合成路线1

This compound can be obtained by two different ways: 1) By cyclization of 2-trifluoromethylbenzaldehyde (I) with methyl 3-amino crotonate (II) and nitropropanone (III) in refluxing ethanol. 2) By cyclization of methyl 2-(2-trifluoromethylbenzylidene)acetoacetate (IV) with 2-amino-1-nitropropene (V) in refluxing ethanol.

合成路线2

By cyclization of isobutyl 2-(2-nitrobenzylidene)acetoacetate (I) and methyl 3-aminocrotonate (II) in refluxing ethanol.

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1) By cyclization of 3-nitrobenzaldehyde (I) with methyl 3-aminocrotonate (II) and N-benzyl-3-pipendinyl acetylacetate (III) in refluxing THF.

合成路线4

The condensation of 1 2-benzenediamine (I) with methyltetrahydro-5-methyl 4-oxo-3-thiophenecarboxylate (II) in toluene using a Dean-Stark trap gives the triyclic system (III), which is dehydrogenated to 4,9-dihydro-3-methyl-10H-thienol[3,4-b][1,5]benzodiazepin-10-one (IV). Treatment of (IV) with chloroacetyl chloride in dioxane in the presence of K2CO3 yields 4-chloroacetyl-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one (V), which is finally reacted with N-methylpiperazine to produce telenzepine, which is isolated as the hydrochloride.

合成路线5

Two new related ways for the synthesis of lercanidipine have been reported: 1) The condensation of diketene (I) with the aminoalcohol (II) gives the corresponding acetoacetate ester (III), which is allowed to react with 3-nitrobenzaldehyde (IV) by means of HCl in chloroform yielding the expected benzylidene derivative (V). Finally, this compound is cyclized with methyl 3-aminocrotonate (VI) in refluxing isopropanol. 2) By esterification of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (VIII) with alcohol (II) by means of SOCl2 in DMF/dichloromethane.

合成路线6

Compound can be prepared in two different ways: 1) By heating at 100 C a mixture of m-nitrobenzaldehyde (I), methyl beta-aminocrotonate (II) and N-benzyl-N-methylaminoethyl acetoacetate (III). 2) By cyclization of a mixture of m-nitrobenzaldehyde (I), methyl acetoacetate (IV) and N-benzyl-N-methylaminoethyl beta + aminocrotonate (V) in refluxing isopropanol.

合成路线7

By cyclization of 2,1,3-benzoxadiazole-4-carbaldehyde (I) with isopropyl acetoacetate (II) and methyl 3-aminocrotonate (III) in refluxing ethanol.

合成路线8

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9

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).

合成路线10

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.

合成路线11

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12

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13

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14

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).

合成路线15

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.

合成路线16

The cyclization of 2,3-dihydroxybenzaldehyde (I) with dibromomethane by means of KF in hot DMF gives 2,3-methylenedioxybenzaldehyde (II), which is condensed with ethyl acetoacetate (III) by means of piperidine and acetic acid in refluxing benzene to afford ethyl 2-acetyl-3-(2,3-methylenedioxyphenyl)acrylate (IV). Finally, this compound is cyclized with methyl 3-aminocrotonate (V) in hot isopropanol.

合成路线17

The reaction of trimethylene glycol (I) with PCl3 gives 2-chloro-1,3,2-dioxaphosphorinane (II), which is condensed with propargyl alcohol (III) by means of triethylamine in acetonitrile to give a mixture of 2-allenyl- and 2-propargyl-2-oxo-1,3,2-dioxaphosphorinane (IV and V). The reaction of this mixture with isobutylamine in acetonitrile affords 2-(2-isobutylamino-1-propenyl)-2-oxo-1,3,2-dioxaphosphorinane (VI). The hydrolysis of the enamine (VI) with malonic acid gives 2-acetonyl-2-oxo-1,3,2-dioxaphosphorinane (VII), which is condensed with isobutyl-(2-nitrobenzylidene)amine (VIII) to yield 2-[1-(2-nitrobenzylidene)-2-oxopropyl]-2-oxo-1,3,2-dioxaphosphorinane (IX). Finally, this compound is cyclized with methyl 3-aminocrotonate (X) in refluxing acetonitrile.

合成路线18

1) The condensation of ethyl acetoacetate (I) with 3-nitrobenzaldehyde (II) in toluene gives ethyl 2-(3-nitrobenzylidene)acetoacetate (III), which is then cyclized with methyl 3-aminocrotonate (IV) [prepared from methyl acetoacetate (V) with NH3 and p-toluenesulfonic acid]; the reaction is carried out in refluxing ethanol.

合成路线19

2) This compound can also be obtained by direct cyclization of ethyl acetoacetate (I) with 3-nitrobenzaldehyde (II) and 3-aminocrotonate (IV) in refluxing ethanol.

