Tetrahydro-4H-pyran-4-one → 5-Fluoro-6-methyl-1-[1-(tetrahydropyran-4-yl)-piperidin-4-yl]-1,3-dihydrobenzimidazol-2-one

Participants

Reaction Steps

5-Fluoro-6-methyl-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (D30) (0.64 mmol, 160 mg) in methanol (3 mL) was treated under argon at room temperature with tetrahydro-4H-pyran-4-one (1.28 mmol, 128 mg, 2 eq), then titanium tetra-isopropoxide (1.28 mmol, 364 mg, 2 eq). The mixture was stirred under argon for 1.5 h, then sodium cyanoborohydride (1.28 mmol, 80.4 mg, 2 eq) was added and stirred for 1.5 h. The mixture was loaded on an SCX cartridge, washed with 6 CV methanol and eluted with 6 CV 2M ammonia in methanol and dichloromethane. The eluate was concentrated under reduced pressure and purified 5-100% 2 m NH3 in MeOH/DCM to give 5-fluoro-6-methyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, which was transformed into the corresponding HCl salt (0.27 mmol, 100 mg, 42% yield), using 1M HCl in diethyl ether. M+H=334.12

Provenance & Evidence