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【结 构 式】 
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【药物名称】TBC-2576 【化学名称】3-[N-(4-Chloro-3-methylisoxazol-5-yl)sulfamoyl]-N-(3-hydroxy-2,4,6-trimethylphenyl)thiophene-2-carboxamide 【CA登记号】205515-63-5 【 分 子 式 】C18H18ClN3O5S2 【 分 子 量 】455.94226 |
【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
Protection of 2,4,6-trimethylphenol (I) as the acetate ester (II), followed by nitration with HNO3/H2SO4 provided nitrophenol acetate (III). This was reduced to the corresponding aniline (IV) employing either Zn/NH4Cl or Fe/HOAc.
| 【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 . |
合成路线2
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 |