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【结 构 式】 
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【分子编号】15923 【品名】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 【CA登记号】31970-04-4 |
【 分 子 式 】C12H13NO2 【 分 子 量 】203.24076 【元素组成】C 70.92% H 6.45% N 6.89% O 15.74% |
合成路线1
该中间体在本合成路线中的序号：(XIII)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：(XLI)Intermediate (XXXVIII) can be prepared by several alternative methods. Protection of diallylamine (XXXIX) with benzyl chloroformate and Et3N in CH2Cl2 yields the benzyloxycarbonyl derivative (XL), which undergoes ring-closing metathesis in the presence of Grubbs’ catalyst to give 1-Cbz-3-pyrroline (XLI). Reaction of compound (XLI) with NBS in aqueous DMSO followed by treatment of the resulting bromohydrin with 1 N NaOH leads to epoxide (XLII), which undergoes ring opening with NaN3 in aqueous dioxane to afford the racemic trans-azidoalcohol (XLIII). Resolution of rac-(XLIII) is then effected by incubation with lipase PS in the presence of vinyl acetate in i-Pr2O to give the (R,R)-acetate (XLIV) along with unreacted (S,S)-alcohol (XLIII). Methylation of (S,S)-alcohol (XLIII) with iodomethane and NaH affords ether (XLV), which is submitted to azide group reduction by means of PPh3 in THF/H2O to give amine (XLVI). Protection of amine (XLVI) with Boc2O and Et3N followed by selective removal of the Cbz group in the resulting bis-carbamate (XLVII) using poly(methylhydrosiloxane) and Pd/C in EtOH leads to the pyrrolidine (XLVIII), which is finally treated with Boc2O and Et3N .
| 【1】 Kamal, A., Shaik, A.A., Sandbhor, M., Malik, M.S., Kaga, H. Chemoenzymatic synthesis of (3S,4S)- and (3R,4R)-3-methoxy-4-methylaminopyrrolidine. Tetrahedron Lett 2004, 45(43): 8057-9. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXVIII) | 69233 | (3S,4S)-tert-butyl 3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidine-1-carboxylate | C15H28N2O5 | 详情 | 详情 | |
| (XXXIX) | 68044 | diallylamine;Di-2-propenylamine;N-2-Propenyl-2-propen-1-amine | 124-02-7 | C6H11N | 详情 | 详情 |
| (XL) | 69234 | benzyl diallylcarbamate | C14H17NO2 | 详情 | 详情 | |
| (XLI) | 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 |
| (XLII) | 69235 | benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate | C12H13NO3 | 详情 | 详情 | |
| (XLIII) | 69236 | (3S,4S)-benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate-benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate | C12H14N4O3 | 详情 | 详情 | |
| (XLIV) | 69237 | (3R,4R)-benzyl 3-acetoxy-4-azidopyrrolidine-1-carboxylate | C14H16N4O4 | 详情 | 详情 | |
| (XLV) | 69238 | (3S,4S)-benzyl 3-azido-4-methoxypyrrolidine-1-carboxylate | C13H16N4O3 | 详情 | 详情 | |
| (XLVI) | 69241 | (3S,4S)-benzyl 3-amino-4-methoxypyrrolidine-1-carboxylate | C13H18N2O3 | 详情 | 详情 | |
| (XLVII) | 69239 | (3S,4S)-benzyl 3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidine-1-carboxylate | C18H26N2O5 | 详情 | 详情 | |
| (XLVIII) | 69240 | tert-butyl ((3S,4S)-4-methoxypyrrolidin-3-yl)carbamate | C10H20N2O3 | 详情 | 详情 |