Practical and efficient synthesis of gefitinib through selective O-alkylation: A novel concept for a transient protection group

Abstract

ABSTRACTA practical process that includes a simple four-step procedure for the preparation of gefitinib (1), a tyrosine kinase inhibitor that targets the epidermal growth factor receptor, is described. Dramatic improvements over previously reported conventional synthetic procedures were achieved. We found effective coupling conditions to minimize the inevitable production of an N-alkylated side product, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)-quinazoline-4-amine (3) using a transient trimethylsilyl protecting group. We synthesized gefitinib in an 81.1% overall yield from a commercially available starting material on a multigram scale using a route that did not require work-up of any of the reaction steps.