【结 构 式】 |
【药物名称】 【化学名称】2-[3-[4-(3-Phenyl-7-propyl-1,2-benzisoxazol-6-yloxy)butoxy]phenyl]acetic acid sodium salt 【CA登记号】194980-75-1 (free acid), 477936-07-5 (labeled) 【 分 子 式 】C28H28NNaO5 【 分 子 量 】481.52886 |
【开发单位】Merck & Co. (Originator) 【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, PPAR Agonists |
合成路线1
Claisen rearrangement of allyl ether (I) in refluxing o-dichlorobenzene affords (II). The allyl group of (II) is subsequently hydrogenated over Pd/C to provide the propyl derivative (III). Benzophenone (III) is converted into the corresponding oxime (IV) by means of hydroxylamine hydrochloride and NaOAc. Acetylation of oxime (IV), followed by refluxing in pyridine gives rise to the benzisoxazole (V). The phenolic hydroxyl group of (V) is then alkylated by 1,4-dibromobutane (VI) producing the bromobutyl ether (VII). 3-Hydroxyphenylacetic acid (VIII) is esterified with MeOH/H2SO4 to give the methyl ester (IX). This is then condensed with bromide (VII) in the presence of K2CO3 to furnish diether (X). Finally, saponification of the methyl ester group of (X) employing LiOH yields the target carboxylic acid (1,2)
【1】 Adams, A.D.; Yuen, W.; Hu, Z.; Santini, C.; Jones, A.B.; MacNaul, K.L.; Berger, J.P.; Doebber, T.W.; Moller, D.E.; Amphipathic 3-phenyl-7-propylbenzisoxazoles; human PPAR gamma, delta and alpha agonists. Bioorg Med Chem Lett 2003, 13, 5, 931. |
【2】 Adams, A.D.; Berger, J.P.; Berger, G.D.; Fitch, K.J.; Graham, D.W.; Jones, A.B.; Von Langen, D.; Leibowitz, M.D.; Moller, D.E.; Patchett, A.A.; Santini, C.; Sahoo, S.P.; Tolman, R.L.; Toupence, R.B.; Walsh, T.F. (Merck & Co., Inc.); Heterocyclic derivs. as antidiabetic and antiobesity agents. EP 0882029; JP 2002503203; US 6090836; WO 9728137 . |
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) | 63548 | [4-(allyloxy)-2-hydroxyphenyl](phenyl)methanone | C16H14O3 | 详情 | 详情 | |
(II) | 63549 | (3-allyl-2,4-dihydroxyphenyl)(phenyl)methanone | C16H14O3 | 详情 | 详情 | |
(III) | 63550 | (2,4-dihydroxy-3-propylphenyl)(phenyl)methanone | C16H16O3 | 详情 | 详情 | |
(IV) | 63551 | (2,4-dihydroxy-3-propylphenyl)(phenyl)methanone oxime | C16H17NO3 | 详情 | 详情 | |
(V) | 63552 | 3-phenyl-7-propyl-1,2-benzisoxazol-6-ol | C16H15NO2 | 详情 | 详情 | |
(VI) | 11883 | 1,4-Dibromobutane; 1,4-Butylene bromide | 110-52-1 | C4H8Br2 | 详情 | 详情 |
(VII) | 63553 | 6-(4-bromobutoxy)-3-phenyl-7-propyl-1,2-benzisoxazole; 4-bromobutyl 3-phenyl-7-propyl-1,2-benzisoxazol-6-yl ether | C20H22BrNO2 | 详情 | 详情 | |
(VIII) | 58561 | 2-(3-hydroxyphenyl)acetic acid | C8H8O3 | 详情 | 详情 | |
(IX) | 58567 | methyl 2-(3-hydroxyphenyl)acetate | C9H10O3 | 详情 | 详情 | |
(X) | 63554 | methyl 2-(3-{4-[(3-phenyl-7-propyl-1,2-benzisoxazol-6-yl)oxy]butoxy}phenyl)acetate | C29H31NO5 | 详情 | 详情 |