2-chloropyridine and ethyl 3-chloropropanoate using manganese dust as the terminal reductant. Several additives were screened for the activation of the manganese reductant in situ, and chlorotriethylsilane (TESCl) was found to provide the optimal conversion. A focused beam reflectance measurement (FBRM) probe was utilized to monitor particle attrition as well as manganese activation during the reaction. Modeling was employed to garner an understanding of mixing requirements that would ensure effective suspension of the manganese during scale-up. The process was successfully demonstrated on a 7 kg scale and afforded 2 in 64% yield.

中文翻译：

Ni（II）催化的2-氯吡啶和3-氯丙酸乙酯的还原性交叉偶联反应的开发和执行

我们描述了锰粉尘作为末端还原剂的镍取代的2-氯吡啶和3-氯丙酸乙酯之间的镍催化的还原亲电偶联反应的发展和规模化。筛选了几种添加剂以原位活化锰还原剂，发现氯三乙基硅烷（TESCl）可提供最佳转化率。聚焦光束反射率测量（FBRM）探针用于监测反应过程中的颗粒磨损和锰活化。通过建模获得对混合要求的理解，以确保在放大过程中有效地悬浮锰。该方法成功地以7千克规模进行了演示，收率2％，为64％。

更新日期：2020-06-19

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