Dane Holte*, Kathy Dao, Nathaniel Kadunce, Henry Morrison, David A. Siler and Anna M. Wagner,
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Development of a Scalable Process for an LPAR1 Antagonist with a Complex Form Landscape, GS-2278
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.
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.
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