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【结 构 式】 
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【分子编号】22575 【品名】4-nitrobenzyl (2R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate 【CA登记号】 |
【 分 子 式 】C17H18N2O7 【 分 子 量 】362.3392 【元素组成】C 56.35% H 5.01% N 7.73% O 30.91% |
合成路线1
该中间体在本合成路线中的序号：(X)The condensation of (3R,4R)-4-acetoxy-3-[1(R)-(tert-butyldimethylsilylioxy)ethyl)azetidin-2-one (I) with benzyl 2-bromopropionate (II) by means of diethylaluminum chloride in hexane - THF gives the isomeric mixture (III), (IIIa), which is separated by column chrornatography and the correct isomer (III) is treated with tert-butyldimethylsilyl chloride to yield the silylated azetidine (IV). The reductive debenzylation of (IV) with H2 over Pd/C in methanol affords the protected free acid (V), which is condensed with magnesium 4-nitrobenzylmalonate (VI) by means of carbonyldiimidazole (CDI) in hot acetonitrile to give the protected ketoester (VII). Partial hydrolysis of (VII) with HCl in methanol affords the free ketoester (VIII), which is treated with p-toluenesulfonylazide in acetonitrile yielding the diazo compound (IX). The cyclization of (IX) by means of rhodium acetate in refluxing toluene gives 6alpha-[1(R)-hydroxyethyl)-1beta-methyl-2-oxo-1-dethia-1-carba-2-penem-3-car boxylic acid 4-nitrobenzyl ester (X), which is condensed with diphenyl chlorophosphate (XI) by means of diisopropylethylamine in acetonitrile, yielding the enol ester (XII).
| 【1】 Fukasawa, M.; Inoue, T.; Kato, M.; Matsumura, H.; Sunagawa, M. (Sumitomo Pharmaceuticals Co., Ltd.); Thiopyrrolidinyl-beta-lactam derivs.. EP 0126587; ES 8600305; JP 1985001186; JP 1985019787; JP 1991041066; US 4933333; US 4943569; US 5122604 . |
| 【2】 Prous, J.; Castaner, J.; SM-7338. Drugs Fut 1988, 13, 6, 534. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 22568 | benzyl (2S)-2-[(2S,3S)-3-(1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propanoate | C21H33NO4Si | 详情 | 详情 | |
| (I) | 22565 | methyl (2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxo-2-azetidinecarboxylate | C13H25NO4Si | 详情 | 详情 | |
| (II) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
| (II) | 22566 | benzyl 2-bromopropanoate | 3017-53-6 | C10H11BrO2 | 详情 | 详情 |
| (III) | 22567 | benzyl 2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propanoate | C21H33NO4Si | 详情 | 详情 | |
| (IV) | 22569 | benzyl 2-[(2S,3S)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propanoate | C27H47NO4Si2 | 详情 | 详情 | |
| (V) | 22570 | 2-[(2S,3S)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid | C20H41NO4Si2 | 详情 | 详情 | |
| (VI) | 22571 | 3-[(4-nitrobenzyl)oxy]-3-oxopropanoate | C10H8MgNO6 | 详情 | 详情 | |
| (VII) | 22572 | 4-nitrobenzyl 4-[(2R,3S)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-3-oxopentanoate | C29H48N2O7Si2 | 详情 | 详情 | |
| (VIII) | 22573 | 4-nitrobenzyl 4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate | C17H20N2O7 | 详情 | 详情 | |
| (IX) | 30150 | (3S,4R)-3-((1R)-1-Hydroxyethyl)-4[(1R)-1-methyl-3-diazo-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one | 137391-68-5 | C17H18N4O7 | 详情 | 详情 |
| (X) | 22575 | 4-nitrobenzyl (2R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C17H18N2O7 | 详情 | 详情 | |
| (XII) | 22577 | 4-nitrobenzyl (5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C29H27N2O10P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Mercaptoproline derivative (I) was condensed with protected piperazine (II) via activation with carbonyl diimidazole to afford amide (III). The 4-methoxybenzyl group of (III) was then removed with trifluoromethanesulfonic acid in the presence of anisole and trifluoroacetic acid, and the resulting mercaptan (IV) was condensed with carbapenem phosphate (VI), (prepared from ketone (V) and diphenylphosphorochloridate), to afford thioether (VII). N-Methylation was carried out using methyl fluorosulfonate to yield quaternary ammonium salt (VIII). Finally, the 4-nitrobenzyl ester and carbamate groups of (VIII) were eliminated by hydrogenation in the presence of Pd/C, and the target product was isolated by ion-exchange chromatography.
