Nimodipine: synthesis and metabolic pathway

Key step of the synthesis of the calcium antagonistic cerebral vasodilator (+/-) isopropyl-2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (Bay e 9736, nimodipine) (5) is the cyclizing Michael addition of 3 onto 4. A pharmacokinetic study with 14C-nimodipine in the rat revealed as major metabolites the dihydropyridines 6 and 8 as well as the pyridines 7, 9, 10, 11, 13 and 14. A potential metabolic pathway is discussed involving ether cleavage and oxidation to the pyridine form as primary biotransformation steps. Reference metabolites were synthesized using 1,4-dihydropyridines with appropriate functionalities as precursors.