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【结 构 式】

【分子编号】26890

【品名】2-bromobenzenesulfonyl chloride

【CA登记号】2905-25-1

【 分 子 式 】C6H4BrClO2S

【 分 子 量 】255.51926

【元素组成】C 28.2% H 1.58% Br 31.27% Cl 13.87% O 12.52% S 12.55%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(I)

The intermediate protected sulfonamide (IV) was prepared by condensation of 2-bromobenzenesulfonyl chloride (I) with 5-amino-3,4-dimethylisoxazole (II), followed by protection of the resulting sulfonamide (III) with (2-methoxyethoxy)methyl chloride and NaH.

1 Biphenylsulfonamide endothelin antagonists: Structure-activity relationships of a series of mono- and disubstituted analogues and pharmacology of the orally active endothelin antagonist 2'-amino-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-methylpropyl)[1,1'-biphe. J Med Chem 1998, 41, 26, 5198.
2 Murugesan, N.; Hunt, J.T. (Bristol-Myers Squibb Co.); Phenyl sulfonamide and their use as endothelin antagonists. EP 0569193; JP 1994049046; US 5514696 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
40670 2-(chloromethoxy)ethyl methyl ether; 1-(chloromethoxy)-2-methoxyethane; (2-methoxyethoxy)methyl chloride 3970-21-6 C4H9ClO2 详情 详情
(I) 26890 2-bromobenzenesulfonyl chloride 2905-25-1 C6H4BrClO2S 详情 详情
(II) 26891 3,4-dimethyl-5-isoxazolamine 19947-75-2 C5H8N2O 详情 详情
(III) 26892 2-bromo-N-(3,4-dimethyl-5-isoxazolyl)benzenesulfonamide C11H11BrN2O3S 详情 详情
(IV) 26893 2-bromo-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide C15H19BrN2O5S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(III)

The hydrolysis of N-(4,5-dimethyl-3-isoxazolyl)carbamic acid tert-butyl ester (I) with HCl in dioxane gives the corresponding amine (II), which is condensed with 2-bromophenylsulfonyl chloride (III) by means of DMAP in pyridine to yield the sulfonamide (IV). The alkylation of (I) with 2-methoxyethoxymethyl chloride (V) and NaH in DMF affords the N,N-disubstituted sulfonamide (VI), which is treated with trimethyl borate (VII) and BuLi in THF to provide the boronate (VIII). The condensation of (VIII) with 2-bromo-5-(2-oxazolyl)benzaldehyde (IX) by means of palladium tetrakis(triphenylphosphine) in hot toluene/ethanol gives the biphenyl derivative (X), which is deprotected by means of HCl in refluxing ethanol/water to yield the sulfonamide (XI). The reductive amination of (XI) with methylamine and NaBH(OAc)3 in dichloromethane/HOAc affords the secondary amine (XII), which is finally acylated with 3,3-dimethylbutyryl chloride and TEA in dichloromethane to furnish the target diamide.

1 Barrish, J.C.; Murugesan, N.; Gu, Z.; Morrison, R.A. (Bristol-Myers Squibb Co.); Endothelin antagonists: N-[[2'-[[4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl) [1,1'-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-. EP 0996618; JP 2002513397; US 6043265; WO 9833780 .
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) 55414 tert-butyl 4,5-dimethyl-3-isoxazolylcarbamate C10H16N2O3 详情 详情
(II) 55415 4,5-dimethyl-3-isoxazolylamine; 4,5-dimethyl-3-isoxazolamine C5H8N2O 详情 详情
(III) 26890 2-bromobenzenesulfonyl chloride 2905-25-1 C6H4BrClO2S 详情 详情
(IV) 55416 2-bromo-N-(4,5-dimethyl-3-isoxazolyl)benzenesulfonamide C11H11BrN2O3S 详情 详情
(V) 40670 2-(chloromethoxy)ethyl methyl ether; 1-(chloromethoxy)-2-methoxyethane; (2-methoxyethoxy)methyl chloride 3970-21-6 C4H9ClO2 详情 详情
(VI) 55417 2-bromo-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide C15H19BrN2O5S 详情 详情
(VII) 55418 trimethyl borate C3H9BO3 详情 详情
(VIII) 55419 dimethyl 2-({(4,5-dimethyl-3-isoxazolyl)[(2-methoxyethoxy)methyl]amino}sulfonyl)phenylboronate C17H25BN2O7S 详情 详情
(IX) 55420 2-bromo-5-(1,3-oxazol-2-yl)benzaldehyde C10H6BrNO2 详情 详情
(X) 55421 N-(4,5-dimethyl-3-isoxazolyl)-2'-formyl-N-[(2-methoxyethoxy)methyl]-4'-(1,3-oxazol-2-yl)[1,1'-biphenyl]-2-sulfonamide C25H25N3O7S 详情 详情
(XI) 55422 N-(4,5-dimethyl-3-isoxazolyl)-2'-formyl-4'-(1,3-oxazol-2-yl)[1,1'-biphenyl]-2-sulfonamide C21H17N3O5S 详情 详情
(XII) 55423 N-(4,5-dimethyl-3-isoxazolyl)-N-methyl-2'-[(methylamino)methyl]-4'-(1,3-oxazol-2-yl)[1,1'-biphenyl]-2-sulfonamide C23H24N4O4S 详情 详情
(XIII) 21738 3,3-dimethylbutanoyl chloride 7065-46-5 C6H11ClO 详情 详情

