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【结 构 式】 
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【药物名称】IRL-3461 【化学名称】N1-(Butylsulfonyl)-N2-[N-(3,5-dimethylbenzoyl)-4-(5-isoxazolyl)-N-methyl-DL-phenylalanyl]-L-valinamide 【CA登记号】 【 分 子 式 】C31H40N4O6S 【 分 子 量 】596.75165 |
【开发单位】Novartis (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Endothelin ETA Receptor Antagonists, Endothelin ETB Receptor Antagonists |
合成路线1
4'-Methylacetophenone (I) was condensed with boiling dimethylformamide dimethylacetal, and the resulting enaminoketone (II) was cyclized to the isoxazole (III) with hydroxylamine O-sulfonic acid in MeOH. Benzylic bromination of (III) with N-bromosuccinimide in the presence of benzoyl peroxide gave bromomethyl compound (IV). Subsequent alkylation of diphenylmethylene glycine ethyl ester (V) with (IV) under phase-transfer conditions, followed by acid deprotection furnished isoxazolylphenylalanine ethyl ester (VII). This compound was condensed with 3,5-dimethyl benzoic acid (VIII) using EDC and HOBt to give amide (IX). Further N-methylation of (IX) with MeI and NaH yielded (X), which was hydrolyzed with LiOH to the carboxylic acid (XI).
| 【1】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Frueh, T.; Pitterna, T.; Iwasaki, G.; Oda, K.; Yamamura, T.; Hayakawa, K.; Discovery of IRL 3461: A novel and potent endothelin antagonist with balanced ETA/ETB affinity. Bioorg Med Chem Lett 1998, 8, 16, 2241. |
| 【2】 Fruh, T.; Pitterna, T.; Murata, T.; Svensson, L.D.; Yuumoto, Y.; Sakaki, J. (Novartis Japan KK); Antagonists of endothelin receptors. EP 0753004; JP 1997510720; US 5703106; WO 9526360 . |
| 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) | 17145 | 1-(4-methylphenyl)-1-ethanone; p-methylacetophenone; 4-methylacetophenone; 4-methylphenylethanone | 122-00-9 | C9H10O | 详情 | 详情 |
| (II) | 26769 | (E)-3-(dimethylamino)-1-(4-methylphenyl)-2-propen-1-one | C12H15NO | 详情 | 详情 | |
| (III) | 26770 | 5-(4-methylphenyl)isoxazole | C10H9NO | 详情 | 详情 | |
| (IV) | 26771 | 5-[4-(bromomethyl)phenyl]isoxazole | C10H8BrNO | 详情 | 详情 | |
| (V) | 26772 | ethyl 2-((diphenylmethylene)amino)acetate;N-(Diphenylmethylene)glycine ethyl ester;Ethyl N-(diphenylmethylene)glycinate;ethyl 2-[(dibenzylene)amino]acetate | 69555-14-2 | C17H17NO2 | 详情 | 详情 |
| (VI) | 26773 | ethyl 2-[(dibenzylene)amino]-3-[4-(5-isoxazolyl)phenyl]propanoate | C27H24N2O3 | 详情 | 详情 | |
| (VII) | 26774 | ethyl 2-amino-3-[4-(5-isoxazolyl)phenyl]propanoate | C14H16N2O3 | 详情 | 详情 | |
| (VIII) | 26775 | 3,5-dimethylbenzoic acid | 499-06-9 | C9H10O2 | 详情 | 详情 |
| (IX) | 26776 | ethyl 2-[(3,5-dimethylbenzoyl)amino]-3-[4-(5-isoxazolyl)phenyl]propanoate | C23H24N2O4 | 详情 | 详情 | |
| (X) | 26777 | ethyl 2-[(3,5-dimethylbenzoyl)(methyl)amino]-3-[4-(5-isoxazolyl)phenyl]propanoate | C24H26N2O4 | 详情 | 详情 | |
| (XI) | 26778 | N-(3,5-dimethylbenzoyl)-4-(5-isoxazolyl)-N-methylphenylalanine | C22H22N2O4 | 详情 | 详情 |
合成路线2
1-Butanesulfonyl chloride (XII) was reacted with ammonia in acetonitrile, and the resulting sulfonamide (XIII) was then converted to the N-trimethylsilyl derivative (XIV). This was coupled with acid fluoride (XVII), (obtained from Boc-valine (XV) and cyanuric fluoride (XVI)), to provide Boc-valinesulfonamide (XVIII). The Boc group of (XVIII) was then removed by acid treatment to give (XIX). Finally, coupling of this chiral intermediate with the previously obtained racemic acid (XI) furnished the title compound as a 7:3 mixture of diastereoisomers.
| 【1】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Frueh, T.; Pitterna, T.; Iwasaki, G.; Oda, K.; Yamamura, T.; Hayakawa, K.; Discovery of IRL 3461: A novel and potent endothelin antagonist with balanced ETA/ETB affinity. Bioorg Med Chem Lett 1998, 8, 16, 2241. |
| 【2】 Fruh, T.; Pitterna, T.; Murata, T.; Svensson, L.D.; Yuumoto, Y.; Sakaki, J. (Novartis Japan KK); Antagonists of endothelin receptors. EP 0753004; JP 1997510720; US 5703106; WO 9526360 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 26778 | N-(3,5-dimethylbenzoyl)-4-(5-isoxazolyl)-N-methylphenylalanine | C22H22N2O4 | 详情 | 详情 | |
| (XII) | 26779 | 1-butanesulfonyl chloride | 2386-60-9 | C4H9ClO2S | 详情 | 详情 |
| (XIII) | 26780 | 1-butanesulfonamide | C4H11NO2S | 详情 | 详情 | |
| (XIV) | 26781 | N-(trimethylsilyl)-1-butanesulfonamide | C7H19NO2SSi | 详情 | 详情 | |
| (XV) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (XVI) | 26782 | Cyanuric fluoride; 2,4,6-trifluoro-1,3,5-triazine | 675-14-9 | C3F3N3 | 详情 | 详情 |
| (XVII) | 26783 | tert-butyl (1S)-1-(fluorocarbonyl)-2-methylpropylcarbamate | C10H18FNO3 | 详情 | 详情 | |
| (XVIII) | 26784 | tert-butyl (1S)-1-[[(butylsulfonyl)amino]carbonyl]-2-methylpropylcarbamate | C14H28N2O5S | 详情 | 详情 | |
| (XIX) | 26785 | N-[(2S)-2-amino-3-methylbutanoyl]-1-butanesulfonamide | C9H20N2O3S | 详情 | 详情 |