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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11

Preparation of a key intermediate in the synthesis of amlodipine: The reaction of ethyl 4-(2-phthalimidoethoxy)acetoacetate (I) with ammonium acetate in refluxing toluene gives the corresponding 3-aminocrotonic acid (II), which is then cyclized with methyl 2-(2-chlorobenzylidene)acetoacetate (III) in refluxing ethanol.

合成路线12

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13

The reduction of 2,2-diethoxyacetic acid ethyl ester (I) with NaBH4 in dimethoxyethane gives 2,2-diethoxyethanol (II), which is condensed with ethyl 4-chloroacetoacetate (III) by means of NaH in hot THF to yield ethyl 4-(2,2-diethoxyethoxy)acetoacetate (IV). The condensation of (IV) with 2-chlorobenzaldehyde (V) by means of piperidine in refluxing toluene affords the acrylic ester (VI), which is cyclized with methyl 3-aminocrotonate (VII) in refluxing toluene to provide the dihydropyridine (VIII). The reaction of (VIII) with hydroxylamine in refluxing methanol/water gives the hydroxyimino derivative (IX), which is finally reduced to the target compound by means of H2 over Pd/C in acetic acid or with NaBH4 and NiCl2 in methanol. Alternatively, intermediate dihydropyridine (VIII) can be obtained as follows: The reaction of acetoacetate (IV) with ammonium acetate in refluxing ethanol gives ethyl 3-amino-4-(2,2-diethoxyethoxy)crotonate (X), which is cyclized with methyl 2-(2-chlorobenzylidene)acetoacetate (XI) in refluxing toluene to yield the target intermediate the dihydropyridine (VIII).

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The protection of ethanolamine (I) with trityl chloride (II) in isopropanol gives N-tritylethanolamine (III), which is condensed with ethyl 4-chloroacetoacetate (IV) by means of NaH in THF to yield ethyl 4-[2-(tritylamino)ethoxy]acetoacetate (V). The cyclization of (V) with 2-chlorobenzaldehyde (VI) and methyl 3-aminocrotonate (VII) in refluxing methanol affords the protected dihydropyridine (VIII), which, without isolation, is finally detritylated by a treatment with aqueous benzenesulfonic acid.

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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16

The reaction of ethyl 4-bromoacetoacetate (I) with 2-chloroethanol (II) by means of NaH in THF gives ethyl 4-(2-chloroethoxy)acetoacetate (III), which is treated with NaI in refluxing acetone to yield the corresponding 2-iodoethoxy derivative (IV). The condensation of (IV) with 2-chlorobenzaldehyde (V) by means of piperidine acetate in isopropanol affords ethyl 2-(2-chlorobenzylidene)-4-(2-iodoethoxy)acetoacetate (VI), which is cyclized with methyl 3-aminocrotonate (VII) in refluxing isopropanol to provide the dihydropyridine (VIII). The reaction of (VIII) with hexamethylenetetramine (IX) in hot acetonitrile gives the aminium salt (X), which is finally treated with benzenesulfonic acid in refluxing butanol (methanol)/water. Alternatively, the intermediate dihydropyridine (VIII) can be obtained as follows: The condensation of ethyl 4-(2-chloroethoxy)acetoacetate (III) with the aldehyde (V) by means of piperidine acetate in isopropanol gives ethyl 2-(2-chlorobenzylidene)-4-(2-chloroethoxy)acetoacetate (XI), which is cyclized with methyl 3-aminocrotonate (VII) in refluxing isopropanol to yield the corresponding dihydropyridine (XII). Finally, this compound is treated with NaI in refluxing isopropanol to afford the target intermediate dihydropyridine (VIII).

合成路线17

The reaction of 4,5-bis(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane (I) with ethyl 4-chloroacetoacetate (II) gives the bis adduct (III), which is cyclized with 2-chlorobenzaldehyde (IV) and methyl 3-aminocrotonate (V) in refluxing ethanol to yield the dimeric dihydropyridine (VI). The cleavage of the dioxolane ring of (VI) by means of Ts-OH in methanol affords the vicinal diol (VII), which is cleaved by means of NaIO4 in methanol to provide the acetaldehyde derivative (VIII). The reaction of (VIII) with hydroxylamine and TEA in methanol affords the corresponding oxime (IX), which is finally reduced to the target compound with Pd(OH)2/carbon and ammonium formate in refluxing methanol. Alternatively, the reductive amination of acetaldehyde (VIII) with ammonium acetate and sodium cyanoborohydride in methanol yields also the target compound.

合成路线18

The reaction of 2,2-dimethyl-1,3-dioxolane-4-methanol (X) with ethyl 4-chloroacetoacetate (II) gives the adduct (XI), which is cyclized with 2-chlorobenzaldehyde (IV) and methyl 3-aminocrotonate (V) in refluxing ethanol to yield the dihydropyridine (XII). The cleavage of the dioxolane ring of (XII) by means of Ts-OH in methanol affords the vicinal diol (XIII), which is cleaved by means of NaIO4 in methanol to provide the already reported acetaldehyde derivative (VIII).

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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20

The condensation of 4-(2-phthalimidoethoxy)acetoacetic acid ethyl ester (I) with 2-chlorobenzaldehyde (II) by means of piperidine in isopropanol gives 2-(2-chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetic acid ethyl ester (III), which is cyclized with 3-aminocrotonic acid methyl ester (IV) in hot isopropanol to yield the phthalimido amlodipine (V). Finally, this compound is deprotected by means of aqueous methylamine to afford the target amlodipine.