A One-Pot Asymmetric Synthesis of a N-Acylated 4,5-Dihydropyrazole, A Key Intermediate of Thrombin Inhibitor AZD8165

A short, chromatography-free, and scalable synthetic route to thrombin inhibitor 1, the active metabolite of the propionic ester prodrug AZD8165, has been developed. The key synthetic step involved cycloaddition of TMS–diazomethane and ethyl acrylate to give an intermediate racemic dihydropyrazole which was reacted with enantiomerically pure 4-fluoro mandelic acid chloride in a one-pot dynamic kinetic resolution (DKR) process.