Development of a Scalable Process for an LPAR1 Antagonist with a Complex Form Landscape, GS-2278

IF 3.5 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2025-09-09 DOI:10.1021/acs.oprd.5c00251

Dane Holte*, Kathy Dao, Nathaniel Kadunce, Henry Morrison, David A. Siler and Anna M. Wagner,

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Abstract

GS-2278 (1) is a lysophosphatidic acid receptor 1 (LPAR1) antagonist with a complex form landscape (15 freebase polymorphs) that was selected for development as a treatment of idiopathic pulmonary fibrosis (IPF). The thermodynamically most stable unsolvated polymorph, 1-A, was selected for initial development, but due to low solubility and poor pharmacokinetics (PK), a salt form was desired for long-term development. Ultimately, the dihydrate hydrochloride salt, 1-HCl 2H₂O, became the desired API for development. However, impurity carryover in this salt-forming step remained high throughout development, placing the burden of impurity control on the penultimate reaction and isolation of freebase 1. During the early process development of 1, several generations of reaction, isolation, and crystallization were designed to ensure form control, chemical purity, and high yield. This manuscript details the challenges faced and overcome during the continuous development of the freebase 1 across a complex form landscape as well as the development and isolation of 1-HCl 2H₂O.

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具有复杂形态景观的LPAR1拮抗剂的可扩展工艺的发展，GS-2278

GS-2278(1)是一种溶血磷脂酸受体1 （LPAR1）拮抗剂，具有复杂的形态结构（15个自由碱基多态性），被选为特发性肺纤维化（IPF）的治疗药物。初始发育选择了热力学最稳定的非溶剂化多晶型1-A，但由于其溶解度低且药代动力学（PK）较差，因此需要盐形式进行长期发育。最终，二水合物盐酸盐（1-HCl 2H2O）成为开发所需的原料药。然而，在整个发育过程中，该成盐步骤中的杂质携带率仍然很高，将杂质控制的负担放在了倒数第二反应和游离碱1的分离上。在1的早期工艺开发过程中，设计了几代反应，分离和结晶，以确保形式控制，化学纯度和高产率。这篇手稿详细介绍了freebase 1在一个复杂的形态景观中不断发展所面临的挑战和克服的困难，以及1- hcl 2H2O的发展和分离。

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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.