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【结 构 式】 
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【分子编号】27895 【品名】N-(benzylamino)acetic acid; N-Benzylglycine; 2-(benzylamino)acetic acid 【CA登记号】17136-36-6 |
【 分 子 式 】C9H11NO2 【 分 子 量 】165.19188 【元素组成】C 65.44% H 6.71% N 8.48% O 19.37% |
合成路线1
该中间体在本合成路线中的序号：(I)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：(IV)The condensation of cyclohexanone (I) with ethyl cyanacetate (II) gives the cyclohexylidene derivative (II), which is cyclized with N-benzylglycine (IV) and formal-dehyde by means of TEA in refluxing benzene yielding the spiro derivative (V). The decarboxylative hydrolysis of (V) with refluxing 6N HCl affords 2-benzyl-2-azaspiro [4,5]decane-4-carboxylic acid (VI), which is esterified with methanol/HCl giving the methyl ester (VII). The debenzylation of (VII) with H2 over Pd(OH)2 in methanol yields 2-azaspiro[4.5]decane-4-carboxylic acid methyl ester (VIII), which is reprotected with benzyl chloroformate and pyridine to provide the carbamate (IX). The hydrolysis of the methyl ester group of (IX) with NaOH in dioxane/water afford the protected carboxylic acid (Xa-b) as a racemic mixture that is treated with oxalyl chloride in dichloromethane to give the acyl chloride (XIa-b). The condensation of (XIa-b) with the chiral (R)(+)-1-(2-naphthyl)ethylamine (XII) yields the amide (XIIIa-b) as a diastereomeric mixture that is resolved by flash chromatography providing chiral (XIV) as a single diastereomer. Finally, this compound is hydrolyzed and deprotected with 6N HCl in refluxing THF.
| 【1】 Singh, L.; Bryans, J.S.; Receveur, J.-M.; Horwell, D.C.; Field, M.J.; Synthesis and biological evaluation of conformationally restricted gabapentin analogues. Bioorg Med Chem Lett 1999, 9, 16, 2329. |
| 【2】 Horwell, D.C.; Bryans, J.S.; Receveur, J.-M. (Pfizer Inc.); Conformationally constrained amino acid cpds. having affinity for the alpha2delta subunit of a calcium channel. WO 9961424 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| (Xa) | 38351 | (4S)-2-[(benzyloxy)carbonyl]-2-azaspiro[4.5]decane-4-carboxylic acid | C18H23NO4 | 详情 | 详情 | |
| (Xb) | 38352 | (4R)-2-[(benzyloxy)carbonyl]-2-azaspiro[4.5]decane-4-carboxylic acid | C18H23NO4 | 详情 | 详情 | |
| (XIa) | 38353 | benzyl (4S)-4-(chlorocarbonyl)-2-azaspiro[4.5]decane-2-carboxylate | C18H22ClNO3 | 详情 | 详情 | |
| (XIb) | 38354 | benzyl (4R)-4-(chlorocarbonyl)-2-azaspiro[4.5]decane-2-carboxylate | C18H22ClNO3 | 详情 | 详情 | |
| (XIIIa) | 38356 | benzyl (4S)-4-([[(1R)-1-(2-naphthyl)ethyl]amino]carbonyl)-2-azaspiro[4.5]decane-2-carboxylate | C30H34N2O3 | 详情 | 详情 | |
| (XIIIb), (XIV) | 38357 | benzyl (4R)-4-([[(1R)-1-(2-naphthyl)ethyl]amino]carbonyl)-2-azaspiro[4.5]decane-2-carboxylate | C30H34N2O3 | 详情 | 详情 | |
| (I) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (II) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (III) | 38345 | ethyl 2-cyano-2-cyclohexylideneacetate | C11H15NO2 | 详情 | 详情 | |
| (IV) | 27895 | N-(benzylamino)acetic acid; N-Benzylglycine; 2-(benzylamino)acetic acid | 17136-36-6 | C9H11NO2 | 详情 | 详情 |
| (V) | 38346 | ethyl 2-benzyl-4-cyano-2-azaspiro[4.5]decane-4-carboxylate | C20H26N2O2 | 详情 | 详情 | |
| (VI) | 38347 | 2-benzyl-2-azaspiro[4.5]decane-4-carboxylic acid | C17H23NO2 | 详情 | 详情 | |
| (VII) | 38348 | methyl 2-benzyl-2-azaspiro[4.5]decane-4-carboxylate | C18H25NO2 | 详情 | 详情 | |
| (VIII) | 38349 | methyl 2-azaspiro[4.5]decane-4-carboxylate | C11H19NO2 | 详情 | 详情 | |
| (IX) | 38350 | 2-benzyl 4-methyl 2-azaspiro[4.5]decane-2,4-dicarboxylate | C19H25NO4 | 详情 | 详情 | |
| (XII) | 38355 | (1R)-1-(2-naphthyl)-1-ethanamine; (1R)-1-(2-naphthyl)ethylamine | C12H13N | 详情 | 详情 |