Use of a Titanium Thienyl Anion and a Simple Procedure for Introducing a Thiol Group into Thiophene in the Development of a Manufacturing Route to the 5-Lipoxygenase Inhibitor ZD4407

Abstract

Process development has been conducted to identify a synthetic route to the 5-lipoxygenase inhibitor ZD4407 that could be used for pilot plant manufacture. Efficient and environmentally acceptable carbon-functionalisation of the 3-position of thiophene using readily available 3-bromothiophene has been achieved using a titanium carbanionic intermediate. An efficient functionalisation of the 5-position with a thiol group has also been realised using dimethyl disulphide, where the side product of the functionalisation reaction is used in situ as the reagent for the subsequent deprotections, thereby considerably reducing the impact on the environment.