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【结 构 式】 
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【分子编号】27846 【品名】2-[benzyl(tert-butoxycarbonyl)amino]acetic acid 【CA登记号】 |
【 分 子 式 】C14H19NO4 【 分 子 量 】265.3092 【元素组成】C 63.38% H 7.22% N 5.28% O 24.12% |
合成路线1
该中间体在本合成路线中的序号：(II)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 |
合成路线2
该中间体在本合成路线中的序号：(III)The N-alkylation of N-(tert-butoxycarbonyl)glycine (I) with benzyl bromide (II) by means of NaH in THF gives N-benzyl-N-(tert-butoxycarbonyl)glycine (III), which is condensed with 4-aminoacetophenone (IV) by means of isobutyl chloroformate and TEA in dichloromethane yielding the corresponding glycinamide (V). The cyclization of (V) with thiourea (VI) by means of I2 in refluxing isopropanol affords, after work up, the N-benzyl-glycinamide (VII), which is finally acylated with pyridine-4-carbonyl chloride by means of TEA and DMAP in dichloromethane.
| 【1】 Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Thavonekham, B.; Grygon, C.A.; Crute, J.J. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Phenyl thiazole derivs. with anti-herpes virus properties. EP 0871619; JP 2000502702; US 6057451; WO 9724343 . |
| 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) | 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 |
| (II) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (III) | 27846 | 2-[benzyl(tert-butoxycarbonyl)amino]acetic acid | C14H19NO4 | 详情 | 详情 | |
| (IV) | 27847 | 1-(4-aminophenyl)-1-ethanone | 99-92-3 | C8H9NO | 详情 | 详情 |
| (V) | 27848 | tert-butyl 2-(4-acetylanilino)-2-oxoethyl(benzyl)carbamate | C22H26N2O4 | 详情 | 详情 | |
| (VI) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (VII) | 27849 | N-[4-(2-amino-1,3-thiazol-4-yl)phenyl]-2-(benzylamino)acetamide | C18H18N4OS | 详情 | 详情 | |
| (VIII) | 27850 | isonicotinoyl chloride | 39178-35-3 | C6H4ClNO | 详情 | 详情 |