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【结 构 式】 
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【分子编号】13950 【品名】5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid 【CA登记号】 |
【 分 子 式 】C16H16N2O6 【 分 子 量 】332.31292 【元素组成】C 57.83% H 4.85% N 8.43% O 28.89% |
合成路线1
该中间体在本合成路线中的序号：(VI)4) By esterification of 1,4-dihydro-2,6-dimethyl 4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid monomethyl ester (VI) with 1-benzyl-3-hydroxypiperidine (VII) by means of SOCl2 in DMF dichloroethane.
| 【1】 Muto, K.; Kuroda, T.; Karasawa, A.; Yamada, K.; Nakamizo, N. (Kyowa Hakko Kogyo Co., Ltd.); 1,4-Dihydropyridine derivatives. CA 1246078; EP 0106275; ES 526441 . |
| 【2】 Prous, J.; Castaner, J.; KW-3049. Drugs Fut 1986, 11, 11, 936. |
合成路线2
该中间体在本合成路线中的序号：(VI)5) The esterification of (VI) with 3-hydroxypipendine (VIII) as before gives the corresponding ester (IX), which is then benzylated with benzyl chloride (X) by means of triethylamine in refluxing THF.
| 【1】 Muto, K.; Kuroda, T.; Karasawa, A.; Yamada, K.; Nakamizo, N. (Kyowa Hakko Kogyo Co., Ltd.); 1,4-Dihydropyridine derivatives. CA 1246078; EP 0106275; ES 526441 . |
| 【2】 Prous, J.; Castaner, J.; KW-3049. Drugs Fut 1986, 11, 11, 936. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 13950 | 5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C16H16N2O6 | 详情 | 详情 | |
| (VIII) | 24255 | 3-piperidinol | 6859-99-0 | C5H11NO | 详情 | 详情 |
| (IX) | 24256 | 3-methyl 5-(3-piperidinyl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C21H25N3O6 | 详情 | 详情 | |
| (X) | 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)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.
| 【1】 Catto, A.; Motta, G.; Pennini, R.; Testa, R.; Sironi, G.; Cerri, A.; Leonardi, A.; Asymmetric N-(3,3-diphenylpropyl)aminoalkyl esters of 4-aryl-2,6-dimethyl-1,4-dihydropyridine-3, 5-dicarboxylic acids with antihypertensive activity. Eur J Med Chem 1998, 33, 5, 399. |
| 【2】 Nardi, D.; Leonardi, A.; Graziani, G.; Bianchi, G. (Recordati Industria Chimica e Farmaceutica SpA); N-(3,3-diphenylpropyl)aminoethylesters of 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid, compositions and use. EP 0153016; JP 60199874; US 4772621; US 4968832 . |
| 【3】 Bianchi, G.; Leonardi, A.; REC 15/2375. Drugs Fut 1987, 12, 12, 1113. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (II) | 17748 | 1-[(3,3-diphenylpropyl)(methyl)amino]-2-methyl-2-propanol | C20H27NO | 详情 | 详情 | |
| (III) | 17749 | 2-[(3,3-diphenylpropyl)(methyl)amino]-1,1-dimethylethyl 3-oxobutanoate | C24H31NO3 | 详情 | 详情 | |
| (IV) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (V) | 17751 | 2-[(3,3-diphenylpropyl)(methyl)amino]-1,1-dimethylethyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C31H34N2O5 | 详情 | 详情 | |
| (VI) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (VII) | 13950 | 5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C16H16N2O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)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.
