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【结 构 式】 
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【药物名称】BMS-187308 【化学名称】2'-Amino-N-(3,4-dimethyl-5-isoxazolyl)-4'-isobutylbiphenyl-2-sulfonamide 【CA登记号】153624-15-8 【 分 子 式 】C21H25N3O3S 【 分 子 量 】399.5157 |
【开发单位】Bristol-Myers Squibb (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Pharmacological Tools, Endothelin ETA Receptor Antagonists, Endothelin ETB Receptor Antagonists |
合成路线1
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
Reaction of 1-bromo-4-isobutylbenzene (V) with magnesium generated the corresponding Grignard reagent (VI), which was condensed with trimethyl borate to afford, after acid hydrolysis, arylboronic acid (VII). This was nitrated with acetyl nitrate to produce nitro derivative (VIII). Subsequent reduction of the nitro group of (VIII) by hydrogenation over Pd/C gave 2-amino-4-isobutylphenyl boronic acid (IX). Suzuki coupling of boronic acid (IX) with bromosulfonamide (IV) produced the required biphenyl (X). The methoxyethoxymethyl group was finally deprotected by treatment with HCl to furnish the title compound.
| 【1】 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 |
|---|---|---|---|---|---|---|
| (IV) | 26893 | 2-bromo-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide | C15H19BrN2O5S | 详情 | 详情 | |
| (V) | 26894 | 1-bromo-4-isobutylbenzene | 2051-99-2 | C10H13Br | 详情 | 详情 |
| (VI) | 26895 | bromo(4-isobutylphenyl)magnesium | C10H13BrMg | 详情 | 详情 | |
| (VII) | 26896 | 4-isobutylphenylboronic acid | C10H15BO2 | 详情 | 详情 | |
| (VIII) | 26897 | 4-isobutyl-2-nitrophenylboronic acid | C10H14BNO4 | 详情 | 详情 | |
| (IX) | 26898 | 2-amino-4-isobutylphenylboronic acid | C10H16BNO2 | 详情 | 详情 | |
| (X) | 26899 | 2'-amino-N-(3,4-dimethyl-5-isoxazolyl)-4'-isobutyl-N-[(2-methoxyethoxy)methyl][1,1'-biphenyl]-2-sulfonamide | C25H33N3O5S | 详情 | 详情 |
合成路线3
In an alternative procedure, Wittig reaction of 3-nitrobenzaldehyde (XI) with isopropyltriphenylphosphonium iodide gave isobutenyl compound (XII). Then, the nitro group of (XII) was selectively reduced to aniline (XIII) by hydrogenation over Pt/C, and this was protected as the pivaloyl amide (XIV) with pivaloyl chloride. Further hydrogenation of (XIV) using Pd/C produced the isobutyl derivative (XV). Lithiation of (XV) with tert-butyllithium generated the intermediate organolithium reagent (XVI), which was subsequently converted to boronic acid (XVII). Further Suzuki coupling of (XVII) with bromosulfonamide (IV) produced biphenyl (XVIII). Reductive removal of the pivaloyl group of (XVIII) using DIBAL-H then gave the precursor (X), which was finally deprotected with HCl to afford the target compound.
| 【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. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40672 | isopropyl(triphenyl)phosphonium | C21H22P | 详情 | 详情 | ||
| (IV) | 26893 | 2-bromo-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide | C15H19BrN2O5S | 详情 | 详情 | |
| (X) | 26899 | 2'-amino-N-(3,4-dimethyl-5-isoxazolyl)-4'-isobutyl-N-[(2-methoxyethoxy)methyl][1,1'-biphenyl]-2-sulfonamide | C25H33N3O5S | 详情 | 详情 | |
| (XI) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (XII) | 26900 | 1-(2-methyl-1-propenyl)-3-nitrobenzene | C10H11NO2 | 详情 | 详情 | |
| (XIII) | 26901 | 3-(2-methyl-1-propenyl)aniline | C10H13N | 详情 | 详情 | |
| (XIV) | 26902 | 2,2-dimethyl-N-[3-(2-methyl-1-propenyl)phenyl]propanamide | C15H21NO | 详情 | 详情 | |
| (XV) | 26903 | N-(3-isobutylphenyl)-2,2-dimethylpropanamide | C15H23NO | 详情 | 详情 | |
| (XVI) | 26904 | [2-[(2,2-dimethylpropanoyl)amino]-4-isobutylphenyl]lithium | C15H22LiNO | 详情 | 详情 | |
| (XVII) | 26905 | 2-[(2,2-dimethylpropanoyl)amino]-4-isobutylphenylboronic acid | C15H24BNO3 | 详情 | 详情 | |
| (XVIII) | 26906 | N-[2'-([(3,4-dimethyl-5-isoxazolyl)[(2-methoxyethoxy)methyl]amino]sulfonyl)-4-isobutyl[1,1'-biphenyl]-2-yl]-2,2-dimethylpropanamide | C30H41N3O6S | 详情 | 详情 |