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【结 构 式】 
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【药物名称】Elgodipine hydrochloride, IQB-875 【化学名称】(±)-2,6-Dimethyl-4-(2,3-methylenedioxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-isopropyl 5-[2-[N-(4-fluorobenzyl)-N-methylamino]ethyl] diester monohydrochloride 【CA登记号】119413-55-7 (free base) 【 分 子 式 】C29H34ClFN2O6 【 分 子 量 】561.05553 |
【开发单位】IIDQB (Originator), Almirall Prodesfarma (Licensee) 【药理作用】Angina pectoris, Treatment of, CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Calcium Channel Blockers |
合成路线1
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 |