| 【1】 Ishikawa, K.; Kojima, K.; Miyauchi, M.; Endo, R.; Yasuda H; Kawamoto I.; Synthesis and structure-activity relationships of 1beta-methylcarbapenems with quaternary ammonium side chains. J Antibiot 1998, 51, 8, 757. |
| 【2】 Kawamoto, I.; Miyauchi, M.; Nakayama, E.; Endo, R.; Ohya, S.; Utsui, Y. (Sankyo Co., Ltd.); Carbapenem derivs. having antibiotic activity, their preparation and their use. EP 0443883; JP 1992211083; US 5310735 . |
| 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) | 26808 | (2S,4S)-4-[(4-methoxybenzyl)sulfanyl]-1-methyl-2-pyrrolidinecarboxylic acid | C14H19NO3S | 详情 | 详情 | |
| (II) | 26809 | 4-nitrophenyl 1-piperazinecarboxylate | C11H13N3O4 | 详情 | 详情 | |
| (III) | 26810 | 4-nitrobenzyl 4-([(2S,4S)-4-[(4-methoxybenzyl)sulfanyl]-1-methylpyrrolidinyl]carbonyl)-1-piperazinecarboxylate | C26H32N4O6S | 详情 | 详情 | |
| (IV) | 26811 | 4-nitrobenzyl 4-[[(2S,4S)-1-methyl-4-sulfanylpyrrolidinyl]carbonyl]-1-piperazinecarboxylate | C18H24N4O5S | 详情 | 详情 | |
| (V) | 22575 | 4-nitrobenzyl (2R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C17H18N2O7 | 详情 | 详情 | |
| (VI) | 13224 | 4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | 90776-59-3 | C29H27N2O10P | 详情 | 详情 |
| (VII) | 26812 | 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-([(3S,5S)-1-methyl-5-[(4-[[(4-nitrobenzyl)oxy]carbonyl]-1-piperazinyl)carbonyl]pyrrolidinyl]sulfanyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C35H40N6O11S | 详情 | 详情 | |
| (VIII) | 26813 | (1R,5S,6S)-6-(1(R)-Hydroxyethyl)-2-[1,1-dimethyl-5(S)-[4-(4-nitrobenzyloxycarbonyl)piperazin-1-ylcarbonyl]pyrrrolidinium-3(S)-ylsulfanyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester fluorosulfonate; (1R,5S,6S)-6-(1(R)-Hydroxyethyl)-2-[1,1-dimethyl-5(S)-[4-(4-nitrobenzyloxycarbonyl)piperazin-1-ylcarbonyl]pyrrrolidinium-3(S)-ylsulfanyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester fluorosulfonate | C36H43FN6O14S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)Mercaptoproline derivative (I) was condensed with N-(carbamoylmethyl)homopiperazine (II) via activation with carbonyl diimidazole to afford amide (III). The 4-methoxybenzyl group of (III) was then removed with trifluoromethanesulfonic acid in the presence of anisole and trifluoroacetic acid, and the resulting mercaptan (IV) was condensed with carbapenem phosphate (VI), (prepared from ketone (V) and diphenylphosphorochloridate), to afford thioether (VII). N-Methylation of (VII) was carried out using methyl fluorosulfonate to yield quaternary ammonium salt (VIII). Finally, the 4-nitrobenzyl ester and carbamate groups of (VIII) were eliminated by hydrogenation in the presence of Pd/C, and the target product was isolated by ion-exchange chromatography.
