Early Process Development of an LPAR1 Antagonist, GS-2278

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-11-05 DOI:10.1021/acs.oprd.4c00369

Nathaniel Kadunce, Anna M. Wagner, Jeromy Cottell, Kathy Dao, Darryl D. Dixon, Blanka M. Hodur, Dane Holte, Michael A. Ischay, Jihun Kang, Seongtaek Kim, Young Ho Kim, Seung Moh Koo, Willard Lew, Lucas Man, Kashi Reddy Methuku, Henry Morrison, Patrick D. Parker, David A. Siler, Chloe Y. Wong

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引用次数: 0

Abstract

(R)-1-(2,5-Difluoropyridin-3-yl)ethyl(1-methyl-4-(5-(2-(trifluoromethyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (GS-2278) is a lysophosphatidic acid receptor 1 antagonist under development for the treatment of idiopathic pulmonary fibrosis. GS-2278 is assembled in a 9-step sequence. Initially, 2-bromo-5-fluoropyridine is metalated and trapped with ethyl difluoroacetate. Then, after condensation with tosyl hydrazide, Sakai cyclization with methylamine, and carboxylation with carbon dioxide, the triazole carboxylic acid core is generated. For the final assembly, the core is elaborated through a two-step hydroxamic acid formation and Lossen rearrangement to form an isocyanate which is trapped in situ by a chiral alcohol. The resulting carbamate is Boc-deprotected and subjected to amide coupling with a pyrimidine carboxylic acid to yield the active pharmaceutical ingredient. Process development was conducted to determine reaction and isolation conditions to enable scale-ups to support preclinical and early clinical studies. This paper focuses on the development of conditions from the medicinal chemistry route to the Ph 1 manufacturing route.

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LPAR1 拮抗剂 GS-2278 的早期工艺开发

(R)-1-(2,5-二氟吡啶-3-基)乙基(1-甲基-4-(5-(2-(三氟甲基)嘧啶-5-甲酰胺基)吡啶-2-基)-1H-1,2,3-三唑-5-基)氨基甲酸酯（GS-2278）是一种溶血磷脂酸受体 1 拮抗剂，正在开发用于治疗特发性肺纤维化。GS-2278 由 9 个步骤组装而成。首先，2-溴-5-氟吡啶被二氟乙酸乙酯金属化和捕获。然后，与对甲苯磺酰肼缩合，与甲胺进行堺环化反应，再与二氧化碳进行羧化反应，生成三唑羧酸核心。在最后的组装过程中，该核心通过羟肟酸形成和洛森重排两个步骤来形成异氰酸酯，异氰酸酯被手性醇就地截留。生成的氨基甲酸酯经 Boc 保护后与嘧啶羧酸进行酰胺偶联，得到活性药物成分。进行工艺开发的目的是确定反应和分离条件，以便扩大规模，支持临床前和早期临床研究。本文重点介绍从药物化学路线到 Ph 1 生产路线的条件开发。

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.