【结 构 式】 |
【分子编号】27896 【品名】ethyl 4-[benzyl(tert-butoxycarbonyl)amino]-3-oxobutanoate 【CA登记号】 |
【 分 子 式 】C18H25NO5 【 分 子 量 】335.40024 【元素组成】C 64.46% H 7.51% N 4.18% O 23.85% |
合成路线1
该中间体在本合成路线中的序号:(IV)An efficient synthesis of 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XI), a key intermediate in the synthesis of DU-6859a, via an asymmetric microbial reduction has been described: The reaction of N-benzylglycine (I) with tert-butoxycarbonyl anhydride gives N-benzyl-N-(tert-butoxycarbonyl)glycine (II), which is condensed with the potassium salt of ethyl hydrogen malonate (III) by means of carbonyldiimidazole (CDI) in THF yielding 4-[N-benzyl-N-(tert-butoxycarbonyl)amino]-3-oxobutyric acid ethyl ester (IV). The cyclopropanation of (IV) with 1,2-dibromoethane (V) by means of K2CO3 in refluxing acetone affords the cyclopropane derivative (VI), which is cyclized by means of trifluoroacetic acid in dichloromethane to give 5-benzyl-5-azaspiro[2.4]heptane-4,7-dione (VII). The enantioselective microbial reduction of (VII) by means of Phaeocreopsis sp. JCM 1880 in a complex medium containing glucose and polypeptone yields 5-benzyl-7(R)-hydroxy-5-azaspiro[2.4]heptan-4-one (VIII), which by reaction with triphenylphosphine, diethyl azodicarboxylate and diphenylphosphoryl azide (DPPA) followed by reduction with LiAlH4, is converted into 7(S)-amino-5-benzyl-5-azaspiro[2.4]heptane (IX). The protection of (IX) with tert-butoxycarbonyl anhydride as usual gives the protected amine (X), which is finally debenzylated by hydrogenation with H2 over Pd/C in ethanol affording the desired 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XI).
【1】 Yukimoto, Y.; Imura, A.; Satoh, K.; Kanai, K.; Miyadera, A.; An efficient synthesis of a key intermediate of DU-6859a via asymmetric microbial reduction. Chem Pharm Bull 1998, 46, 4, 587. |
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) | 27895 | N-(benzylamino)acetic acid; N-Benzylglycine; 2-(benzylamino)acetic acid | 17136-36-6 | C9H11NO2 | 详情 | 详情 |
(II) | 27846 | 2-[benzyl(tert-butoxycarbonyl)amino]acetic acid | C14H19NO4 | 详情 | 详情 | |
(III) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
(IV) | 27896 | ethyl 4-[benzyl(tert-butoxycarbonyl)amino]-3-oxobutanoate | C18H25NO5 | 详情 | 详情 | |
(V) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
(VI) | 27897 | ethyl 1-[2-[benzyl(tert-butoxycarbonyl)amino]acetyl]cyclopropanecarboxylate | C20H27NO5 | 详情 | 详情 | |
(VII) | 27898 | 5-benzyl-5-azaspiro[2.4]heptane-4,7-dione | C13H13NO2 | 详情 | 详情 | |
(VIII) | 27899 | (7R)-5-benzyl-7-hydroxy-5-azaspiro[2.4]heptan-4-one | C13H15NO2 | 详情 | 详情 | |
(IX) | 27900 | (7S)-5-benzyl-5-azaspiro[2.4]hept-7-ylamine | C13H18N2 | 详情 | 详情 | |
(X) | 27901 | tert-butyl (7S)-5-benzyl-5-azaspiro[2.4]hept-7-ylcarbamate | C18H26N2O2 | 详情 | 详情 | |
(XI) | 15193 | tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate | C11H20N2O2 | 详情 | 详情 |