op5b00389_si_001.cif (947.05 kB)

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

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posted on 2016-02-02, 00:00 authored by Daniel W. Widlicka, John C. Murray, Karen J. Coffman, Chunguang Xiao, Michael A. Brodney, Joseph P. Rainville, Brian Samas
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.