Preparation of a clinically investigated ras farnesyl transferase inhibitor

The synthesis of ras farnesyl-protein transferase inhibitor 1 is described on a multi-kilogram scale. Retrosynthetic analysis reveals chloromethylimidazole 2 and a piperazinone 3 as viable precursors. The 1,5-disubstituted imidazole system was regioselectively assembled via an improved Marckwald imidazole synthesis. A new imidazole dethionation procedure has been developed to convert the Marckwald mercaptoimidazole product to the desired imidazole. This methodology was found to be tolerant of a variety of functional groups providing good to excellent yields of 1,5-disubstituted imidazoles. A new Mitsunobu cyclization strategy was developed to prepare the arylpiperazinone fragment 3.