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【结 构 式】 
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【分子编号】13332 【品名】isopropyl 3-oxobutanoate; Isopropyl acetoacetate 【CA登记号】542-08-5 |
【 分 子 式 】C7H12O3 【 分 子 量 】144.17048 【元素组成】C 58.32% H 8.39% O 33.29% |
合成路线1
该中间体在本合成路线中的序号：(II)By cyclization of 2,1,3-benzoxadiazole-4-carbaldehyde (I) with isopropyl acetoacetate (II) and methyl 3-aminocrotonate (III) in refluxing ethanol.
| 【1】 Neumann, P. (Novartis AG); Benzoxadiazoles and benzothiadiazoles, their preparation and pharmaceutical compsns. containing them. US 4466972 . |
合成路线2
该中间体在本合成路线中的序号：(I)The condensation of isopropyl acetoacetate (I) with 3-nitrobenzaldehyde (II) gives isopropyl 2-(3-nitrobenzylidene)acetoacetate (III), which is cyclized with methyl 3-amino-4,4-dimethoxycrotonate (IV) at 100 C yielding 5-isopropyl-3-methyl-2-(dimethoxymethyl)-6-methyl-4-(3-nitropheny)-1,4-dihydropyridine-3,5-dicarboxylate (V). The hydrolysis of the acetal group of (V) with HCl in acetone affords the corresponding 2-formyl derivative (VI), which is finally treated with hydroxylamine and acetic anhydride in acetic acid at 100 C.
| 【1】 Satu, Y. (Fujisawa Pharmaceutical Co., Ltd.); 1,4-Dihydropyridine derivatives and pharmaceutical method of the same. BE 0879263; DE 2940833; FR 2438654; GB 2036722; US 4284634; US 4338322 . |
| 【2】 Blancafort, P.; Castaner, J.; Serradell, M.N.; FR-34,235. Drugs Fut 1983, 8, 9, 776. |
| 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) | 13332 | isopropyl 3-oxobutanoate; Isopropyl acetoacetate | 542-08-5 | C7H12O3 | 详情 | 详情 |
| (II) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (III) | 12595 | isopropyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C14H15NO5 | 详情 | 详情 | |
| (IV) | 31096 | methyl (E)-3-amino-4,4-dimethoxy-2-butenoate | C7H13NO4 | 详情 | 详情 | |
| (V) | 31097 | 5-isopropyl 3-methyl 2-(dimethoxymethyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C21H26N2O8 | 详情 | 详情 | |
| (VI) | 31098 | 5-isopropyl 3-methyl 2-formyl-6-methyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C19H20N2O7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)By cyclocondensation of 3-chloro-6-fluoro-2-(trifluoromethyl)benzaldehyde (I), isopropyl 3-aminocrotonate (II) and methyl 4-fluoroacetylacetate (III) by heating at 110 C. The starting products are prepared as follows: Aldehyde (I) is obtained by reaction of 1-chloro-4-fluoro-3-(trifluoromethyl)benzene (IV) with N-methyl-N-phenylformamide (V) by means of butyllithium in TNF. Aminocrotonate (II) is obtained by reaction of isopropyl acetoacetate (VI) with dry ammonia in methanol. Finally, the acylation of 2,2-dimethyl-1,3-dioxane-4,6-dione (VII) with fluoroacetyl chloride (VIII) by means of pyridine in dichloromethane gives 5-(fluoroacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (IX), which is then treated with refluxing methanol to give 4-fluoroacetylacetate (III).
