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【结 构 式】 
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【药物名称】Tolrestatin, Tolrestat, AY-27773, Alrestin, Lorestat, Alredase 【化学名称】N-[6-Methoxy-5-(trifluoromethyl)-1-naphthylthiocarbonyl]-N-methylglycine 【CA登记号】82964-04-3 【 分 子 式 】C16H14F3NO3S 【 分 子 量 】357.35408 |
【开发单位】Wyeth Pharmaceuticals (Originator), Recordati (Licensee) 【药理作用】ENDOCRINE DRUGS, Symptomatic Antidiabetic Agents, Treatment of Diabetic Complications, Aldose Reductase Inhibitors |
合成路线1
The reaction of 6-methoxy-5-(trifluoromethyl)naphthalene-1-carboxylic acid (I) with SOCl2 in refluxing DMF gives the corresponding acyl chloride (II), which is condensed with methyl N-methylglycinate (III) by means of hydroxybenzotriazole and dicyclohexylcarbodiimide in DMF yielding methyl N-[[5-(trifluoromethyl)-6-methoxy-1-naphthyl]carbonyl]-N-methylglycinate (IV). The reaction of (IV) with P2S5 refluxing pyridine affords methyl N-[[5-(trifluoromethyl)-6-methoxy-1-naphthyl]thioxomethyl]-N-methylglycinate (V), which is finally hydrolyzed with NaOH in methanol water. The synthesis of [14C]-labeled tolrestat has also been described.
| 【1】 Hicks, D.R.; Synthesis of [14C]-labelled tolrestat (N-[[5-(trifluoromethyl)-6-methoxy-1-naphthalenyl]-[14C]thioxomethyl]-N-methylglycine. J Label Compd Radiopharm 1984, 21, 3, 229-236. |
| 【2】 Humber, L.G.; Simar-Duquesne, N.; Sestanj, K.; Bellini, F.; Treasurywala, A.; Abraham, N.A.; Dvornik, D.; Fung, S.; N-[[5-(Trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]-N-methylglycine (tolrestat), a potent, orally active aldose reductase inhibitor. J Med Chem 1984, 27, 43, 255-256. |
| 【3】 Sestanj, K.; Abraham, N.A.; Bellini, F.; Treasurywala, A.; Humber, L.G. (Ayerst Laboratories Inc.); N-Naphtoylglycine derivatives. EP 0059596; JP 570158756; US 4391825 . |
| 【4】 Castaner, J.; Serradell, M.N.; Tolrestat. Drugs Fut 1984, 9, 9, 670. |
| 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) | 30596 | 6-methoxy-5-(trifluoromethyl)-1-naphthoic acid | C13H9F3O3 | 详情 | 详情 | |
| (II) | 30597 | 6-methoxy-5-(trifluoromethyl)-1-naphthoyl chloride | C13H8ClF3O2 | 详情 | 详情 | |
| (III) | 10430 | methyl 2-(methylamino)acetate; methyl N-methylglycinate | 5473-12-1 | C4H9NO2 | 详情 | 详情 |
| (IV) | 30598 | methyl 2-[[6-methoxy-5-(trifluoromethyl)-1-naphthoyl](methyl)amino]acetate | C17H16F3NO4 | 详情 | 详情 | |
| (V) | 30599 | methyl 2-[[[6-methoxy-5-(trifluoromethyl)-1-naphthyl]carbothioyl](methyl)amino]acetate | C17H16F3NO3S | 详情 | 详情 |