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【结 构 式】 
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【分子编号】26774 【品名】ethyl 2-amino-3-[4-(5-isoxazolyl)phenyl]propanoate 【CA登记号】 |
【 分 子 式 】C14H16N2O3 【 分 子 量 】260.29272 【元素组成】C 64.6% H 6.2% N 10.76% O 18.44% |
合成路线1
该中间体在本合成路线中的序号：(VII)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
该中间体在本合成路线中的序号：(VII)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.; Hayakawa, K.; Stereoselective synthesis of a novel and bifunctional endothelin antagonist, IRL 3630. Bioorg Med Chem Lett 1998, 8, 16, 2247. |
| 【2】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Okada, T. (Novartis Japan KK); Antagonists of endothelin receptors. JP 1999512702; WO 9711960 . |
| 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 |