合成路线20

This compound can be prepared in two related ways: 1) The condensation of diketene (I) with 2,2-(ethylenedioxy)propanol (II) by means of NaH in refluxing benzene gives 2,2-(ethylenedioxy)propyl acetylacetate (III), which is condensed with 2-nitrobenzaldehyde (IV) by means of piperidine and acetic acid in benzene, yielding 2,2-(ethylenedioxy)propyl 2-(2-nitrobenzylidene)acetoacetate (V). The cyclization of (V) with methyl 3-aminocrotonate (VI) in refluxing ethanol affords the protected dihydropyridine (VII), which is finally hydrolyzed with acetic acid in hot water. 2) The reaction of the acetoacetate (III), obtained as before, with ammonia in methanol gives the 3-aminocrotonate (VIII), which is cyclized with methyl 2-(2-nitrobenzylidene)acetoacetate (IX) in refluxing ethanol to afford the dihydropyridine (VII), already obtained.

合成路线21

1) The reaction of N-methyl-N-benzylamine (I) with isobutyraldehyde (II) and formaldehyde (III) in refluxing isopropanol, followed by hydrogenation with NaBH4 gives 3-(N-benzyl-N-methylamino)-2,2-dimethylpropanol (IV), which is condensed with diketene (V) in refluxing benzene to yield 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl acetoacetate (VI). Finally, this compound is submitted to cyclization with 2-fluoro-5-nitrobenzeldehyde (VII) (prepared by oxidation of 2-fluoro-5-nitrotoluene (VIII) with CrO3 in acetic ahydride-H2SO4) and methyl 3-aminocrotonate (IX) in refluxing isopropanol.

合成路线22

2) The condensation of acetoacetic ester (VI) with aldehyde (VII) gives the benzylidene derivative (X), which is then submitted to cyclization with crotonate (IX) as before. 3) Finally, the title product can also be obtained by cyclization of benzylidene derivative (X) with methyl acetoacetate (XI) and concentrated aqueous ammonia in refluxing isopropanol.

合成路线23

Hantzsch condensation of 2-[4-(3,4-dichlorophenyl)piperazin-1-yl]ethyl acetylacetate (III) with methyl 3-aminocrotonate (II) and 3-nitrobenzaldehyde (I) in eftuxing isopropanol affords title compound.

合成路线24

A synthesis of the (R)- and (S)-isomers of manidipine hydrochloride has been described: The cyclization of 3-nitrobenzaldehyde (I) with methyl 3-aminocrotonate (II) and methylacetylacetate (III) gives 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (IV), which is alkylated with ethoxymethyl chloride and NaH yielding the 1-(ethoxymethyl) derivative (V). Selective hydrolysis of (V) with 1-(dimethylamino)-2-propanol - Na - H2O affords the monomethyl ester (VI), which is submitted to optical resolution with cinchonidine and cinchonine giving (R)-1-(ethoxymethyl-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)- 1,4-dihydropyridine-3-carboxylic acid (VIII) and the corresponding (S)-isomer (IX), respectively. The cleavage of the ethoxymethyl group of (VIII) and (IX) in acidic medium affords the corresponding free (R)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyrid ine-3-carboxylic acid (X) and the (S)-isomer (XI). Both compounds are esterified with 2-[4-(diphenylmethyl)piperazin-1-yl]ethanol (XII) by means of PCl5 and NaHCO3, finally yielding the (S)- and (R)-isomers of manidipine hydrochloride, respectively.

合成路线25

1) The reaction of 2-(4-piperazinyl)ethanol (I) with diphenylmethyl bromide (II) by means of K2CO3 in DMF gives 2-[4-(diphenylmethyl)-1-piperazinyl] ethanol (III), which is condensed with diketene (IV) at 80 C to yield 2-[4-(diphenylmethyl)-1-piperazinyl] ethyl acetoacetate (V). The condensation of (V) with 3-nitrobenzaldehyde (VI) gives the intermediate benzylidene derivative (VII), which is finally cyclized with methyl 3-aminocrotonate (VIII) in refluxing isopropanol.

合成路线26

3) By cyclization of acetoacetate (V) with aldehyde (VI) and methyl 3-aminocrotonate (VIII) in refluxing isopropanol.

合成路线27

By cyclocondensation of 3-nitrobenzaldehyde (I) with methyl 3-aminocrotonate (II) and 1-benzyl-3-(acetoacetoxy)pyrrolidine (III) in refluxing isopropanol. The pyrrolidine (III) is obtained as follows: The condensation of 2-hydroxysuccinic acid (IV) with benzylamine (VI), which is reduced with LiAlH4 in dry THF yielding N-benzyl-3-hydroxypyrrolidine (VIII). Finally, this compound is condensed with diketene (VII) by means of sodium acetate at 80 C.

