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【结 构 式】 
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【药物名称】Edonentan hydrate, BMS-207940-02, BMS-207940(anhydrous) 【化学名称】N-[2'-(4,5-Dimethylisoxazol-3-ylsulfamoyl)-4-(2-oxazolyl)biphenyl-2-ylmethyl]-N,3,3-trimethylbutyramide hydrate 【CA登记号】264609-13-4, 210891-04-6 (anhydrous), 210891-08-0 (K salt), 210891-06-8 (Li salt), 210891-07-9 (Na salt) 【 分 子 式 】C28H34N4O6S 【 分 子 量 】554.67038 |
【开发单位】Bristol-Myers Squibb (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, Endothelin ETA Receptor Antagonists |
合成路线1
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 |