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【结 构 式】 
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【分子编号】15911 【品名】Ethyldiazoacetate; ethyl 2-diazoacetate 【CA登记号】623-73-4 |
【 分 子 式 】C4H6N2O2 【 分 子 量 】114.10392 【元素组成】C 42.11% H 5.3% N 24.55% O 28.04% |
合成路线1
该中间体在本合成路线中的序号：(I)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：(IV)The cyclization of 5-benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole (I) with 4-chlorophenacyl bromide (II) ethyl ether/ethanol gives 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine (III), which is condensed with ethyl diazoacetate (IV) by means of copper powder in refluxing toluene to afford 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetic acid ethyl ester (V). Finally, this ester is hydrolyzed with NaOH in ethanol/water.
| 【1】 Rabasseda, X.; Mealy, N.; Castañer, J.; ML-3000. Drugs Fut 1995, 20, 10, 1007. |
| 【2】 Augustin, J.; Kiefer, W.; Dannhardt, G.; Laufer, S.A.; (6,7-Diaryldihydropyrrolizin-5-yl)acetic acids, a novel class of potent dual inhibitors of both cyclooxygenase and 5-lipoxygenase. J Med Chem 1994, 37, 12, 1894-7. |
| 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) | 16719 | 5-benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole | 116673-95-1 | C13H17N | 详情 | 详情 |
| (II) | 16720 | 2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone | 536-38-9 | C8H6BrClO | 详情 | 详情 |
| (III) | 16721 | 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine | C21H20ClN | 详情 | 详情 | |
| (IV) | 15911 | Ethyldiazoacetate; ethyl 2-diazoacetate | 623-73-4 | C4H6N2O2 | 详情 | 详情 |
| (V) | 16723 | ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetate | C25H26ClNO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(A)Suzuki coupling of vinyl bromide (VIII) with boronic acid (XVI) gives bromotetraene (XVII). The methoxyamide function of (XVII) is then reduced to aldehyde (XVIII) employing DIBAL in THF. Two carbon homologation of aldehyde (XVIII) with ethyl diazoacetate leads to keto ester (XIX). Selective removal of the primary tert-butyl diphenylsilyl ether of (XIX) with tetrabutylammonium fluoride affords the allylic alcohol (XX), which is then converted into iodide (XXI) by means of I2 and PPh3.
| 【1】 Evans, D.A.; Starr, J.T.; A cascade cycloaddition strategy leading to the total synthesis of (-)-FR182877. Angew Chem. Int Ed 2002, 41, 10, 1787. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 15911 | Ethyldiazoacetate; ethyl 2-diazoacetate | 623-73-4 | C4H6N2O2 | 详情 | 详情 |
| (VIII) | 60352 | 10,10-dibromo-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-N,2,6-trimethyl-N-(methyloxy)-6,9-decadienamide | C20H37Br2NO3Si | 详情 | 详情 | |
| (XVI) | 60358 | 3,5-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-8-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-4-methyl-1,6-octadienylboronic acid | C37H63BO5Si3 | 详情 | 详情 | |
| (XVII) | 60422 | 10-bromo-3,13,15-tris{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-18-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-N,2,6,14-tetramethyl-N-(methyloxy)-6,9,11,16-octadecatetraenamide | C57H98BrNO6Si4 | 详情 | 详情 | |
| (XVIII) | 60423 | 10-bromo-3,13,15-tris{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-18-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2,6,14-trimethyl-6,9,11,16-octadecatetraenal | C55H93BrO5Si4 | 详情 | 详情 | |
| (XIX) | 60424 | ethyl 12-bromo-5,15,17-tris{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-20-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-4,8,16-trimethyl-3-oxo-8,11,13,18-icosatetraenoate | C59H99BrO7Si4 | 详情 | 详情 | |
| (XX) | 60425 | ethyl 12-bromo-5,15,17-tris{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-20-hydroxy-4,8,16-trimethyl-3-oxo-8,11,13,18-icosatetraenoate | C43H81BrO7Si3 | 详情 | 详情 | |
