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【结 构 式】 
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【药物名称】 【化学名称】(Z)-2-[4-(5-Methyl-2-phenyloxazol-4-ylmethoxy)benzyloxyimino]-2-(4-phenoxyphenyl)acetic acid 【CA登记号】250601-08-2, 250601-09-3 (E-isomer) 【 分 子 式 】C32H26N2O6 【 分 子 量 】534.57382 |
【开发单位】Takeda (Originator) 【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, PPARgamma Agonists |
合成路线1
Reduction of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (I) with NaBH4 affords alcohol (II). Subsequent chlorination of (II) employing thionyl chloride in toluene leads to the benzyl chloride (III)
| 【1】 Imoto, H.; Imamiya, E.; Momose, Y.; Sugiyama, Y.; Kimura, H.; Sohda, T.; Studies on non-thiazolidinedione antidiabetic agents. 1. Discovery of novel oxyiminoacetic acid derivatives. Chem Pharm Bull 2002, 50, 10, 1349. |
| 【2】 Kimura, H.; Momose, Y.; Odaka, H.; Sakamoto, J.; Imoto, H. (Takeda Chemical Industries, Ltd.); Oxyiminoalkanoic acid derivs. with hypoglycemic and hypolipidemic activity. EP 1077957; JP 2000034266; JP 2000198772; US 6251926; US 6495581; WO 9958510 . |
| 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) | 60072 | 4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzaldehyde | C18H15NO3 | 详情 | 详情 | |
| (II) | 60073 | {4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}methanol | C18H17NO3 | 详情 | 详情 | |
| (III) | 60074 | 4-(chloromethyl)phenyl (5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl ether; 4-{[4-(chloromethyl)phenoxy]methyl}-5-methyl-2-phenyl-1,3-oxazole | C18H16ClNO2 | 详情 | 详情 |
合成路线2
Friedel-Crafts acylation of diphenyl ether (IV) with ethyl chloroglyoxylate (V) affords the (4-phenoxyphenyl)glyoxylate (VI). This is then treated with hydroxylamine to produce a mixture of Z- and E-oximes (VII) and (VIII), which can be separated by recrystallization, followed by column chromatography. The desired Z-oxime (VII) is alkylated by the benzyl chloride derivative (III) to furnish the O-benzyl oxime (IX). Finally, saponification of the ethyl ester group of (IX) with NaOH in MeOH gives rise to the target carboxylic acid
| 【1】 Imoto, H.; Imamiya, E.; Momose, Y.; Sugiyama, Y.; Kimura, H.; Sohda, T.; Studies on non-thiazolidinedione antidiabetic agents. 1. Discovery of novel oxyiminoacetic acid derivatives. Chem Pharm Bull 2002, 50, 10, 1349. |
| 【2】 Kimura, H.; Momose, Y.; Odaka, H.; Sakamoto, J.; Imoto, H. (Takeda Chemical Industries, Ltd.); Oxyiminoalkanoic acid derivs. with hypoglycemic and hypolipidemic activity. EP 1077957; JP 2000034266; JP 2000198772; US 6251926; US 6495581; WO 9958510 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 60074 | 4-(chloromethyl)phenyl (5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl ether; 4-{[4-(chloromethyl)phenoxy]methyl}-5-methyl-2-phenyl-1,3-oxazole | C18H16ClNO2 | 详情 | 详情 | |
| (IV) | 60075 | 1-phenoxybenzene; diphenyl ether | C12H10O | 详情 | 详情 | |
| (V) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (VI) | 60076 | ethyl 2-oxo-2-(4-phenoxyphenyl)acetate | C16H14O4 | 详情 | 详情 | |
| (VII) | 60080 | ethyl 2-(hydroxyimino)-2-(4-phenoxyphenyl)acetate | C16H15NO4 | 详情 | 详情 | |
| (VIII) | 60077 | ethyl 2-(hydroxyimino)-2-(4-phenoxyphenyl)acetate | C16H15NO4 | 详情 | 详情 | |
| (IX) | 60078 | ethyl 2-[({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)imino]-2-(4-phenoxyphenyl)acetate | C34H30N2O6 | 详情 | 详情 |