Two Routes to 4-Fluorobenzisoxazol-3-one in the Synthesis of a 5-HT4 Partial Agonist

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• 作者：Daniel W. Widlicka ; John C. Murray ; Karen J. Coffman ; Chunguang Xiao ; Michael A. Brodney ; Joseph P. Rainville ; Brian Samas
• 刊名：Organic Process Research & Development
• 出版年：2016
• 出版时间：February 19, 2016
• 年：2016
• 卷：20
• 期：2
• 页码：233-241
• 全文大小：321K
• ISSN：1520-586X

文摘

A potent 5-HT₄ partial agonist, 1 (PF-04995274), targeted for the treatment of Alzheimer’s disease and cognitive impairment, has been prepared on a multi-kilogram scale. The initial synthetic route, that proceeded through a 4-substituted 3-hydroxybenzisoxazole core, gave an undesired benzoxazolinone through a Lossen-type rearrangement. Route scouting led to two new robust routes to the desired 4-substituted core. Process development led to the efficient assembly of the API on a pilot plant scale under process-friendly conditions with enhanced throughput. In addition, crystallization of a hemicitrate salt of the API with pharmaceutically beneficial properties was developed to enable progression of clinical studies.