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【结 构 式】 
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【分子编号】15917 【品名】benzyl (1R,5S)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 【CA登记号】 |
【 分 子 式 】C14H17NO3 【 分 子 量 】247.29392 【元素组成】C 68% H 6.93% N 5.66% O 19.41% |
合成路线1
该中间体在本合成路线中的序号：(VII)Trovafloxacin can be obtained by two related ways: 1) The cyclization of ethyl diazoacetate (I) with N-benzylmaleimide (II) in ethyl ether gives 5-benzyl-4,6-dioxo-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid ethyl ester (III), which by thermolysis at 185 C is converted into (1alpha,5alpha,6alpha)-3-benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (IV). The reduction of (IV) with LiAlH4 in refluxing THF affords (1alpha,5alpha,6alpha)-3-benzyl-6-(hydroxymethyl)-3-azabicyclo[3.1.0] hexane (V), which is debenzylated by hydrogenolysis with H2 over Pd/C in methanol to the free azabicyclo compound (VI) (1, 2). The reaction of (VI) with benzyl chloroformate and NaHCO3 in doxane/water yields the corresponding N-benzyloxycarbonyl compound (VII), which is oxidized with the Jones reagent to (1alpha,5alpha,6alpha)-3-(benzyloxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (VIII). The reaction of (VIII) with diphenylphosphoryl azide (DPA) and triethylamine in refluxing tert-butanol gives (1alpha,5alpha,6alpha)-3-(benzyloxycarbonyl)-6-(tert-butoxycarbonylamino)-3-azabicyclo[3.1.0]hexane (IX), which is submitted to hydrogenolysis with ammonium formate over Pd/C to afford (1alpha,5alpha,6alpha)-6-(tert-butoxycarbonylamino)-3-azabicyclo[3.1.0] hexane (X). The condensation of (X) with 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester (XI) by means of triethylamine in hot acetonitrile gives (1alpha,5alpha,6alpha)-7-[6-(tert-butoxycarbonylamino)-3-azabicyclo [3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester (XII) (1-3), which is finally deprotected with refluxing 6N HCl (1) or methanesulfonic acid in dioxane/water. The cyclization of 1-(benzyloxycarbonyl)-2,5-dihydro-1H-pyrrole (XIII) with ethyl diazoacetate (I) gives 5-(benzyloxycarbonyl)-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid ethyl ester (XIV), which by thermolysis is converted into (1alpha,5alpha,6alpha)-3-(benzyloxycarbonyl)-2,4-dioxo-3-azabicyclo [3.1.0]hexane-6-carboxylic acid ethyl ester (XV). Finally, this compound is hydrolyzed to the desired carboxylic acid (VIII). 2) The carboxylic acid (VIII) can also be obtained as follows:
| 【1】 Fromtling, R.A.; Castaner, J.; Trovafloxacin Mesylate. Drugs Fut 1996, 21, 5, 496. |
| 【2】 Brighty, K.E. (Pfizer Inc.); Azabicyclo quinolone carboxylic acids. AU 9161042; EP 0413455; JP 1991086875; US 5164402; WO 9102526 . |
| 【3】 Gootz, T.D.; Brighty, K.E.; Anderson, M.R.; Haskell, S.L.; Sutcliffe, J.A.; Castaldi, M.J.; Miller, S.A.; In vitro activity and synthesis of CP-99,219, a novel 7-(3-azabicyclo[3.1.0]hexyl)naphthyridone. 32nd Intersci Conf Antimicrob Agents Chemother (Oct 11-14, Anaheim) 1992, Abst 751. |
| 【4】 Brighty, K.E.; Gootz, T.D.; Girard, A.; et al.; 7-(3-Azabicyclo[3.1.0]hexyl)quinolone antibacterial agents: Synthesis and biological evaluation resulting in identification of CP-99,219. 33rd Intersci Conf Antimicrob Agents Chemother (Oct 17-20, New Orleans) 1993, Abst 1509. |
| 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 | |
| (I) | 15911 | Ethyldiazoacetate; ethyl 2-diazoacetate | 623-73-4 | C4H6N2O2 | 详情 | 详情 |
| (II) | 15912 | N-Benzylmaleimide; 1-benzyl-1H-pyrrole-2,5-dione | 1631-26-1 | C11H9NO2 | 详情 | 详情 |
| (III) | 15913 | ethyl 5-benzyl-4,6-dioxo-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrazole-3-carboxylate | C15H15N3O4 | 详情 | 详情 | |
| (IV) | 15914 | ethyl 2-[(1R,5S)-3-benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-6-yl]acetate | C16H17NO4 | 详情 | 详情 | |
| (V) | 15915 | [(1R,5S)-3-benzyl-3-azabicyclo[3.1.0]hex-6-yl]methanol | C13H17NO | 详情 | 详情 | |
| (VI) | 15916 | (1R,5S)-3-azabicyclo[3.1.0]hex-6-ylmethanol | C6H11NO | 详情 | 详情 | |