合成路线28

The reaction of diketene (I) with 2-bromoethanol (II) by means of dimethylaminopyridine (DMAP) in dichloromethane gives acetoacetic acid 2-bromoethyl ester (III), which is condensed with 3-nitrobenzaldehyde (IV) by means of piperidine acetate in isopropanol yielding the corresponding 3-nitrobenzylidene derivative (V). The cyclization of (V) with methyl 3-aminocrotonate (VI) by heating at 80 C affords 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-bromoethyl) 5-methyl diester (VII), which is condensed with chloromethyl ethyl ether (VIII) by means of NaH in THF to afford the corresponding 1-ethoxymethyl derivative (IX). The reaction of diester (IX) with NaCN and tetrabutylammonium cyanide or sodium p-toluenesulfonate and benzyltriethylammonium chloride (BTEACl) in DMF gives 1-(ethoxymethyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (X). The optical resolution of (X) through the cinchonidine salt yields, after crystallization, the cinchonidine salt of the (R)-enantiomer (XI), which is treated with HCl to eliminate the cinchonidine, and esterified with 1,3-dibromopropane and K2CO3 in acetone to afford (R)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(3-bromopropyl) 5-methyl diester (XII). Finally, this compound is condensed with 4,4-diphenylpiperidine (XIII) by means of K2CO3 in DMF at 100 C.

合成路线29

Iganidipine can be obtained by two similar ways: 1) The condensation of 1-(tert-butoxycarbonyl)piperazine (I) with isobutyraldehyde (II) and formaldehyde in acetic acid gives 3-[4-(tert-butoxycarbonyl)piperazin-1-yl]-2,2-dimethylpropionaldehyde (III), which is reduced with NaBH4 in isopropanol to the corresponding alcohol (IV). The condensation of (IV) with diketene (V) by mens of dimethylaminopyridine (DMAP) in dichloromethane affords the acetoacetic ester (VI), which is cyclized with 3-nitrobenzaldehyde (VII) and methyl 3-aminocrotonate (VIII) in refluxing isopropanol to give the protected dihydropyridine (IX). The elimination of the tert-butoxycarbonyl group of (IX) with HCl in ethanol yields dihydropyridine (X), which is finally alkylated with allyl chloride (XI) and triethylamine in hot THF. 2) The condensation of 3-(4-allylpiperazin-1-yl)-2,2-dimethylpropanol (XII) with diketene (V) in dichloromethane gives the corresponding acetoacetic ester (XIII), which is treated with dry NH3 in methanol to yield the 3-aminocrotonic ester (XIV). Finally, this compound is cyclized with 2-(3-nitrobenzylidene)acetoacetic acid methyl ester (XV) in hot isopropanol.

合成路线30

This compound can be obtained by three different ways: 1) The reaction of 3-nitrobenzaldehyde (I) with methyl acetoacetate (II) by means of m-toluidine in methanol gives methyl 2-(3-nitrobenzylidene)acetoacetate (III), which is then cyclized with 3-aminocrotonic acid 3-phenyl-2(E)-propenyl ester (IV) in refluxing isopropanol. 2) By cyclization of methyl 3-aminocrotonate (V) with aldehyde (I) and acetoacetic acid 3-phenyl-2(E)-propenyl ester (VI) in refluxing isopropanol. 3) By esterification of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (VII) with 3-phenyl-2(E)-propenyl alcohol (VIII), by means of dicyclohexylcarbodiimide (DCC) in pyridine.

合成路线31

Reaction of 2-(4-aminophenyl)ethanol (I) with bis(2-chloroethyl)amine hydrochloride (II) in butanol gives 2-[4-(1-piperazinyl)phenyl]ethanol (III), which is alkylated with diphenylbromomethane (IV) and potassium carbonate in dimethyl formamide to afford 2-[4-[4-(diphenylmethyl)-1-piperazinyl]phenyl]ethanol (V). Treatment of (V) with diketene (VI) in the presence of 4-dimethylaminopyridine in tetrahydrofuran yields 2-[4-[4-(diphenylmethyl)-1-piperazinyl]phenyl]ethyl acetoacetate (VII), which is finally condensed with 3-nitrobenzaldehyde (VIII) and methyl 3-aminocrotonate (IX) in isopropanol (1-5). This last condensation can be performed in two steps by reaction of compound (VII) with compound (VIII) in the presence of piperidine and acetic acid in benzene to give 2-[4-[4-(diphenylmethyl)-1-piperazinyl]phenyl]ethyl 2-(3-nitrobenzylidene)acetoacetate (X), which is finally treated with (IX) in isopropanol. An alternative procedure involves condensation of 3-nitrobenzaldehyde (VIII), diketene (VI), methyl 3-aminocrotonate (IX) and 3-hydroxypropionitrile (XI) in isopropanol to give 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 2-cyanoethyl ethyl diester (XII), which is hydrolyzed with sodium hydroxide to 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (XIII). Compound (XIII) is finally esterified with compound (V) in a mixture of dimethylformamide and chloroform.

合成路线32

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