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【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%

与该中间体有关的原料药合成路线共 1 条

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
Extended Information