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【结 构 式】 
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【分子编号】15131 【品名】N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamic acid tert-butyl ester 【CA登记号】127199-45-5 |
【 分 子 式 】C11H20N2O2 【 分 子 量 】212.29208 【元素组成】C 62.24% H 9.5% N 13.2% O 15.07% |
合成路线1
该中间体在本合成路线中的序号：(VII)The condensation of 3-chloro-2,4,5-trifluorobenzoylacetic acid ethyl ester (I) with (1R,2S)-N-(tert-butoxycarbonyl)-2-fluorocyclopropylamine (III) and ethyl orthoformate (II) in hot acetic anhydride gives (1R,2S)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(2-fluorocyclopropylamino)acrylic acid ethyl ester (IV). The cyclization of (IV) by means of NaH yields the quinolone (V), which is hydrolyzed with HCl to the free acid (VI). The condensation of (VI) with 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (VII) by means of triethylamine in refluxing acetonitrile affords the protected final product (VIII), which is finally deprotected with trifluoroacetic acid and anisole.
| 【1】 Hayakawa, I.; Kimura, Y. (Daiichi Pharmaceutical Co., Ltd.); Optically active pyridone carboxylic acid derivs. AU 8933702; EP 0341493; JP 1990231475; JP 1995300416; JP 1999124367; JP 1999124380; US 5587386; US 5767127 . |
| 【2】 Castaner, J.; Graul, A.; Prous, J.; DU-6859. Drugs Fut 1994, 19, 9, 827. |
| 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) | 11681 | ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate | 101987-86-4 | C11H8ClF3O3 | 详情 | 详情 |
| (II) | 11927 | 5-Sulfanyl-1,3,4-thiadiazol-2-ylhydrosulfide; 1,3,4-Thiadiazole-2,5-dithiol | 1072-71-5 | C2H2N2S3 | 详情 | 详情 |
| (III) | 15127 | tert-butyl N-[(1R,2S)-2-fluorocyclopropyl]carbamate | 127199-16-0 | C8H14FNO2 | 详情 | 详情 |
| (IV) | 15128 | ethyl (E)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-[[(1R,2S)-2-fluorocyclopropyl]amino]-2-propenoate | C15H12ClF4NO3 | 详情 | 详情 | |
| (V) | 15129 | ethyl 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C15H11ClF3NO3 | 详情 | 详情 | |
| (VI) | 15130 | 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | 127199-27-3 | C13H7ClF3NO3 | 详情 | 详情 |
| (VII) | 15131 | N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamic acid tert-butyl ester | 127199-45-5 | C11H20N2O2 | 详情 | 详情 |
| (VIII) | 15132 | 7-[(7S)-7-(carboxyamino)-5-azaspiro[2.4]hept-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C20H18ClF2N3O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)b) The intermediate 7(S)-(tert-Butoxycarbonylamino)-5-azaspiro[2.4]heptane (VII) can also be obtained as follows: 1) The cyclopropanation of ethyl acetoacetate (XXXI) with 1,2-dibromoethane (XXXII) by means of K2CO3 in DMF gives 1-acetylcyclopropane-1-carboxylic acid ethyl ester (XXXIII), which is brominated with Br2 in ethanol yielding the bromoacetyl derivative (XXXIV). The cyclization of (XXXI) with (R)-alpha-methylbenzylamine (XIII) by means of triethylamine affords 5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione (XXXV), which by reaction with hydroxylamine is converted into the monooxime (XXXVI). The reduction of (XXXVI) with H2 over RaNi in methanol affords 7-amino-5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptan-4-one as a diastereomeric mixture (XXXVII) + (XXXVIII), which is separated by column chromatography. The reduction of the (7S)-isomer (XXXVIII) with LiAlH4 in THF gives 7(S)-amino-5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane (XXXIX), which is protected in the usual way to the tert-butoxycarbonyl derivative (XL). Finally, this compound is debenzylated to (VII) by hydrogenation with H2 over Pd/C in ethanol.
| 【1】 Hayakawa, I.; Kimura, Y. (Daiichi Pharmaceutical Co., Ltd.); Optically active pyridone carboxylic acid derivs. AU 8933702; EP 0341493; JP 1990231475; JP 1995300416; JP 1999124367; JP 1999124380; US 5587386; US 5767127 . |
| 【2】 Castaner, J.; Graul, A.; Prous, J.; DU-6859. Drugs Fut 1994, 19, 9, 827. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXIX)) | 15177 | (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-7-amine; (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-ylamine | C14H20N2 | 详情 | 详情 | |
| (VII) | 15131 | N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamic acid tert-butyl ester | 127199-45-5 | C11H20N2O2 | 详情 | 详情 |
| (XIII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XXXI) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (XXXII) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (XXXIII) | 15171 | ethyl 1-acetylcyclopropanecarboxylate | C8H12O3 | 详情 | 详情 | |
| (XXXIV) | 15172 | ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate | C8H11BrO3 | 详情 | 详情 | |
| (XXXV) | 15173 | 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione | C14H15NO2 | 详情 | 详情 | |
| (XXXVI) | 15174 | 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione 7-oxime | C14H16N2O2 | 详情 | 详情 | |
| (XXXVII) | 15175 | (7R)-7-amino-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-4-one | C14H18N2O | 详情 | 详情 | |
| (XXXVIII) | 15176 | (7S)-7-amino-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-4-one | C14H18N2O | 详情 | 详情 | |
| (XL) | 15178 | N-[(7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-yl]carbamic acid | C15H20N2O2 | 详情 | 详情 |