Studies on nilvadipine. IV. Synthesis of deuteriated and optically active isopropyl 2-cyano-3-methoxycarbonyl-4-(3-nitrophenyl)-6-methyl-1,4- dihydropyridine-5-carboxylate (nilvadipine).

Nilvadipine, I, has already entered clinical use for the treatment of hypertension. In the process of the developing nilvadipine, we prepared the deuteriated analogue of I as an internal standard for the determination of I in human plasma by capillary column gas chromatography-negative-ion chemical-ionization mass spectrometer. Nilvadipine has an asymmetric center at the C-4 position of the dihydropyridine ring, and characterization of the optical isomers with regard to their activity and bioavailability is of interest. Thus, we synthesized both the enantiomers of I by optical resolution via the 5-carboxy derivative (3), which was previously prepared as one of the metabolites of I.