合成路线3

该中间体在本合成路线中的序号:(I)

Coupling of 2-bromobenzenesulfonyl chloride (I) with 5-amino-3,4-dimethylisoxazole (II) affords sulfonamide (III), which is further protected as the N-methoxyethoxymethyl derivative (IV) employing MEM-chloride in DMF. Lithiation of bromosulfonamide (IV), followed by treatment with trimethyl borate and acidic work up leads to the boronic acid intermediate (V). This is then subjected to Suzuki coupling with 4-bromo-3-methylbenzaldehyde (VI) to yield the biphenyl adduct (VII). After reduction of aldehyde (VII) to the benzylic alcohol (VIII) with NaBH4, reaction with methanesulfonyl chloride and diisopropylethylamine gives rise to the mesylate (IX) (1-3).

1 Tellew, J.E.; Baska, R.A.F.; Beyer, S.M.; Carlson, K.E.; Cornelius, L.A.; Fadnis, L.; Gu, Z..; Kunst, B.L.; Kowala, M.C.; Monshizadegan, H.; Murugesan, N.; Ryan, C.S.; Valentine, M.T.; Yang, Y.; Macor, J.E.; Discovery of 4'-[(Imidazol-1-yl)methyl]biphenyl-2-sulfonamides as dual endothelin/Angiotensin II receptor antagonists. Bioorg Med Chem Lett 2003, 13, 6, 1093.
2 Macor, J.E.; Murugesan, N.; Gu, Z.; Tellew, J.E. (Bristol-Myers Squibb Co.); Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists. EP 1094816; JP 2002519380; US 2002143024; WO 0001389 .
3 Macor, J.E.; Murugesan, N.; Gu, Z.; Tellew, J.E. (Bristol-Myers Squibb Co.); Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists. EP 1237888; WO 0144239 .
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) 26890 2-bromobenzenesulfonyl chloride 2905-25-1 C6H4BrClO2S 详情 详情
(II) 26891 3,4-dimethyl-5-isoxazolamine 19947-75-2 C5H8N2O 详情 详情
(III) 26892 2-bromo-N-(3,4-dimethyl-5-isoxazolyl)benzenesulfonamide C11H11BrN2O3S 详情 详情
(IV) 26893 2-bromo-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide C15H19BrN2O5S 详情 详情
(V) 60918 2-({(3,4-dimethyl-5-isoxazolyl)[(2-methoxyethoxy)methyl]amino}sulfonyl)phenylboronic acid C15H21BN2O7S 详情 详情
(VI) 64344 4-bromo-3-methylbenzaldehyde C8H7BrO 详情 详情
(VII) 64345 N-(3,4-dimethyl-5-isoxazolyl)-4'-formyl-N-[(2-methoxyethoxy)methyl]-2'-methyl[1,1'-biphenyl]-2-sulfonamide C23H26N2O6S 详情 详情
(VIII) 64346 N-(3,4-dimethyl-5-isoxazolyl)-4'-(hydroxymethyl)-N-[(2-methoxyethoxy)methyl]-2'-methyl[1,1'-biphenyl]-2-sulfonamide C23H28N2O6S 详情 详情
(IX) 64347 [2'-({(3,4-dimethyl-5-isoxazolyl)[(2-methoxyethoxy)methyl]amino}sulfonyl)-2-methyl[1,1'-biphenyl]-4-yl]methyl methanesulfonate C24H30N2O8S2 详情 详情
Extended Information