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【结 构 式】 
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【药物名称】Ciglitazone, U-63287, ADD-3878 【化学名称】(±)-5-[[4-[(1-Methylcyclohexyl)methoxy]phenyl]methyl]-2,4-thiazolidinedione 【CA登记号】74772-77-3 【 分 子 式 】C18H23NO3S 【 分 子 量 】333.45291 |
【开发单位】Takeda (Originator) 【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Insulin Sensitizers, PPARgamma Agonists, Thiazolidinediones (Glitazones) |
合成路线1
The reaction of 1-methylcyclohexylmethanol (II) with 4-chloronitrobenzene (III) by means of NaH in hot DMSO gives 4-(1-methylcyclohexylmethoxylnitrobenzene (III), which is reduced with H2 over Pd/C in methanol yielding 4-(1-methylcyclohexylmethoxylaniline (IV). Diazotation of (IV) with NaNO2 and HCl in water affords a solution of the corresponding diazonium chloride (V), which is condensed with methyl acrylate (VI) by means of Cu2O affording methyl 2-chloro-3-[4-(1-methylcyclohexylmethoxyl)phenyl]propionate (VII). The cyclization of (VII) with thiourea (VIII) by means of sodium acetate in hot 2-methoxyethanol gives 2-imino-5-[4-(1-methylcyclohexylmethoxy)benzyl]thiazolidin-4-one (IX), which is finally hydrolyzed with HCl in refluxing 2-methoxyethanol - water.
| 【1】 Kawamatsu, Y.; Mizuno, K.; Sugiyama, Y.; Imamiya, E.; Fujita, T.; Sohda, T.; Studies on antidiabetic agents. II. Synthesis of 5-[4-(1-methylcyclohexylmethoxy)benzyl]thiazolidine-2,4-dione (ADD-3878) and its derivatives. Chem Pharm Bull 1982, 30, 10, 3580. |
| 【2】 Nohria, V.; Castaner, J.; Serradell, M.N.; Ciglitazone. Drugs Fut 1984, 9, 4, 258. |
| 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) | 34173 | (1-methylcyclohexyl)methanol | C8H16O | 详情 | 详情 | |
| (II) | 13909 | 1-Chloro-4-nitrobenzene; p-Nitrochlorobenzene | 100-00-5 | C6H4ClNO2 | 详情 | 详情 |
| (III) | 34174 | 1-[(1-methylcyclohexyl)methoxy]-4-nitrobenzene; (1-methylcyclohexyl)methyl 4-nitrophenyl ether | C14H19NO3 | 详情 | 详情 | |
| (IV) | 34175 | 4-[(1-methylcyclohexyl)methoxy]phenylamine; 4-[(1-methylcyclohexyl)methoxy]aniline | C14H21NO | 详情 | 详情 | |
| (V) | 34176 | 4-[(1-methylcyclohexyl)methoxy]benzenediazonium chloride | C14H19ClN2O | 详情 | 详情 | |
| (VI) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (VII) | 34177 | methyl 2-chloro-3-[4-[(1-methylcyclohexyl)methoxy]phenyl]propanoate | C18H25ClO3 | 详情 | 详情 | |
| (VIII) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (IX) | 34178 | 2-imino-5-[4-[(1-methylcyclohexyl)methoxy]benzyl]-1,3-thiazolidin-4-one | C18H24N2O2S | 详情 | 详情 |
合成路线2
By cyclization of (VIII) with methyl 2-(methanesulfonyloxy)-3-[4-(1-methylcyclohexylmethoxy)phenyl]propionate (X) by means of sodium acetate in hot 2-methoxyethanol, followed by hydrolysis with HCl in ethanol water.
| 【1】 Fujita, T.; Kawamatsu, Y.; Thiazolidine derivatives. EP 0008203; US 4287200; US 4340605; US 4438141; US 4444779 . |
| 【2】 Nohria, V.; Castaner, J.; Serradell, M.N.; Ciglitazone. Drugs Fut 1984, 9, 4, 258. |