Preparation of a clinically investigated ras farnesyl transferase inhibitor

The synthesis of rasfarnesylprotein transferase inhibitor 1is described on a multikilogram scale. Retrosynthetic analysis reveals chloromethylimidazole 2and a piperazinone 3as viable precursors. The 1,5disubstituted imidazole system was regioselectively assembled viaan 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 1,5disubstituted imidazoles. A new Mitsunobu cyclization strategy was developed to prepare the arylpiperazinone fragment 3.