| 【1】 Ishikawa, K.; Kojima, K.; Miyauchi, M.; Endo, R.; Yasuda H; Kawamoto I.; Synthesis and structure-activity relationships of 1beta-methylcarbapenems with quaternary ammonium side chains. J Antibiot 1998, 51, 8, 757. |
| 【2】 Kawamoto, I.; Miyauchi, M.; Nakayama, E.; Endo, R.; Ohya, S.; Utsui, Y. (Sankyo Co., Ltd.); Carbapenem derivs. having antibiotic activity, their preparation and their use. EP 0443883; JP 1992211083; US 5310735 . |
| 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) | 26814 | (2S,4S)-4-[(4-methoxybenzyl)sulfanyl]-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid | C21H22N2O7S | 详情 | 详情 | |
| (II) | 26815 | 2-(1,4-diazepan-1-yl)acetamide | C7H15N3O | 详情 | 详情 | |
| (III) | 26816 | 4-nitrobenzyl (2S,4S)-2-[[4-(2-amino-2-oxoethyl)-1,4-diazepan-1-yl]carbonyl]-4-[(4-methoxybenzyl)sulfanyl]-1-pyrrolidinecarboxylate | C28H35N5O7S | 详情 | 详情 | |
| (IV) | 26817 | 4-nitrobenzyl (2S,4S)-2-[[4-(2-amino-2-oxoethyl)-1,4-diazepan-1-yl]carbonyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C20H27N5O6S | 详情 | 详情 | |
| (V) | 22575 | 4-nitrobenzyl (2R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C17H18N2O7 | 详情 | 详情 | |
| (VI) | 13224 | 4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | 90776-59-3 | C29H27N2O10P | 详情 | 详情 |
| (VII) | 26818 | 4-nitrobenzyl (4R,5S,6S)-3-[((3S,5S)-5-[[4-(2-amino-2-oxoethyl)-1,4-diazepan-1-yl]carbonyl]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C37H43N7O12S | 详情 | 详情 | |
| (VIII) | 26819 | (1R,5S,6S)-2-[5(S)-[4-(carbamoylmethyl)-4-methylperhydro-1,4-diazepinium-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-(S)-ylsulfanyl]-6-(1(R)-hydroxyethyl)-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester fluorosulfonate; (1R,5S,6S)-2-[5(S)-[4-(carbamoylmethyl)-4-methylperhydro-1,4-diazepinium-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-(S)-ylsulfanyl]-6-(1(R)-hydroxyethyl)-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester fluorosulfonate | C38H46FN7O15S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Imidazothiazole (I) is converted into methylsulfanyl derivative (II) by first reaction with EtMgBr in THF followed by treatment with MeSSO2Me. Lithiation of derivative (II) by means of BuLi in THF/hexane, followed by reaction with tributyltin chloride and LiHMDS, provides tributyltin derivative (III), which is then condensed with carbapenem derivative (VI) by means of Pd(dba)3, P(2-furyl)3 and ZnCl2 in NMP to afford (VII). (Derivative (VI) in turn can be obtained by first cyclization of the diazo compound (IV) by means of ZnBr2 and Rh2Oct4 in MeOAc/THF to provide bicyclic ketoester (V), which is finally treated with triflic anhydride (Tf2O) and DIEA in acetonitrile. The target product is finally obtained by first N-alkylation of the imidazothiazole ring of (VII) with iodoacetamide (VIII) in acetonitrile followed by deprotection of the carboxylic acid by hydrogenation over Pd/C inTHF/H2O.
