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【结 构 式】

【分子编号】26770

【品名】5-(4-methylphenyl)isoxazole

【CA登记号】

【 分 子 式 】C10H9NO

【 分 子 量 】159.1876

【元素组成】C 75.45% H 5.7% N 8.8% O 10.05%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(III)

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:(III)

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
Extended Information