| 【1】 Baxter, A.J.G.; Dixon, J.; Gould, K.J.; McInally, T.; Tinker, A.C. (Celltech Group plc); Pharmaceutically active dihydropyridines. EP 0125803 . |
| 【2】 Baxter, A.J.G.; Dixon, J.; Gould, K.J.; Tinker, A.C. (Celltech Group plc); Dihydropyridine derivs.. EP 0174131; ES 8800154; ES 8801632; JP 1986065867 . |
| 【3】 Prous, J.; Castaner, J.; FPL-62129XX. Drugs Fut 1989, 14, 2, 121. |
| 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) | 20356 | 3-chloro-6-fluoro-2-(trifluoromethyl)benzaldehyde | C8H3ClF4O | 详情 | 详情 | |
| (II) | 13331 | isopropyl (E)-3-amino-2-butenoate | 143093-33-8 | C7H13NO2 | 详情 | 详情 |
| (III) | 20358 | methyl 4-fluoro-3-oxobutanoate | C5H7FO3 | 详情 | 详情 | |
| (IV) | 20359 | 1-chloro-4-fluoro-2-(trifluoromethyl)benzene | C7H3ClF4 | 详情 | 详情 | |
| (V) | 20360 | methyl(phenyl)formamide;N-Methylformanilide;N-Formyl-N-methylaniline;Methylphenylformamide;N-methyl-N-phenylformamide;N-Methyl-N-formylaniline;N-Formyl-N-methylaniline | 93-61-8 | C8H9NO | 详情 | 详情 |
| (VI) | 13332 | isopropyl 3-oxobutanoate; Isopropyl acetoacetate | 542-08-5 | C7H12O3 | 详情 | 详情 |
| (VII) | 14738 | Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester | 2033-24-1 | C6H8O4 | 详情 | 详情 |
| (VIII) | 20363 | 2-fluoroacetyl chloride | 359-06-8 | C2H2ClFO | 详情 | 详情 |
| (IX) | 20364 | 5-(2-fluoroacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione | C8H9FO5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)Elgodipine can be obtained in three main steps: The alkylation of N-methyl-2-aminoethanol (I) with 4-fluorobenzyl chloride (II) gives 2-[N-(4-fluorobenzyl)-N-methylamino]ethanol (III), which is esterified with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (IV) yielding the corresponding acetoacetic ester (V). The condensation of (V) with 2,3-methylenedioxybenzaldehyde (VI) affords 2-[N-(4-fluorobenzyl)-N-methylamino]ethyl 2-(2,3-methylenedioxybenzylidene]acetoacetate (VII), which is finally cyclized with isopropyl 3-aminocrotonate (VIII). The intermediate aldehyde (VI) is obtained starting from 2,3-dimethoxybenzaldehyde (X), which by demethylation with HCl or HBr yields 2,3-dihydroxybenzaldehyde (XI). Finally, this compound is converted into (VI) in the usual way. The intermediate crotonate (VIII) is obtained by reaction of isopropyl acetoacetate (IX) with ammonia.
| 【1】 Galiano, A.; Elgodipine Hydrochloride. Drugs Fut 1995, 20, 3, 231. |
| 【2】 Fernandez Torija, C.; Galiano Ramos, J.A. (IIDQB (Madrid)); 1,4-Dihydropyridines, process for their preparation and their use as medicaments. AU 8820330; BE 1001055; CH 675999; EP 0302980; GB 2208861; JP 1989294675; US 4952592 . |
| 【3】 Serradell, M.N.; Castaner, J.; Castaner, R.M.; Oxodipine. Drugs Fut 1987, 12, 7, 633. |
| 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) | 13324 | 2-Methylaminoethanol; 2-(Methylamino)-1-ethanol | 109-83-1 | C3H9NO | 详情 | 详情 |
| (II) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
| (III) | 13333 | 2-[(4-Fluorobenzyl)(methyl)amino]-1-ethanol | C10H14FNO | 详情 | 详情 | |
| (IV) | 13327 | 2,2,6-Trimethyl-4H-1,3-dioxin-4-one；2,2,6-trimethyl-1,3-dioxin-4-one；2,2,6-trimethyl-m-Dioxin-4-one;3-(1-hydroxy-1-methylethoxy)-d-lactone Crotonicacid | 5394-63-8 | C7H10O3 | 详情 | 详情 |
| (V) | 13328 | 2-[(4-fluorobenzyl)(methyl)amino]ethyl 3-oxobutanoate | C14H18FNO3 | 详情 | 详情 | |
| (VI) | 13329 | 2,3-(Methylenedioxy)benzaldehyde; 1,3-Benzodioxole-4-carbaldehyde | 7797-83-3 | C8H6O3 | 详情 | 详情 |
| (VII) | 13330 | 2-[(4-fluorobenzyl)(methyl)amino]ethyl (Z)-2-acetyl-3-(1,3-benzodioxol-4-yl)-2-propenoate | C22H22FNO5 | 详情 | 详情 | |
| (VIII) | 13331 | isopropyl (E)-3-amino-2-butenoate | 143093-33-8 | C7H13NO2 | 详情 | 详情 |
| (IX) | 13332 | isopropyl 3-oxobutanoate; Isopropyl acetoacetate | 542-08-5 | C7H12O3 | 详情 | 详情 |
| (X) | 17615 | 2,3-Dimethoxybenzaldehyde | 86-51-1 | C9H10O3 | 详情 | 详情 |
| (XI) | 12380 | 2,3-Dihydroxybenzaldehyde | 24677-78-9 | C7H6O3 | 详情 | 详情 |