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【结 构 式】 
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【分子编号】41320 【品名】methyl 3-[[(4-chloro-3-methyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thiophenecarboxylate 【CA登记号】 |
【 分 子 式 】C12H13ClN2O6S2 【 分 子 量 】380.8298 【元素组成】C 37.85% H 3.44% Cl 9.31% N 7.36% O 25.21% S 16.84% |
合成路线1
该中间体在本合成路线中的序号：(IX)5-Amino-3-methylisoxazole (V) was chlorinated to (VI) by means of N-chlorosuccinimide. Subsequent coupling of (VI) with 2-carbomethoxy-3-thiophenesulfonyl chloride (VII) in the presence of NaH gave sulfonamide (VIII). The sulfonamide NH group of (VII) was then protected by treatment with bromomethyl methyl ether to afford the methoxymethyl derivative (IX). Hydrolysis of the ester group of (IX) with NaOH and treatment of the resulting the carboxylic acid with oxalyl chloride furnished acid chloride (X). This was coupled with aniline (IV) to yield amide (XI). The acetyl and methoxymethyl protecting groups of (XI) were finally removed by treatment with HCl.
| 【1】 Decker, E.R.; Blok, N.; Wu, C.; et al.; Endothelin antagonists: Substituted mesitylcarboxamides with high potency and selectivity for ETA receptors. J Med Chem 1999, 42, 22, 4485. |
| 【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 . |
| 【3】 Woodard, P.; Kogan, T.P.; Raju, B.G.; Wu, C.; Blok, N. (Texas Biotechnology Corp.); Sulfonamides and derivs. thereof that modulate the activity of endothelin. JP 2000507607; WO 9813366 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 41319 | 3-amino-2,4,6-trimethylphenyl acetate | C11H15NO2 | 详情 | 详情 | |
| (V) | 17834 | 3-methyl-5-isoxazolylamine; 3-methyl-5-isoxazolamine; 5-Amino-3-methylisoxazole | 14678-02-5 | C4H6N2O | 详情 | 详情 |
| (VI) | 17835 | 4-chloro-3-methyl-5-isoxazolamine; 4-chloro-3-methyl-5-isoxazolylamine | C4H5ClN2O | 详情 | 详情 | |
| (VII) | 17836 | Methyl 3-(chlorosulfonyl)-2-thiophenecarboxylate; Methyl-3-chlorosulfonylthiophene-2-carboxylate | C6H5ClO4S2 | 详情 | 详情 | |
| (VIII) | 17837 | methyl 3-[[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl]-2-thiophenecarboxylate | C10H9ClN2O5S2 | 详情 | 详情 | |
| (IX) | 41320 | methyl 3-[[(4-chloro-3-methyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thiophenecarboxylate | C12H13ClN2O6S2 | 详情 | 详情 | |
| (X) | 41321 | 3-[[(4-chloro-3-methyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thiophenecarbonyl chloride | C11H10Cl2N2O5S2 | 详情 | 详情 | |
| (XI) | 41322 | 3-[[(3-[[(4-chloro-3-methyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thienyl)carbonyl]amino]-2,4,6-trimethylphenyl acetate | C22H24ClN3O7S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)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 |