| 【2】 Lynch, J.E.; Liu, T.M.-H.; Volante, R.P. (Merck & Co., Inc.); Process for synthesizing carbapenem intermediates using a rhodium catalyst and Lewis acid. US 5493018 . |
| 【1】 Sakakibara, S.; Takata, T.; Yamamoto, K.; Shitara, E.; Shibasaki, Y.; Shimizu, A.; Komiya, I.; CP5068, a new carbapenem: Synthesis and structure-activity relationships. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1236. |
| 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) | 47193 | 7-iodoimidazo[5,1-b][1,3]thiazole | C5H3IN2S | 详情 | 详情 | |
| (II) | 47194 | 7-(methylsulfanyl)imidazo[5,1-b][1,3]thiazole; imidazo[5,1-b][1,3]thiazol-7-yl methyl sulfide | C6H6N2S2 | 详情 | 详情 | |
| (III) | 47195 | 7-(methylsulfanyl)-2-(tributylstannyl)imidazo[5,1-b][1,3]thiazole; methyl 2-(tributylstannyl)imidazo[5,1-b][1,3]thiazol-7-yl sulfide | C18H32N2S2Sn | 详情 | 详情 | |
| (IV) | 38749 | 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate | C17H18N4O7 | 详情 | 详情 | |
| (V) | 22575 | 4-nitrobenzyl (2R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C17H18N2O7 | 详情 | 详情 | |
| (VI) | 38750 | 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(trifluoromethyl)sulfonyl]oxy]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C18H17F3N2O9S | 详情 | 详情 | |
| (VII) | 47196 | 4-nitrobenzyl (4S,5R)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[7-(methylsulfanyl)imidazo[5,1-b][1,3]thiazol-2-yl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C23H22N4O6S2 | 详情 | 详情 | |
| (VIII) | 47197 | 2-iodoacetamide | 144-48-9 | C2H4INO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)Metalation of 7-iodoimidazo[5,1-b]thiazole (I) with ethylmagnesium bromide, followed by addition to 3-pyridinecarboxaldehyde (II) provides carbinol (III), which is further oxidized to ketone (IV) by means of MnO2. Lithiation of (IV) and further treatment with chlorotributyltin affords the stannyl derivative (V). The carbapenem ketone (VI) is converted into the vinyl triflate (VII) upon treatment with trifluoromethanesulfonic anhydride and diisopropyl ethylamine. Then, Stille coupling between vinyl triflate (VII) and the stannyl derivative (V) gives rise to the imidazothiazolyl carbapenem (VIII). Quaternization of the pyridine ring of (VIII) with iodoacetamide furnishes the pyridinium salt (IX). Finally the p-nitrobenzyl ester group of (IX) is removed by hydrogenolysis over Pd/C to provide the title compound
| 【1】 Shitara, E.; Yamamoto, Y.; Kano, Y.; Maruyama, T.; Takahashi, M.; Atsumi, K.; CP5609, a novel parenteral carbapenem: Synthesis and structure-activity relationships. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-319. |
| 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) | 47193 | 7-iodoimidazo[5,1-b][1,3]thiazole | C5H3IN2S | 详情 | 详情 | |
| (II) | 12849 | Nicotinaldehyde; 3-Pyridinecarboxaldehyde | 500-22-1 | C6H5NO | 详情 | 详情 |
| (III) | 62675 | imidazo[5,1-b][1,3]thiazol-7-yl(3-pyridinyl)methanol | C11H9N3OS | 详情 | 详情 | |
| (IV) | 62676 | imidazo[5,1-b][1,3]thiazol-7-yl(3-pyridinyl)methanone | C11H7N3OS | 详情 | 详情 | |
| (V) | 62677 | 3-pyridinyl[2-(tributylstannyl)imidazo[5,1-b][1,3]thiazol-7-yl]methanone | C23H33N3OSSn | 详情 | 详情 | |
| (VI) | 22575 | 4-nitrobenzyl (2R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C17H18N2O7 | 详情 | 详情 | |
| (VII) | 38750 | 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(trifluoromethyl)sulfonyl]oxy]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C18H17F3N2O9S | 详情 | 详情 | |
| (VIII) | 62678 | 4-nitrobenzyl (4S,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[7-(3-pyridinylcarbonyl)imidazo[5,1-b][1,3]thiazol-2-yl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C28H23N5O7S | 详情 | 详情 | |
| (IX) | 62679 | 1-(2-amino-2-oxoethyl)-3-{[2-((4S,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-{[(4-nitrobenzyl)oxy]carbonyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl)imidazo[5,1-b][1,3]thiazol-7-yl]carbonyl}pyridinium iodide | C30H27IN6O8S | 详情 | 详情 |