Efficient Synthesis of Crisaborole from m-Cresol: A Practical and Scalable Process

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2025-05-02 DOI:10.1021/acs.oprd.5c00075

Chunxiao Wang, Yuanming Jiang, Hongsen Zhang, Xiaonan Liu, Kangjie Liu, Chao Li, Renzhong Qiao

引用次数: 0

Abstract

Herein, process improvement work on the phosphodiesterase-4 inhibitor crisaborole is described. The starting material 2-bromo-5-hydroxybenzaldehyde was replaced with the low-cost m-cresol. The process involves the purification of the low-melting-point bromophenol by a cocrystal strategy, selective debromination of the gem-dibromide byproduct, boronation through a telescoped process, and design of experiments optimization in the active pharmaceutical ingredient (API) synthesis stage. The economic, efficient, and practical synthesis of crisaborole was successfully achieved. It is worth noting that filtration unit operations were applied in the scale-up process of Miyaura borylation to address the common issue of incomplete conversion in this process.

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间甲酚高效合成Crisaborole：一种实用且可扩展的工艺

本文介绍了磷酸二酯酶-4抑制剂crisaborole的工艺改进工作。以低成本间甲酚代替原料2-溴-5-羟基苯甲醛。该工艺包括通过共晶策略提纯低熔点溴苯酚，选择性脱溴副产物，通过伸缩工艺进行硼化，并在活性药物成分（API）合成阶段设计实验优化。成功地合成了经济、高效、实用的crisaborole。值得注意的是，在Miyaura硼化放大过程中采用了过滤单元操作，以解决该过程中常见的转化不完全问题。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

期刊介绍： The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.