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【结 构 式】 
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【药物名称】MK-0767, MK-767, KRP-297 【化学名称】5-(2,4-Dioxothiazolidin-5-ylmethyl)-2-methoxy-N-[4-(trifluoromethyl)benzyl]benzamide 【CA登记号】185808-55-3 【 分 子 式 】C20H17F3N2O4S 【 分 子 量 】438.42869 |
【开发单位】Kyorin (Originator), Merck & Co. (Licensee), Banyu (Codevelopment) 【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Type 2 Diabetes Mellitus, Agents for, Insulin Sensitizers, PPARalpha Agonists, PPARgamma Agonists |
合成路线1
1) The Knoevenagel condensation of aldehyde (I) with rhodanine (II) using NH4OAc and AcOH afforded benzylidene- thiazolidine (III). The methyl ester group of (III) was hydrolyzed with HCl in AcOH, and the resulting carboxylic acid (IV) was coupled to 4-(trifluoromethyl)benzylamine (V) in the presence of diethyl phosphorocyanidate and Et3N to produce amide (VI). Subsequent hydrogenation of the olefinic double bond of (VI) over Pd/C provided the target benzylthiazolidine.
| 【1】 Nomura, M.; et al.; (3-Substituted benzyl)thiazolidine-2,4-diones as structurally new antihyperglycemic agents. Bioorg Med Chem Lett 1999, 9, 4, 533. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 42235 | Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC | 2942-58-7 | C5H10NO3P | 详情 | 详情 | |
| (I) | 21921 | methyl 5-formyl-2-methoxybenzoate | C10H10O4 | 详情 | 详情 | |
| (II) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |
| (III) | 21923 | methyl 5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2-methoxybenzoate | C13H11NO5S | 详情 | 详情 | |
| (IV) | 21924 | 5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2-methoxybenzoic acid | C12H9NO5S | 详情 | 详情 | |
| (V) | 21925 | [4-(trifluoromethyl)phenyl]methanamine; 4-(trifluoromethyl)benzylamine | 3300-51-4 | C8H8F3N | 详情 | 详情 |
| (VI) | 21926 | 5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2-methoxy-N-[4-(trifluoromethyl)benzyl]benzamide | C20H15F3N2O4S | 详情 | 详情 |
合成路线2
2) An alternative method starting from aniline (VII) employed the Meerwein arylation of methyl acrylate (IX) with the intermediate diazonium salt (VIII) in the presence of cuprous oxide. The resulting bromoester (X) was cyclized with thiourea (XI) in Et2O, followed by hydrolysis with HCl in sulfolane to afford (XIII). Finally, acid (XIII) was coupled to benzylamine (V) in the presence of (EtO)2POCN and Et3N.
| 【1】 Nomura, M.; et al.; (3-Substituted benzyl)thiazolidine-2,4-diones as structurally new antihyperglycemic agents. Bioorg Med Chem Lett 1999, 9, 4, 533. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 42235 | Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC | 2942-58-7 | C5H10NO3P | 详情 | 详情 | |
| (V) | 21925 | [4-(trifluoromethyl)phenyl]methanamine; 4-(trifluoromethyl)benzylamine | 3300-51-4 | C8H8F3N | 详情 | 详情 |
| (VII) | 21927 | methyl 5-amino-2-methoxybenzoate | C9H11NO3 | 详情 | 详情 | |
| (VIII) | 21928 | methyl 5-(1lambda(5)-diazynyl)-2-methoxybenzoate | C9H10N2O3 | 详情 | 详情 | |
| (IX) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (X) | 21930 | methyl 5-(2-bromo-3-methoxy-3-oxopropyl)-2-methoxybenzoate | C13H15BrO5 | 详情 | 详情 | |
| (XI) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (XII) | 21932 | methyl 5-[(2-imino-4-oxo-1,3-thiazolidin-5-yl)methyl]-2-methoxybenzoate | C13H14N2O4S | 详情 | 详情 | |
| (XIII) | 21933 | 5-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]-2-methoxybenzoic acid | C12H11NO5S | 详情 | 详情 |