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【结 构 式】 
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【药物名称】SB-334867 【化学名称】N-(2-Methylbenzoxazol-6-yl)-N'-(1,5-naphthyridin-4-yl)urea 【CA登记号】249889-64-3 (monohydrochloride) 【 分 子 式 】C17H13N5O2 【 分 子 量 】319.32546 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Antiobesity Drugs, METABOLIC DRUGS, Treatment of Nutritional Disorders, Orexin OX-1 Antagonists |
合成路线1
The known 4-hydroxy-1,5-naphthyridine-3-carboxylic acid (I) was decarboxylated to (II) upon refluxing in quinoline. Heating of (II) with POCl3 furnished 4-chloro-1,5-naphthyridine (III), which was converted to amine (IV) by reaction with n-propylamine in pyridine. Curtius rearrangement of 2-methyl-6-benzoxazolecarboxylic acid (V) in the presence of diphenylphosphoryl azide gave isocyanate (VI). Finally, coupling between isocyanate (VI) and amine (IV) provided the title urea.
| 【1】 Johns, A.; Porter, R.A. (SmithKline Beecham plc); Phenylurea and phenylthio urea derivs.. EP 1075478; WO 9958533 . |
| 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) | 43932 | 4-hydroxy[1,5]naphthyridine-3-carboxylic acid | C9H6N2O3 | 详情 | 详情 | |
| (II) | 43933 | [1,5]naphthyridin-4-ol | C8H6N2O | 详情 | 详情 | |
| (III) | 43934 | 4-chloro[1,5]naphthyridine | C8H5ClN2 | 详情 | 详情 | |
| (IV) | 43935 | [1,5]naphthyridin-4-amine; [1,5]naphthyridin-4-ylamine | C8H7N3 | 详情 | 详情 | |
| (V) | 43936 | 2-methyl-1,3-benzoxazole-6-carboxylic acid | C9H7NO3 | 详情 | 详情 | |
| (VI) | 43937 | 6-isocyanato-2-methyl-1,3-benzoxazole; 2-methyl-1,3-benzoxazol-6-yl isocyanate | C9H6N2O2 | 详情 | 详情 |
合成路线2
The cyclization of 3aminopyridine (I) with diethyl ethoxymethylenemalonate (II) in refluxing Dowtherm gives 4-hydroxy-1,5-naphthyridine-3-carboxylic acid ethyl ester (III), which is hydrolyzed with NaOH in refluxing water to yield the corresponding hydroxyacid (IV). The decarboxylation of (IV) by heating at 320 C in mineral oil affords 4-hydroxy-1,5-naphthyridine (V), which is acylated with trifluoromethanesulfonic anhydride to provide the triflate (VI). The reaction of (VI) with propylamine in pyridine affords 4-amino-1,5-naphthyridine (VII), which is condensed with 2-methylbenzoxazole-6-ylcarbonyl azide (VIII) (obtained by reaction of the corresponding acid (IX) with DPPA) in refluxing toluene to provide the target urea.
| 【1】 Porter, R.A.; et al.; 1,3-Biarylureas as selective non-peptide antagonists of the orexin-1 receptor. Bioorg Med Chem Lett 2001, 11, 14, 1907. |
| 【2】 Adams, J.T.; et al.; Synthesis of antimalarials. VI. Synthesis of certain 1,5- and 1,8-naphthyridine derivatives. J Am Chem Soc 1946, 68, 1317. |
| 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) | 33327 | 3-Pyridinylamine; 3-Aminopyridine; 3-Pyridinamine | 462-08-8 | C5H6N2 | 详情 | 详情 |
| (II) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (III) | 53616 | ethyl 4-hydroxy[1,5]naphthyridine-3-carboxylate | 13801-51-9 | C11H10N2O3 | 详情 | 详情 |
| (IV) | 43932 | 4-hydroxy[1,5]naphthyridine-3-carboxylic acid | C9H6N2O3 | 详情 | 详情 | |
| (V) | 43933 | [1,5]naphthyridin-4-ol | C8H6N2O | 详情 | 详情 | |
| (VI) | 53617 | [1,5]naphthyridin-4-yl trifluoromethanesulfonate | n/a | C9H5F3N2O3S | 详情 | 详情 |
| (VII) | 43935 | [1,5]naphthyridin-4-amine; [1,5]naphthyridin-4-ylamine | C8H7N3 | 详情 | 详情 | |
| (VIII) | 53618 | 2-methyl-1,3-benzoxazole-6-carbonyl azide | n/a | C9H6N4O2 | 详情 | 详情 |
| (IX) | 43936 | 2-methyl-1,3-benzoxazole-6-carboxylic acid | C9H7NO3 | 详情 | 详情 |