| (XXI) | 60426 | ethyl 12-bromo-5,15,17-tris{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-20-iodo-4,8,16-trimethyl-3-oxo-8,11,13,18-icosatetraenoate | C43H80BrIO6Si3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Addition of ethyl diazoacetate (II) to 2,3-dibromopropene (I) in the presence of dirhodium tetraacetate furnished ethyl 2-bromo-2-(bromomethyl)cyclopropane-1-carboxylate (III) as a mixture of cis- and trans-isomers. Subsequent condensation of the dibromo ester (III) with the sodium salt of adenine (IV) produced adduct (V) as a diastereomeric mixture. Then, elimination of HBr using potassium tert-butoxide gave olefin (VIa-b). Alternatively, a direct synthesis of (VIa-b) was carried out by reaction of adenine (IV) with dibromo ester (III) in the presence of K2CO3 in hot DMF. Reduction of ester (VIa-b) with diisobutylaluminum hydride afforded alcohol (VIIa-b) as a mixture of syn- and anti-isomers. Isolation of the desired syn-isomer (VIII) was achieved by conversion to the corresponding formamidines, followed by chromatographic separation. The formamidine function of (VIII) was then hydrolyzed with methanolic ammonia to yield the racemic synadenol (IX). Incubation of (IX) with adenosine deaminase converted the (S)-enantiomer to the hypoxanthine derivative (XI), which was separated from the unreacted (R)-synadenol (X) by column chromatography. Acetylation of alcohol (XI) with Ac2O in pyridine provided ester (XII). Chloropurine derivative (XIV) was then obtained by treatment of (XII) with N,N-dimethylamino(chloromethylene)ammonium chloride (XIII) in CHCl3. Finally, chloride displacement in (XIV) and simultaneous ester cleavage with methanolic ammonia in a pressure vessel gave rise to the title compound.
| 【1】 Drach, J.C.; Zemlicka, J.; Ptak, R.G.; Qiu, Y.-L. (University of Michigan; Wayne State University); 2-Hydroxy methylcyclopropylidenemethyl purines and -pyrimidines as antiviral agents. WO 0053603 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa),(IX) | 21754 | ethyl 2-[(Z)-(6-amino-9H-purin-9-yl)methylidene]cyclopropanecarboxylate | C12H13N5O2 | 详情 | 详情 | |
| (VIb) | 21755 | ethyl 2-[(E)-(6-amino-9H-purin-9-yl)methylidene]cyclopropanecarboxylate | C12H13N5O2 | 详情 | 详情 | |
| (VIIa) | 21756 | [2-[(Z)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methanol | C10H11N5O | 详情 | 详情 | |
| (VIIb) | 21757 | [2-[(E)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methanol | C10H11N5O | 详情 | 详情 | |
| (I) | 21748 | 2,3-dibromo-1-propene | 513-31-5 | C3H4Br2 | 详情 | 详情 |
| (II) | 15911 | Ethyldiazoacetate; ethyl 2-diazoacetate | 623-73-4 | C4H6N2O2 | 详情 | 详情 |
| (III) | 42613 | ethyl 2-bromo-2-(bromomethyl)cyclopropanecarboxylate | C7H10Br2O2 | 详情 | 详情 | |
| (IV) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (V) | 48356 | ethyl 2-[(6-amino-9H-purin-9-yl)methyl]-2-bromocyclopropanecarboxylate | C12H14BrN5O2 | 详情 | 详情 | |
| (VIII) | 21758 | N'-(9-[[2-(hydroxymethyl)cyclopropylidene]methyl]-9H-purin-6-yl)-N,N-dimethyliminoformamide | C13H16N6O | 详情 | 详情 | |
| (X) | 21781 | [(1R)-2-[(E)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methanol | C10H11N5O | 详情 | 详情 | |
| (XI) | 21759 | 9-[[(2S)-2-(hydroxymethyl)cyclopropylidene]methyl]-1,9-dihydro-6H-purin-6-one | C10H10N4O2 | 详情 | 详情 | |
| (XII) | 48357 | [(1S)-2-[(Z)-(6-oxo-1,6-dihydro-9H-purin-9-yl)methylidene]cyclopropyl]methyl acetate | C12H12N4O3 | 详情 | 详情 | |
| (XIII) | 17643 | (Chloromethylene)dimethylammonium chloride; N-(chloromethylene)-N-methylmethanaminium chloride | 3724-43-4 | C3H7Cl2N | 详情 | 详情 |
| (XIV) | 48358 | [(1S)-2-[(Z)-(6-chloro-9H-purin-9-yl)methylidene]cyclopropyl]methyl acetate | C12H11ClN4O2 | 详情 | 详情 |