| (VII) | 15917 | benzyl (1R,5S)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate | C14H17NO3 | 详情 | 详情 | |
| (VIII) | 15918 | (1R,5S)-3-[(benzyloxy)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid | C14H15NO4 | 详情 | 详情 | |
| (IX) | 15919 | benzyl (1R,5S)-6-[(tert-butoxycarbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate | C18H24N2O4 | 详情 | 详情 | |
| (X) | 15920 | tert-butyl (1R,5S)-3-azabicyclo[3.1.0]hex-6-ylcarbamate | C10H18N2O2 | 详情 | 详情 | |
| (XI) | 15230 | ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate | C17H10ClF3N2O3 | 详情 | 详情 | |
| (XII) | 15922 | ethyl 7-[(1R,5S)-6-[(tert-butoxycarbonyl)amino]-3-azabicyclo[3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate | C27H27F3N4O5 | 详情 | 详情 | |
| (XIII) | 15923 | 1-Benzyloxycarbonyl-3-pyrroline;3-Pyrroline-1-carboxylicacid, benzyl ester ;N-(Benzyloxycarbonyl)-3-pyrroline;Benzyl 3-pyrroline-1-carboxylate;2H,5H-Pyrrole-1-carboxylicacid benzyl ester;2,5-Dihydropyrrole-1-carboxylic acid benzyl ester;benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate | 31970-04-4 | C12H13NO2 | 详情 | 详情 |
| (XIV) | 15924 | 5-benzyl 3-ethyl 3a,4,6,6a-tetrahydropyrrolo[3,4-c]pyrazole-3,5(1H)-dicarboxylate | C16H19N3O4 | 详情 | 详情 | |
| (XV) | 15925 | 3-benzyl 6-ethyl (1R,5S)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate | C16H19NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Addition of ethyl diazoacetate to N-benzylmaleimide (I) generated the bicyclic compound (II). Subsequent reduction of ester and imide groups of (II) with LiAlH4 gave 3-benzyl-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane (III). After hydrogenolytic removal of the N-benzyl group of (III), the resulting amine (IV) was protected as the corresponding benzyl carbamate (V) by treatment with benzyl chloroformate. Jones oxidation of the primary alcohol of (V) provided carboxylic acid (VI). This was subjected to a Curtius rearrangement using diphenylphosphoryl azide in the presence of tert-butanol to afford the Boc-protected amine (VII). The benzyl carbamate group of (VII) was then selectively removed by transfer hydrogenolysis with ammonium formate and Pd/C, yielding amine (VIII). Condensation of amine (VIII) with the ethyl ester of 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (IX) gave rise to adduct (X). Further hydrolysis of the ethyl ester and N-Boc groups of (X) yielded amino acid (XI).
| 【1】 Brighty, K.E. (Pfizer Inc.); Anti-bacterial azabicyclo quinolone carboxylic acids. US 5229396 . |
| 【2】 Brighty, K.E. (Pfizer Inc.); Azabicyclo quinolone and naphthyridone carboxylic acids. US 5164402 . |
| 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) | 15912 | N-Benzylmaleimide; 1-benzyl-1H-pyrrole-2,5-dione | 1631-26-1 | C11H9NO2 | 详情 | 详情 |
| (II) | 43087 | ethyl (1R,5S)-3-benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate | C15H15NO4 | 详情 | 详情 | |
| (III) | 15915 | [(1R,5S)-3-benzyl-3-azabicyclo[3.1.0]hex-6-yl]methanol | C13H17NO | 详情 | 详情 | |
| (IV) | 15916 | (1R,5S)-3-azabicyclo[3.1.0]hex-6-ylmethanol | C6H11NO | 详情 | 详情 | |
| (V) | 15917 | benzyl (1R,5S)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate | C14H17NO3 | 详情 | 详情 | |
| (VI) | 15918 | (1R,5S)-3-[(benzyloxy)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid | C14H15NO4 | 详情 | 详情 | |
| (VII) | 15919 | benzyl (1R,5S)-6-[(tert-butoxycarbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate | C18H24N2O4 | 详情 | 详情 | |
| (VIII) | 15920 | tert-butyl (1R,5S)-3-azabicyclo[3.1.0]hex-6-ylcarbamate | C10H18N2O2 | 详情 | 详情 | |
| (IX) | 43088 | ethyl 6-chloro-1-(2,4-difluorophenyl)-7-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate | C17H10ClF3N2O3 | 详情 | 详情 | |
| (X) | 15922 | ethyl 7-[(1R,5S)-6-[(tert-butoxycarbonyl)amino]-3-azabicyclo[3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate | C27H27F3N4O5 | 详情 | 详情 | |
| (XI) | 43089 | 7-[(1R,5S)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid | C20H15F3N4O3 | 详情 | 详情 |