The condensation of isopropyl acetoacetate (I) with 3-nitrobenzaldehyde (II) gives isopropyl 2-(3-nitrobenzylidene)acetoacetate (III), which is cyclized with methyl 3-amino-4,4-dimethoxycrotonate (IV) at 100 C yielding 5-isopropyl-3-methyl-2-(dimethoxymethyl)-6-methyl-4-(3-nitropheny)-1,4-dihydropyridine-3,5-dicarboxylate (V). The hydrolysis of the acetal group of (V) with HCl in acetone affords the corresponding 2-formyl derivative (VI), which is finally treated with hydroxylamine and acetic anhydride in acetic acid at 100 C.
1) The synthesis of deuterated nilvadipine has been reported: The selective hydrolysis of nilvadipine (I) with lithium iodide and pyridine gives the monolithium salt (II), which is then treated with perdeuterated methanol and 2-bromo-1-methylpyridinium bromide and dimethylaniline in DMF.
2) The optical isomers of nilvidapine have also been synthesized: The selective hydrolysis of nilvadipine (I) with formic acid gives the monocarboxylic acid (II), which is treated with (-)-cinconidine, yielding the corresponding salt (IV) as a diastereomeric mixture, which is separated by fractional crystallization to give, after hydrolysis with HCl, 2-cyano-3-(methoxycarbonyl)-6-methyl-4(R)-(3-nitrophenyl)-1,4-dihydropy ridine-5-carboxylic acid (Va) and 2-cyano-3-(methoxycarbonyl)-6-methyl-4(S)-(3-nitrophenyl)-1,4-dihydropy ridine-5-carboxylic acid (Vb) as pure optical isomers. Both compounds are esterified by conversion to the corresponding acyl chlorides with PCl5 and esterification with isopropyl alcohol.