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【结 构 式】 
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【药物名称】 【化学名称】2-(5-Methyl-2-phenyloxazol-4-ylmethoxy)-5-[3-(1H-tetrazol-5-yl)propyl]pyridine 【CA登记号】166254-17-7 【 分 子 式 】C20H20N6O2 【 分 子 量 】376.4214 |
【开发单位】Takeda (Originator) 【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, Insulin Sensitizers, PPARgamma Agonists |
合成路线1
Coupling of 2-chloro-5-nitropyridine (II) with the sodium alkoxide of 5-methyl-2-phenylisoxazol-4-ylmethanol (I) gave the 2-alkoxy-5-nitropyridine (III), which was reduced to the aminopyridine (IV) by catalytic hydrogenation over Pd/C. Meerwein arylation of methyl acrylate with the diazonium salt generated from amine (IV) furnished the bromopropionate (V), which was further dehydrohalogenated in the presence of DBU to the pyridyl acrylate (VI). Ester reduction in (VI) employing DIBAL yielded the allylic alcohol (VII). This was hydrogenated to the saturated alcohol (VIII) in the presence of Pd/C. After activation of alcohol (VIII) as the corresponding mesylate (IX), displacement by KCN in hot DMF yielded nitrile (X). This was finally converted to the desired tetrazole by treatment with sodium azide and ammonium chloride.
| 【1】 Momose, Y.; Ikeda, H.; Odaka, H.; Maekawa, T.; Sohda, T.; Novel 5-substituted-1H-tetrazole derivatives as potent glucose and lipid lowering agents. Chem Pharm Bull 2002, 50, 1, 100. |
| 【2】 Sohda, T.; Ikeda, H.; Momose, Y. (Takeda Chemical Industries, Ltd.); Tetrazole derivs., their production and use. CA 2125549; EP 0629624; JP 1995053555; US 5591862 . |
| 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) | 55939 | (5-methyl-2-phenyl-1,3-oxazol-4-yl)methanol | 70502-03-3 | C11H11NO2 | 详情 | 详情 |
| (II) | 29610 | 2-chloro-5-nitropyridine | 4548-45-2 | C5H3ClN2O2 | 详情 | 详情 |
| (III) | 55940 | (5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl 5-nitro-2-pyridinyl ether; 2-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-5-nitropyridine | C16H13N3O4 | 详情 | 详情 | |
| (IV) | 55941 | 6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinamine; 6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinylamine | C16H15N3O2 | 详情 | 详情 | |
| (V) | 55942 | methyl 2-bromo-3-{6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinyl}propanoate | C20H19BrN2O4 | 详情 | 详情 | |
| (VI) | 55943 | methyl (E)-3-{6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinyl}-2-propenoate | C20H18N2O4 | 详情 | 详情 | |
| (VII) | 55944 | (E)-3-{6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinyl}-2-propen-1-ol | C19H18N2O3 | 详情 | 详情 | |
| (VIII) | 55945 | 3-{6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinyl}-1-propanol | C19H20N2O3 | 详情 | 详情 | |
| (IX) | 55946 | 3-{6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinyl}propyl methanesulfonate | C20H22N2O5S | 详情 | 详情 | |
| (X) | 55947 | 4-{6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinyl}butanenitrile | C20H19N3O2 | 详情 | 详情 |