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【结 构 式】 
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【药物名称】TBC-3214 【化学名称】N-(2-Acetyl-4,6-dimethylphenyl)-3-[N-(4-chloro-3-methylisoxazol- 5-yl)sulfamoyl]thiophene-2-carboxamide 【CA登记号】215501-47-6 【 分 子 式 】C19H18ClN3O5S2 【 分 子 量 】467.95341 |
【开发单位】Encysive Pharmaceuticals (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Pulmonary Hypertension, Treatment of, Endothelin ETA Receptor Antagonists |
合成路线1
5-Amino-3-methylisoxazole (I) was chlorinated with N-chlorosuccinimide to afford (II), which was condensed with 2-carbomethoxy-3-thiophenesulfonyl chloride (III) in the presence of NaH in THF to furnish sulfonamide (IV). After protection of the sulfonamide NH group of (IV) with methoxymethyl bromide, basic hydrolysis of the methyl ester function provided carboxylic acid (VI). This was then converted to acid chloride (VII) upon treatment with oxalyl chloride and pyridine. Aminoacetophenone derivative (IX) was prepared by BCl3-catalyzed acylation of 2,4-dimethylaniline (VIII) with acetonitrile. Coupling of aniline (IX) with acid chloride (VII) to give (X) was carried out either using an excess of aniline or, alternatively, in the presence of 4-(dimethylamino)benzonitrile as the base. Finally, removal of the methoxymethyl protecting group of (X) under acidic conditions furnished the title compound.
| 【1】 Decker, E.R.; Blok, N.; Wu, C.; et al.; Acyl substitution at the ortho position of anilides enhances oral bioavailability of thiophene sulfonamides: TBC3214, and ETA selective endothelin antagonist. J Med Chem 2001, 44, 8, 1211. |
| 【2】 Blok, N.; Keller, K.; Wu, C.; Kogan, T.; Woodard, P. (Texas Biotechnology Corp.); Sulfonamides for treatment of endothelin-mediated disorders. EP 0980369; US 5783705; WO 9849162 . |
| 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) | 17834 | 3-methyl-5-isoxazolylamine; 3-methyl-5-isoxazolamine; 5-Amino-3-methylisoxazole | 14678-02-5 | C4H6N2O | 详情 | 详情 |
| (II) | 17835 | 4-chloro-3-methyl-5-isoxazolamine; 4-chloro-3-methyl-5-isoxazolylamine | C4H5ClN2O | 详情 | 详情 | |
| (III) | 17836 | Methyl 3-(chlorosulfonyl)-2-thiophenecarboxylate; Methyl-3-chlorosulfonylthiophene-2-carboxylate | C6H5ClO4S2 | 详情 | 详情 | |
| (IV) | 17837 | methyl 3-[[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl]-2-thiophenecarboxylate | C10H9ClN2O5S2 | 详情 | 详情 | |
| (V) | 41320 | methyl 3-[[(4-chloro-3-methyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thiophenecarboxylate | C12H13ClN2O6S2 | 详情 | 详情 | |
| (VI) | 47989 | 3-[[(4-chloro-3-methyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thiophenecarboxylic acid | C11H11ClN2O6S2 | 详情 | 详情 | |
| (VII) | 41321 | 3-[[(4-chloro-3-methyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thiophenecarbonyl chloride | C11H10Cl2N2O5S2 | 详情 | 详情 | |
| (VIII) | 32911 | 2,4-dimethylaniline; 2,4-dimethylphenylamine | 95-68-1 | C8H11N | 详情 | 详情 |
| (IX) | 47990 | 1-(2-amino-3,5-dimethylphenyl)-1-ethanone | C10H13NO | 详情 | 详情 | |
| (X) | 47991 | N-(2-acetyl-4,6-dimethylphenyl)-3-[[(4-chloro-3-methyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thiophenecarboxamide | C21H22ClN3O6S2 | 详情 | 详情 |