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【结 构 式】 
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【分子编号】17836 【品名】Methyl 3-(chlorosulfonyl)-2-thiophenecarboxylate; Methyl-3-chlorosulfonylthiophene-2-carboxylate 【CA登记号】 |
【 分 子 式 】C6H5ClO4S2 【 分 子 量 】240.688 【元素组成】C 29.94% H 2.09% Cl 14.73% O 26.59% S 26.65% |
合成路线1
该中间体在本合成路线中的序号：(V)The reaction of methyl 3-hydroxythiophene-2-carboxylate (I) with PCl5 in refluxing CCl4 gives 3-chlorothiophene-2-carboxylic acid (II), which by treatment with NaHSO3 and Cu in basic water at 143 C in a pressure vessel is converted into 3-sulfothiophene-2-carboxylic acid (III). The esterification of (III) with refluxing methanol affords methyl 3-sulfothiophene-2-carboxylate (IV), which by reaction with refluxing SOCl2 yields methyl-3-chlorosulfonylthiophene-2-carboxylate (V). The condensation of (V) with sarcosine ethyl ester (VI) in hot CHCl3 gives methyl-3-(N-ethoxycarbonyl-methyl-N-methylsulfamoyl)thiophene-2-carboxylate (VII), which is cyclized by treatment with sodium methoxide in refluxing methanol affording 3-ethoxycarbonyl-4-hydroxy-2-methyl-2H-thieno-[2,3-e]-1,2-thiazine-1,1-dioxide (VIII). Finally, this compound is condensed with 2-aminopyridine (IX) in refluxing toluene.
| 【1】 Horomatka, O.; Binder, D.; Pfister, R.; Zeller, P. (F. Hoffmann-La Roche AG); Thienothaiazine derivatives. DE 2537070; FR 2303803; JP 51048694; NL 7510057 . |
| 【2】 Serradell, M.N.; Blancafort, P.; Castaner, J.; Tenoxicam. Drugs Fut 1982, 7, 7, 493. |
| 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) | 32134 | Methyl 3-hydroxy-2-thiophenecarboxylate | C6H6O3S | 详情 | 详情 | |
| (II) | 32135 | 3-Chloro-2-thiophenecarboxylic acid | 59337-89-2 | C5H3ClO2S | 详情 | 详情 |
| (III) | 32136 | 3-Sulfothiophene-2-carboxylic acid; 3-Sulfo-2-thiophenecarboxylic acid | C5H4O5S2 | 详情 | 详情 | |
| (IV) | 32137 | Methyl 3-sulfothiophene-2-carboxylate; 2-(Methoxycarbonyl)-3-thiophenesulfonic acid | C6H6O5S2 | 详情 | 详情 | |
| (V) | 17836 | Methyl 3-(chlorosulfonyl)-2-thiophenecarboxylate; Methyl-3-chlorosulfonylthiophene-2-carboxylate | C6H5ClO4S2 | 详情 | 详情 | |
| (VI) | 32138 | Sarcosine ethyl ester; Ethyl 2-(methylamino)acetate | 52605-49-9 | C5H11NO2 | 详情 | 详情 |
| (VII) | 32139 | Methyl-3-(N-ethoxycarbonyl-methyl-N-methylsulfamoyl)thiophene-2-carboxylate; Methyl 3-[[(2-ethoxy-2-oxoethyl)(methyl)amino]sulfonyl]-2-thiophenecarboxylate | C11H15NO6S2 | 详情 | 详情 | |
| (VIII) | 32140 | Ethyl 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-thieno[2,3-e][1,2]thiazine-3-carboxylate; 3-Ethoxycarbonyl-4-hydroxy-2-methyl-2H-thieno-[2,3-e]-1,2-thiazine-1,1-dioxide | C10H11NO5S2 | 详情 | 详情 | |
| (IX) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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3
该中间体在本合成路线中的序号：(III)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4
该中间体在本合成路线中的序号：(III)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 |
合成路线5
该中间体在本合成路线中的序号：(VII)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6
该中间体在本合成路线中的序号：(III)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 |
合成路线7
该中间体在本合成路线中的序号：(I)Coupling between 2-(methoxycarbonyl)-3-thiophenesulfonyl chloride (I) and 5-amino-3,4-dimethylisoxazole (II) afforded the corresponding sulfonamide (III). The sulfonamide NH group of (III) was then protected by reaction with bromomethyl methyl ether to produce the methoxymethyl derivative (IV). Basic hydrolysis of the methyl ester function of (IV), followed by treatment of the resultant carboxylic acid (V) with oxalyl chloride, furnished the acid chloride (VI). This was then coupled with 2'-amino-3',5'-dimethylacetophenone (VII) to yield amide (VIII). The methoxymethyl protecting group of (VIII) was finally removed by acidic treatment to provide the title compound.
| 【1】 Blok, N.; Holland, G.W.; Wu, C. (Texas Biotechnology Corp.); Sulfonamides and derivs. thereof that modulate the activity of endothelin. WO 0149685 . |
| 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) | 26891 | 3,4-dimethyl-5-isoxazolamine | 19947-75-2 | C5H8N2O | 详情 | 详情 |
| (III) | 48185 | methyl 3-[[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl]-2-thiophenecarboxylate | C11H12N2O5S2 | 详情 | 详情 | |
| (IV) | 48186 | methyl 3-[[(3,4-dimethyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thiophenecarboxylate | C13H16N2O6S2 | 详情 | 详情 | |
| (V) | 48187 | 3-[[(3,4-dimethyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thiophenecarboxylic acid | C12H14N2O6S2 | 详情 | 详情 | |
| (VI) | 48188 | 3-[[(3,4-dimethyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thiophenecarbonyl chloride | C12H13ClN2O5S2 | 详情 | 详情 | |
| (VII) | 47990 | 1-(2-amino-3,5-dimethylphenyl)-1-ethanone | C10H13NO | 详情 | 详情 | |
| (VIII) | 48189 | N-(2-acetyl-4,6-dimethylphenyl)-3-[[(3,4-dimethyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thiophenecarboxamide | C22H25N3O6S2 | 详情 | 详情 |