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【结 构 式】 
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【分子编号】17838 【品名】3-[[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl]-2-thiophenecarboxylic acid 【CA登记号】 |
【 分 子 式 】C9H7ClN2O5S2 【 分 子 量 】322.74976 【元素组成】C 33.49% H 2.19% Cl 10.98% N 8.68% O 24.79% S 19.87% |
合成路线1
该中间体在本合成路线中的序号：(IV)The condensation of 3-(chlorosulfonyl)thiophene-2-carboxylic acid methyl ester (I) with 4-chloro-3-methylisoxazol-5-amine by means of NaH in THF gives the corresponding sulfonamide (III), which is hydrolyzed with NaOH in methanol to yield the expected carboxylic acid (IV). The reaction of (IV) with N,O-dimethylhydroxylamine and carbonyldiimidazole (CDI) in THF affords the corresponding amide (V), which is finally condensed with the Grignard reagent 6-methyl-1,3-benzodioxol-5-ylmethyl magnesium chloride (VI) in THF. The intermediate Grignard reagent (VI) is obtained by chloromethylation of 5-methyl-1,3-benzodioxole (VII) with formaldehyde and HCl, giving 5-(chloromethyl)-6-methyl-1,3-benzodioxole (VIII), followed by reaction of this compound with Mg in THF.
| 【1】 Okun, I.; Keller, K.M.; Brock, T.; Kogan, T.P.; Stavros, F.; Chan, M.F.; Mong, S.; Raju, B.; Dixon, R.A.F.; Wu, C.; Discovery of TBC11251, a potent, long acting, orally active endothelin receptor-A selective antagonist. J Med Chem 1997, 40, 11, 1690-97. |
| 【2】 Leeson, P.A.; Castañer, J.; Graul, A.; Sitaxsentan Sodium. Drugs Fut 2000, 25, 2, 159. |
| 【3】 Chan, M.F.; Raju, B.G.; Kois, A.; Verner, E.J.; Wu, C.; Castillo, R.S.; Yalamoori, V.; Balaji, V.N. (Texas Biotechnology Corp.); Thienyl-, furyl-, pyrrolyl- and biphenylsulfonamides and derivs. thereof that modulate the activity of endothelin. EP 0819125; JP 1999507015; WO 9631492 . |
| 【4】 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) | 17836 | Methyl 3-(chlorosulfonyl)-2-thiophenecarboxylate; Methyl-3-chlorosulfonylthiophene-2-carboxylate | C6H5ClO4S2 | 详情 | 详情 | |
| (II) | 17835 | 4-chloro-3-methyl-5-isoxazolamine; 4-chloro-3-methyl-5-isoxazolylamine | C4H5ClN2O | 详情 | 详情 | |
| (III) | 17837 | methyl 3-[[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl]-2-thiophenecarboxylate | C10H9ClN2O5S2 | 详情 | 详情 | |
| (IV) | 17838 | 3-[[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl]-2-thiophenecarboxylic acid | C9H7ClN2O5S2 | 详情 | 详情 | |
| (V) | 32875 | 3-[[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl]-N-methoxy-N-methyl-2-thiophenecarboxamide | C11H12ClN3O5S2 | 详情 | 详情 | |
| (VI) | 32876 | chloro[(6-methyl-1,3-benzodioxol-5-yl)methyl]magnesium | C9H9ClMgO2 | 详情 | 详情 | |
| (VII) | 32878 | 5-methyl-1,3-benzodioxole | 7145-99-5 | C8H8O2 | 详情 | 详情 |
| (VIII) | 32877 | 5-(chloromethyl)-6-methyl-1,3-benzodioxole | C9H9ClO2 | 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 (NCS) in chloroform to afford 5-amino-4-chloro-3-methylisoxazole (II) (1). Condensation of this isoxazole (II) with 3-(chlorosulfonyl)thiophene-2-carboxylic acid methyl ester (III) was effected in the presence of sodium hydride in THF to give sulfonamide (IV), which was then hydrolyzed to the acid (V) on treatment with methanolic sodium hydroxide. This acid (V) was activated by reaction with carbonyldiimidazole (CDI) in DMF, and the resulting solution of acylimidazole was then cannulated into a cooled mixture of 2-amino-4,5-(methylenedioxy)benzonitrile (VI) and sodium hydride in DMF to yield the title amide.
| 【1】 Wu, C.; et al.; Structure-activity relationships of N2-aryl-3-(isoxazolylsulfamoyl)-2-thiophenecarboxamides as selective endothelin receptor-A antagonists. J Med Chem 1997, 40, 11, 1682. |
| 【2】 Chan, M.F.; Raju, B.G.; Kois, A.; Verner, E.J.; Wu, C.; Castillo, R.S.; Yalamoori, V.; Balaji, V.N. (Texas Biotechnology Corp.); Thienyl-, furyl-, pyrrolyl- and biphenylsulfonamides and derivs. thereof that modulate the activity of endothelin. EP 0819125; JP 1999507015; WO 9631492 . |
| 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) | 17838 | 3-[[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl]-2-thiophenecarboxylic acid | C9H7ClN2O5S2 | 详情 | 详情 | |
| (VI) | 17839 | 6-amino-1,3-benzodioxole-5-carbonitrile | C8H6N2O2 | 详情 | 详情 |
合成路线3
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 (NCS) in chloroform to afford 5-amino-4-chloro-3-methylisoxazole (II). Condensation of this isoxazole (II) with 3-(chlorosulfonyl)thiophene-2-carboxylic acid methyl ester (III) was effected in the presence of sodium hydride in THF to give sulfonamide (IV), which was then hydrolyzed to the acid (V) on treatment with methanolic sodium hydroxide. This acid (V) was activated by reaction with carbonyldiimidazole (CDI) in DMF, and the resulting solution of acylimidazole was then cannulated into a cooled mixture of 2-amino-4,5-(methylenedioxy)benzonitrile (VI) and sodium hydride in DMF to yield the title amide.
| 【1】 Chan, M.F.; Raju, B.G.; Kois, A.; Verner, E.J.; Wu, C.; Castillo, R.S.; Yalamoori, V.; Balaji, V.N.; Ramnarayan, K. (ImmunoPharmaceutics, Inc.); Sulfonamides and derivs. thereof that modulate the activity of endothelin. EP 0699191; EP 0870764; GB 2285625; JP 1996510744; US 5464853; WO 9427979 . |
| 【2】 Chan, M.F.; Raju, B.G.; Kois, A.; Verner, E.J.; Wu, C.; Castillo, R.S.; Yalamoori, V.; Balaji, V.N. (Texas Biotechnology Corp.); Thienyl-, furyl-, pyrrolyl- and biphenylsulfonamides and derivs. thereof that modulate the activity of endothelin. EP 0819125; JP 1999507015; WO 9631492 . |
| 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) | 17838 | 3-[[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl]-2-thiophenecarboxylic acid | C9H7ClN2O5S2 | 详情 | 详情 | |
| (VI) | 17839 | 6-amino-1,3-benzodioxole-5-carbonitrile | C8H6N2O2 | 详情 | 详情 |