A Large Scale Process for the Preparation of Thymitaq

Abstract

The large scale manufacturing of the anticancer agent 2-amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3 H -quinazolin-4-one dihydrochloride (thymitaq) from 6-bromo-5-methylanthranilic acid is described. The chemical route consists of two chemical steps: formation of a bromoquinazolinone and a copper-mediated Ullman-like coupling between 4-mercaptopyridine and the bromoquinazolinone. During process development, sodium hydride was replaced with sodium hydroxide and a method for removal of copper, based on 2,4,6-trimercapto- s -triazine, was developed. A number of purification operations were performed to ensure a product of pharmaceutical quality.