Chemoselective Saponification in the Synthesis of Danuglipron Facilitated with Trifluoroethanol

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-06-27 DOI:10.1021/acs.oprd.4c00085

Lu Han*, Bryan Li*, Ke Wang, David B. Damon, Javier Magano, Mark T. Maloney, Jason Mustakis, Ronald J. Post, Ruizhi Li and Truong Nguyen,

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Abstract

Danuglipron (PF-06882961), a potent, orally bioavailable small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist, is currently being developed for glycemic control among patients with Type-2 diabetes (J. Med. Chem. 2022, 65, 8208–8226; JAMA Netw. Open. 2023; 6(5): e2314493). The earlier synthesis of danuglipron suffered from chemoselective issues due to the competing nitrile hydrolysis in the final saponification step, which resulted in highly convoluted operations and extensive chromatographic purifications. We found that the methyl ester could be converted to trifluoroethyl ester, and the latter underwent hydrolysis to carboxylic acid in a much cleaner reaction profile. A thorough design of experiments (DOE) was conducted to expand the operating time window of the process to aid the process robustness during manufacturing. The improved process increased the yield by ∼20% and reduced the process mass intensity (PMI) by 86%.

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用三氟乙醇促进合成丹参酮的化学选择性皂化反应

Danuglipron（PF-06882961）是一种强效、口服生物可利用的小分子胰高血糖素样肽-1 受体（GLP-1R）激动剂，目前正在开发用于控制 2 型糖尿病患者的血糖（J. Med.Chem.2022, 65, 8208-8226; JAMA Netw.Open.2023; 6(5): e2314493).由于在最后的皂化步骤中存在竞争性的腈水解，丹格列净的早期合成存在化学选择性问题，这导致了高度复杂的操作和大量的色谱纯化。我们发现，甲酯可以转化为三氟乙酯，而后者在水解成羧酸的过程中反应曲线更为简洁。我们进行了全面的实验设计 (DOE)，以扩大工艺的操作时间窗口，从而提高生产过程中的工艺稳定性。改进后的工艺使产量提高了 20%，工艺质量强度（PMI）降低了 86%。

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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.