| 【1】 Nishitani, S.; Minamikawa, J.; Kano, M.; Otsubo, J.; Manabe, Y. (Otsuka Pharmaceutical Co., Ltd.); Process for preparing novel dihydropyridine derivs. EP 0173126 . |
| 【2】 Tamada, S.; Ei, K.; Teramoto, S.; Tanaka, T.; Nakagawa, T. (Otsuka Pharmaceutical Co., Ltd.); Dihydropyridine derivs. JP 1986140567 . |
| 【3】 Tamada, S.; Nagami, K.; Teramoto, S.; Tanaka, T.; Nakagawa, K. (Otsuka Pharmaceutical Co., Ltd.); Novel dihydropyridine derivs. and process for preparing the same. EP 0145434; ES 8604516; ES 8701726; ES 8701727; JP 1985120861; JP 1989151557; US 5034395; US 5137889 . |
| 【4】 Prous, J.; Castaner, J.; OPC-13340. Drugs Fut 1991, 16, 2, 119. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (II) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (III) | 12276 | methyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C12H11NO5 | 详情 | 详情 | |
| (IV) | 13947 | (E)-3-phenyl-2-propenyl (E)-3-amino-2-butenoate | C13H15NO2 | 详情 | 详情 | |
| (V) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (VI) | 13949 | (E)-3-phenyl-2-propenyl 3-oxobutanoate | C13H14O3 | 详情 | 详情 | |
| (VII) | 13950 | 5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C16H16N2O6 | 详情 | 详情 | |
| (VIII) | 13951 | (E)-3-Phenyl-2-propen-1-ol | 104-54-1 | C9H10O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIII)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.
| 【1】 Ashimori, A.; Ono, T.; Inoue, Y.; Fukaya, C. (Welfide Corporation); Dihydropyridine derivs. and pharmaceutical compsns. Thereof. EP 0257616; JP 1988099042; JP 1988225356; US 4886819 . |
| 【2】 (Welfide Corporation); Use of dihydropyridines in cardiotonic pharmaceutical compsns. EP 0109039; US 4543354 . |
| 【3】 Kido, H.; Uchida, T.; Fukaya, C.; Yokoyama, K.; Uchida, Y. (Welfide Corporation); Dihydropyridine derivs. for the treatment of angiospasm. EP 0379737; JP 1990180826 . |
| 【4】 Ono, T.; Ashimori, A.; Inoue, Y.; Novel 1,4-dihydropyridine calcium antagonists. II. Synthesis and antihypertensive activity of 3-[4-(substituted amino)phenylalkyl]ester derivatives. Chem Pharm Bull 1991, 39, 1, 91-9. |
| 【5】 Ohe, K.; Tanaka, M.; Yokoyama, K.; Uchida, T.; Fukaya, C.; Watanabe, M.; Ohtaki, Y.; Ashimori, A.; Kagitani, M.; Synthesis and pharmacological effects of optically active 2-[4-(4-benzhydryl-1-piperazinyl)phenyl]ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicrboxylate hydrochloride. Chem Pharm Bull 1991, 39, 1, 108-11. |
| 【6】 Castaner, J.; Mealy, N.; Prous, J.; AE0047. Drugs Fut 1994, 19, 7, 627. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 14019 | p-Aminophenylethanol; 2-(4-Aminophenyl)-1-ethanol | 104-10-9 | C8H11NO | 详情 | 详情 |
| (II) | 14020 | N,N-Bis(2-chloroethyl)amine hydrochloride; 2-Chloro-N-(2-chloroethyl)-1-ethanamine hydrochloride | C4H10Cl3N | 详情 | 详情 | |
| (III) | 14021 | 2-(4-Piperazinophenyl)-1-ethanol | C12H18N2O | 详情 | 详情 | |
| (IV) | 12079 | Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide | 776-74-9 | C13H11Br | 详情 | 详情 |
| (V) | 14023 | 2-[4-(4-Benzhydrylpiperazino)phenyl]-1-ethanol | C25H28N2O | 详情 | 详情 | |
| (VI) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (VII) | 14025 | 4-(4-benzhydrylpiperazino)phenethyl 3-oxobutanoate | C29H32N2O3 | 详情 | 详情 | |
| (VIII) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (IX) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (X) | 14028 | 4-(4-benzhydryl-1-piperazinyl)phenethyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C36H35N3O5 | 详情 | 详情 | |
| (XI) | 14029 | Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile | 109-78-4 | C3H5NO | 详情 | 详情 |
| (XII) | 14030 | 3-(2-cyanoethyl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C19H19N3O6 | 详情 | 详情 | |
| (XIII) | 13950 | 5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C16H16N2O6 | 详情 | 详情 |