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【结 构 式】 
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【分子编号】12100 【品名】ethyl 2-[3-(hydroxymethyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetate 【CA登记号】 |
【 分 子 式 】C13H14N2O4 【 分 子 量 】262.26524 【元素组成】C 59.54% H 5.38% N 10.68% O 24.4% |
合成路线1
该中间体在本合成路线中的序号：(VI)Zopolrestat can be obtained by several different ways: 1) The reaction of 2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetic acid ethyl ester (I) with 2-chloroacetonitrile by means of potassium tert-butoxide in DMF gives 2-[3-(cyanomethyl)-4-oxo-3,4-dihydrophthalazin-1-yl]acetic acid ethyl ester (II), which is cyclized with 2-amino-4-(trifluoromethyl)thiophenol (III) in refluxing ethanol yielding zopolrestat ethyl ester (IV). Finally, this compound is hydrolyzed with KOH in methanol/water/THF. 2) Compound (IV) can also be obtained by cyclization of (II) with 4-chloro-3-nitrobenzotrifluoride (V) in hot DMF saturated with H2S. 3) Compound (II) can also be obtained as follows: The reaction of phthalazine (I) with aqueous formaldehyde gives 2-[3-(hydroxymethyl)-4-oxo-3,4-dihydrophthalazin-1-yl]acetic acid ethyl ester (VI), which is treated with PBr3 in ethyl ether yielding the bromomethyl derivative (VII). Finally, this compound is treated with potassium cyanide and KI in acetone/water.
| 【1】 Mylari, B.L.; Zembrowski, W.J.; Synthesis of aldose reductase inhibitor, 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2 14C benzothiazolyl]methyl]-1-phthalazineacetic acid. J Label Compd Radiopharm 1991, 29, 2, 143-8. |
| 【2】 Mealy, N.; Prous, J.; Castaner, J.; Zopolrestat. Drugs Fut 1995, 20, 1, 33. |
| 【3】 Mylari, B.L.; Zembrowski, W.J. (Pfizer Inc.); Preparation of oxophthalazinyl acetic acids having benzothiazole or other heterocyclic side chains. EP 0295051 . |
| 【4】 Mylari, B.L.; Larson, E.R.; Zembrowski, W.J. (Pfizer Inc.); Heterocyclic oxophthalazinylacetic acids. EP 0222576; JP 1987114988; US 4939140 . |
| 【5】 Siegel, T.W.; Aldinger, C.E.; Mylari, B.L.; Singleton, D.H.; Zembrowski, W.J.; Larson, E.R.; Beyer, T.A.; Dee, M.F.; Novel, potent aldose reductase inhibitors: 3,4-Dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1-phthalazine-acetic acid (zopolrestat) and congeners. J Med Chem 1991, 34, 1, 108-22. |
| 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) | 12095 | ethyl 2-(4-oxo-3,4-dihydro-1-phthalazinyl)acetate; Ethyl 3,4-dihydro-4-oxo-1-phthalazineacetate | 25947-13-1 | C12H12N2O3 | 详情 | 详情 |
| (II) | 12096 | ethyl 2-[3-(2-nitriloethyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetate | C14H13N3O3 | 详情 | 详情 | |
| (III) | 12097 | 2-Amino-4-(trifluoromethyl)benzenethiol; 2-Amino-4-(trifluoromethyl)phenylhydrosulfide | C7H6F3NS | 详情 | 详情 | |
| (IV) | 12098 | ethyl 2-(4-oxo-3-[[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]methyl]-3,4-dihydro-1-phthalazinyl)acetate | C21H16F3N3O3S | 详情 | 详情 | |
| (V) | 12099 | 4-Chloro-3-nitro-alpha,alpha,alpha-trifluorotoluene; 1-Chloro-2-nitro-4-(trifluoromethyl)benzene | 121-17-5 | C7H3ClF3NO2 | 详情 | 详情 |
| (VI) | 12100 | ethyl 2-[3-(hydroxymethyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetate | C13H14N2O4 | 详情 | 详情 | |
| (VII) | 12101 | ethyl 2-[3-(bromomethyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetate | C13H13BrN2O3 | 详情 | 详情 |