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【结 构 式】 
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【分子编号】11375 【品名】Methyl-2-(2-nitrobenzylidene)acetoacetate; methyl (Z)-2-acetyl-3-(2-nitrophenyl)-2-propenoate 【CA登记号】39562-27-1 |
【 分 子 式 】C12H11NO5 【 分 子 量 】249.22308 【元素组成】C 57.83% H 4.45% N 5.62% O 32.1% |
合成路线1
该中间体在本合成路线中的序号：(IX)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.
| 【1】 Ohno, S.; Mizukoshi, K.; Komatsu, O.; Ichiara, K.; Morishima, T. (Maruko Seiyaku); Novel 1,4-dihydropyridines, especially useful as hypotensives. FR 2514761 . |
| 【2】 Castaner, J.; Prous, J.; MPC-1304. Drugs Fut 1991, 16, 1, 25. |
| 【3】 Sumita, T.; Nakamura, Y.; Ichihara, K.; Mizukoshi, K.; Komatsu, O.; Morishima, T.; Ohno, S.; Synthesis of asymmetric 4-aryl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylates with vasodilating and antihypertensive activities. Chem Pharm Bull 1986, 34, 4, 1589-606. |
| 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) | 11368 | (2-Methyl-1,3-dioxolan-2-yl)methanol | C5H10O3 | 详情 | 详情 | |
| (III) | 11369 | (2-methyl-1,3-dioxolan-2-yl)methyl 3-oxobutanoate | C9H14O5 | 详情 | 详情 | |
| (IV) | 11370 | 2-Nitrobenzaldehyde | 552-89-6 | C7H5NO3 | 详情 | 详情 |
| (V) | 11371 | (2-methyl-1,3-dioxolan-2-yl)methyl (Z)-2-acetyl-3-(2-nitrophenyl)-2-propenoate | C16H17NO7 | 详情 | 详情 | |
| (VI) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (VII) | 11373 | 3-methyl 5-[(2-methyl-1,3-dioxolan-2-yl)methyl] 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C21H24N2O8 | 详情 | 详情 | |
| (VIII) | 11374 | (2-methyl-1,3-dioxolan-2-yl)methyl (E)-3-amino-2-butenoate | C9H15NO4 | 详情 | 详情 | |
| (IX) | 11375 | Methyl-2-(2-nitrobenzylidene)acetoacetate; methyl (Z)-2-acetyl-3-(2-nitrophenyl)-2-propenoate | 39562-27-1 | C12H11NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)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.
| 【1】 Robinson, C.P.; Robinson, K.A.; Castaner, J.; Iganidipine Hydrochloride. Drugs Fut 1997, 22, 1, 23. |
| 【2】 Matsui, H.; Fukata, F.M.; Mori, T.; Kakeya, N.; Kitao, K. (Kyoto Pharmaceutical Industries, Ltd.); 1,4-Dihydropyridine derivs. and pharmaceutical compsn. Thereof. AU 8812519; EP 0289746; JP 1988225355; US 4937242 . |
| 【3】 Kakeya, N.; Fukada, F.; Nishizawa, S. (Kyoto Pharmaceutical Industries, Ltd.); 3-Aminocrotonic acid ester. JP 1991099064 . |
| 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) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (II) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
| (III) | 13227 | tert-butyl 4-(2,2-dimethyl-3-oxopropyl)-1-piperazinecarboxylate | C14H26N2O3 | 详情 | 详情 | |
| (IV) | 13228 | tert-butyl 4-(3-hydroxy-2,2-dimethylpropyl)-1-piperazinecarboxylate | C14H28N2O3 | 详情 | 详情 | |
| (V) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (VI) | 13230 | tert-butyl 4-[3-(acetoacetoxy)-2,2-dimethylpropyl]-1-piperazinecarboxylate | C18H32N2O5 | 详情 | 详情 | |
| (VII) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (VIII) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (IX) | 13233 | 3-[3-[4-(tert-butoxycarbonyl)-1-piperazinyl]-2,2-dimethylpropyl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C30H42N4O8 | 详情 | 详情 | |
| (X) | 13234 | 3-[2,2-dimethyl-3-(1-piperazinyl)propyl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C25H34N4O6 | 详情 | 详情 | |
| (XI) | 13235 | Allyl chloride; 3-Chloro-1-propene | 107-05-1 | C3H5Cl | 详情 | 详情 |
| (XII) | 13236 | 3-(4-Allyl-1-piperazinyl)-2,2-dimethyl-1-propanol | C12H24N2O | 详情 | 详情 | |
| (XIII) | 13237 | 3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl 3-oxobutanoate | C16H28N2O3 | 详情 | 详情 | |
| (XIV) | 13238 | 3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl (E)-3-amino-2-butenoate | C16H29N3O2 | 详情 | 详情 | |
| (XV) | 11375 | Methyl-2-(2-nitrobenzylidene)acetoacetate; methyl (Z)-2-acetyl-3-(2-nitrophenyl)-2-propenoate | 39562-27-1 | C12H11NO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)Synthesis of Furaldipine (EN:163877)
| 【1】 Frank, A.; Karn, H.; Spanig, H. (Abbott GmbH & Co. KG); Production of 1-hydroxyalkyl-5-nitroimidazoles. DE 2359625; FR 2253019; GB 1481349 . |
| 【2】 Frank, A.; Dockner, T.; Karn, H. (Abbott GmbH & Co. KG); Process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. EP 0150407 . |
| 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) | 14082 | tetrahydro-2-furanylmethyl 3-oxobutanoate | C9H14O4 | 详情 | 详情 | |
| (II) | 11370 | 2-Nitrobenzaldehyde | 552-89-6 | C7H5NO3 | 详情 | 详情 |
| (III) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (IV) | 14085 | tetrahydro-2-furanylmethyl (E)-3-amino-2-butenoate | C9H15NO3 | 详情 | 详情 | |
| (V) | 11375 | Methyl-2-(2-nitrobenzylidene)acetoacetate; methyl (Z)-2-acetyl-3-(2-nitrophenyl)-2-propenoate | 39562-27-1 | C12H11NO5 | 详情 | 详情 |