A new synthesis of efonidipine has been described: The cyclization of 2,2-dimethylbutane-1,4-diol (I) with triethyl phosphite (II) by heating at 100 C gives 2-methoxy-5,5-dimethyl-1,3,2-dioxaphosphorinan (III), which, by treatment with iodoacetone (IV) in refluxing ether, yields 2-acetonyl-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one (V). The condensation of (V) with 3-nitrobenzaldehyde (VI) by means of piperidine in acetic acid affords 3-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitrophenyl)-3-buten-2-one (VII), which is finally cyclized with 3-amino-2-propenoic acid 2-(N-benzyl-N-phenylamino)ethyl ester (VIII) in refluxing toluene.

A new synthesis for (4S)-efonidipine has been described: The reaction of 5,5-dimethyl-2-(2-oxopropyl)-1,3,2-dioxaphosphorinan-2-one (I) with dimorpholino(3-nitrophenyl)methane (II) by means of trifluoroacetic acid in hot toluene gives 5,5-dimethyl-2-[1-acetyl-2-(3-nitrophenyl)vinyl]-1,3,2-dioxaphosphorina n-2-one (III), which is cyclized with 3-aminocrotonic acid 2(S)-methoxy-2-phenylethyl ester (IV) in refluxing toluene; the recrystallization of the resulting product affords 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4(S)-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 2(S)-methoxy-2-phenylethyl ester (V). The protection of the NH group of (V) with chloromethyl methyl ether and NaH in THF yields the N-methoxymethyl derivative (VI), which is transesterified with 2-(N-benzyl-N-methylamino)ethanol (VII) and NaH in DMSO, giving the protected final product (VIII). Finally, this compound is deprotected with HCl in ethanol.

An enantioselective synthesis of efonidipine has been described: The enantioselective hydrolysis of 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3-n itrophenyl)-1,4-dihydropyridine-3-carboxylic acid propionyloxymethyl ester (I) with lipase AH in 2,5-dimethyltetrahydrofuran saturated with water gives the corresponding free acid of the (S)-isomer (III), while the propionyloxymethyl ester of the (R)-isomer (II) remains undisturbed. After chromatographic separation, the (R)-ester (II) is hydrolyzed with NaOH in methanol to the (R)-acid (IV). Finally, both enantiomerically pure acids (III) and (IV) are separately esterified with 2-(N-benzyl-N-phenylamino)ethanol in the usual way.