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 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3

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4

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5

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6

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7

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8

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9

Condensation of 2-chlorobenzaldehyde (I) with methyl 3-methoxy-2(E)-butenoate (II) in the presence of a strong base in dimethyl sulfoxide/water affords, after acidification and reesterification by ethyl bromide/potassium carbonate ethyl 5-(2-chlorophenyl)-3-methyl-2(E),4(E)-pentadienoate (III). Osmium tetroxide catalyzed dihydroxylation of (III) in acetone/water with N-methylmorpholine-N-oxide (NMO) as cooxidant exclusively yields ethyl 5-(2-chlorophenyl)-4,5-threo-dihydroxy-3-methoxy-2(E)-pentenoate (IV), which in acidic medium spontaneously lactonizes to give the parent compound.

合成路线10

The reaction of [benzene-U-13C]benzoic acid (I) with SOCl2 gives the corresponding acyl chloride (II), which is cyclized with the ethanolamine (III) to yield the oxazoline (IV).The chlorination of (IV) with sec-BuLi and hexachloroethane in toluene affords the 2-chlorophenyl derivative (V), which is methylated with MeI to provide the oxazolinium salt (VI). The reduction of (VI) with NaBH4 in ethanol yields the oxazolidine (VII), which is hydrolyzed with HCl to afford the labeled 2-chlorobenzaldehyde (VIII). The condensation of aldehyde (VIII) with the tetrahydrothienopyridine (IX) by means of acetone cyanohydrine in hot toluene affords the substituted acetonitrile (X), which is hydrolyzed to the substituted acetamide (XI) with HCl in methanol. Finally, this compound is treated with H2SO4 in refluxing methanol to afford the target labeled methyl ester as a racemic mixture.

合成路线11

The condensation of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (I) with 2-chlorobenzaldehyde (II) by means of either KCN/HCl, KCN/AcOH, NaHSO3/KCN, NaHSO3 /NaCN, NaHSO3/Tms-CN, NaCN/HCl or AcOH/cyclo[(S)-His-(S)-Phe] and HCN purge gives 2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)acetonitrile (III), which is hydrolyzed to the corresponding acetamide (IV) by means of either KOH, NaOH, NaOH followed by H2O2, refluxing HCl/TFA, formic acid/HCl, refluxing HBr, refluxing H2SO4 or refluxing HClO4. Finally, compound (III) is converted into the corresponding methyl ester with MeOH and either dimethylformamide dimethylacetal, H2SO4, Ms-OH, PPA, TiCl4, POCl3 or HCl.

合成路线12

The synthesis of moxifetin was described according to the following methods: 1) The first synthesis starts from the acid (I), which is prepared either by reaction of 3-methoxythiophenol (V) with 2-iodobenzoic acid (IX) in boiling aqueous potassium hydroxide in the presence of copper, or by reaction of thiosalicylic acid (X) with 3-bromoanisole (XI) in boiling dimethylformamide in the presence of potassium carbonate and copper. The acid (I) is transformed to the acid chloride (II) by treatment with thionyl chloride in boiling benzene in the presence of a small quantity of dimethylformamide. Treatment of the benzene solution of (II) with dimethylamine (XII) under various conditions results in the amide (III), which is reduced to the amine (IV) either with lithium aluminum hydride in ether or with diborane, generated in situ by reaction of sodium borohydride with boron trifluoride etherate in tetrahydrofuran (this method proceeds via the corresponding amine borane which has to be hydrolyzed with sodium hydroxide in boiling aqueous ethanol). The reaction of (III) with phosphoryl chloride, followed by sodium borohydride in ethanol, also results in the amine (IV). This methoxy compound is demethylated in the final step to the desired compound (V) either by heating with pyridine hydrochloride to 210-220 C, by treatment with boron tribromide in chloroform or by refluxing with hydrobromic acid. 2) A shorter synthesis begins with the aldehyde (VI), obtained by reaction of 3-methoxythiophenol (XIII) with 2-chlorobenzaldehyde (XIV) in dimethylformamide at 90 C in the presence of potassium carbonate. Leuckart reaction of (VI) with dimethylformamide and formic acid at 180 C directly affords the methoxy amine (IV). Even a procedure via intermediates (VII) and (VIII), i.e., without protection of the phenolic hydroxyl, is feasible. Refluxing 3-hydroxythiophenol (XV) with 2-iodobenzoic acid (XVI) in aqueous potassium hydroxide in the presence of copper affords the hydroxy acid (VII) in a reasonable yield. The following reaction with dimethylamine (XII), leading to the hydroxy amide (VIII), proceeds in the presence of the complex of triphenylphosphine and tetrachloromethane. The final reduction of (VIII) to moxifetin (V) is carried out with lithium aluminum hydride in tetrahydrofuran. The moxifetin base is converted by reactions with acids to crystalline salts, viz. hydrobromide and hydrogen maleate.

合成路线13

Reaction of 2',5'-dihydroxyacetophenone (I) with dihydropyran (II) and pyridinium p-toluenesulfonate gives the protected bis-tetrahydropyranyl ether (III), which is submitted to Claisen-Schmidt condensation with 2-chlorobenzaldehyde (IV) in the presence of barium hydroxide, yielding the chalcone (V). Finally, the tetrahydropyranyl protecting groups of (V) are removed by acidic hydrolysis with p-toluenesulfonic acid in MeOH.

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