合成路线1

The condensation of ethyl 4-chloroacetoacetate (I) with 2-azidoethanol (II) by means of NaH in THF gives ethyl 4-(2-azidoethoxy)acetoacetate (III), which is submitted to a Hantzsch cyclocondensation with methyl 3-aminocrotonate (IV) and 2-chlorobenzaldehyde (V) in refluxing methanol affording 3-ethyl 5-methyl 2-(2-azidoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate (VI), Finally, this compound is reduced with Zn and 3N HCl in methanol, or with H2 over Pd/CaCO3 in ethanol.

合成路线2

The reaction of ethyl 4-chloroacetoacetate (I) with 2-azidoethanol (II) by means of NaH in THF gives ethyl 4-(2-azidoethoxy)acetoacetate (II), which is cyclized with methyl 2-(2-chlorobenzylidene)acetoacetate (IV) and ammonium acetate in refluxing ethanol to yield the azido-dihydropyridine (V). Finally, the azido group of (V) is reduced with H2 over Pd/C in ethanol to afford the target amlodipine.

合成路线3

The two enantiomers of amlodipine have been obtained as follows: The reaction of 2-azidoethanol (I) with chloroacetic acid (II) by means of NaH in THF gives 2-(2-azidoethoxy)acetic acid (III), which is condensed with Meldrum's acid (IV) and 3-hydroxypropionitrile (V) in dichloromethane to yield the 2-cyanoethyl acetoacetate (VI). The cyclization of (VI) with 2-chlorobenzaldehyde (VII) and methyl 3-aminocrotonate (VIII) in refluxing ethanol affords the dihydropyridine (IX), which is selectively hydrolyzed at the 2-cyanoethylester with NaOH to give the dihydropyridine monocarboxylic acid (X). The esterification of (X) with (S)-2-methoxy-2-phenylethanol (XI) by means of CDI in dichloromethane provides the ester (XII) as a diastereomeric mixture, which is separated by chromatography to furnish diastereomers (XXI A) and (XII B). The selective ethanolysis of (XII A) and (XII B) with sodium ethoxide in refluxing ethanol/diglyme gives enantiomers (+)-(XIII) and (-)-(XIII), which are finally reduced with H2 over Pd/CaCO3 in ethanol to afford the (-)- and (+)-isomers, respectively, of the target compound.

合成路线4

The cyclization of 2-butynoic acid methyl ester (I) with 2-(2-chlorobenzylidene)-3-oxobutyric acid ethyl ester (II) and benzylamine (III) in refluxing toluene gives the N-benzylated dihydropyridine (IV), which is debenzylated by reduction with formic acid over Pd/C in refluxing methanol to yield the dihydropyridine (V). The bromination of (V) with C5H5NH+ HBr3- in dichloromethane affords the bromomethyl compound (VI), which is condensed with 2-azidoethanol (VII) by means of NaH in ethyl ether to provide the 2-azidoethoxymethyl compound (VIII). Finally, the azido group of (VIII) is reduced with Zn and HCl in methanol to furnish the desired 2-aminoethoxymethyl compound.

合成路线5