Exploiting the Physical Properties of Diethanolamine Boronic Esters for Process Improvements in AZD5718,Organic Process Research & Development

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Exploiting the Physical Properties of Diethanolamine Boronic Esters for Process Improvements in AZD5718
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2023-03-09 , DOI: 10.1021/acs.oprd.2c00342
Jean-Marc Henry ₁ , David Milne ₁ , Dave Perkins ₁ , William Hicks ₁ , David R. J. Hose ₁ , Andrew D. Campbell ₁ , Alexander K. Mullen ₁ , Phillip A. Inglesby ₁ , Steven A. Raw ₁ , Martin F. Jones ₁

Affiliation

The process development toward synthesizing a diethanolamine (DEA) boronic ester and the subsequent Suzuki–Miyaura coupling (SMC) is disclosed herein. A one-pot lithiation–borylation–transesterification was successfully developed to isolate the DEA boronic ester as a stable crystalline solid and avoided the formation of boronic acid or pinacol boronic ester analogues, which have poor physical properties and purity profiles. The crystalline DEA boronic ester was also successfully employed in the SMC, and the improved input quality allowed for a simpler and more robust process to be developed with enhanced quality of the isolated intermediate. The borylation and SMC were operated on 60 and 350 kg scales, respectively, and generated 2300 kg of the active pharmaceutical ingredient AZD5718.

中文翻译：

利用二乙醇胺硼酸酯的物理特性改进 AZD5718 的工艺

本文公开了合成二乙醇胺 (DEA) 硼酸酯和随后的铃木-宫浦偶联 (SMC) 的工艺开发。成功开发了一种一锅法锂化-硼酸化-酯交换反应，将 DEA 硼酸酯分离为稳定的结晶固体，并避免了硼酸或频哪醇硼酸酯类似物的形成，这些类似物具有较差的物理性质和纯度。结晶 DEA 硼酸酯也成功用于 SMC，改进的输入质量允许开发更简单、更稳健的工艺，同时提高分离中间体的质量。硼化和 SMC 分别在 60 公斤和 350 公斤的规模上运行，并产生了 2300 公斤的活性药物成分 AZD5718。

更新日期：2023-03-09

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