Chemical Development of ZD9331:  Synthesis of a Bromomethylquinazolinone Avoiding a Nonselective Radical Bromination

Abstract

An efficient regiospecific synthesis of ZD9331 Pivaloyloxymethyl (POM) Bromide (4) has been accomplished via ZD9331 Quinacetate HCl (15) avoiding a nonselective bromination. The original route used a radical bromination on a substrate with three methyl groups, which generated a range of bromomethyl derived compounds that carried through to the final active pharmaceutical ingredient (API). A strategy, based on the Zinin reaction, was developed to synthesize the required bromomethyl compound in a regioselective manner. This approach was successfully scaled to manufacture a tonne of material.