RESUMEN
A multidisciplinary approach covering synthetic, physical, and analytical chemistry, high-throughput experimentation and experimental design, process engineering, and solid-state chemistry is used to develop a large-scale (kilomole) Suzuki-Miyaura process. Working against clear criteria and targets, a full process investigation and optimization package is described highlighting how and why key decisions are made in the development of large-scale pharmaceutical processes.
Asunto(s)
Diseño de Fármacos , Industria Farmacéutica , Pirazinas/síntesis química , Triazinas/síntesis química , Ensayos Analíticos de Alto Rendimiento , Estructura Molecular , Pirazinas/química , Triazinas/químicaRESUMEN
Enantiopure, Boc-protected alkoxyamines 12 and 13, derived from the readily available homoallylic alcohols 4 via a reaction that involves either inversion or retention of configuration, undergo a diastereoselective Pd-catalyzed ring-closing carbonylative amidation to produce isoxazolidines 16/17 (≤50:1 diastereoisomer ratio (d.r.)) that can be readily converted into the N-Boc-protected esters of ß-amino-δ-hydroxy acids and their γ-substituted homologues 37. The key carbonylative cyclization proceeds through an unusual syn addition of the palladium and the nitrogen nucleophile across the C=C bond (19â21), as revealed by the reaction of 15, which afforded isoxazolidine 18 with high diastereoselectivity.