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【结 构 式】 
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【分子编号】41923 【品名】(4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,3S)-3-(methylamino)-2-oxocyclohexyl]-2-azetidinone 【CA登记号】 |
【 分 子 式 】C18H34N2O3Si 【 分 子 量 】354.56514 【元素组成】C 60.98% H 9.67% N 7.9% O 13.54% Si 7.92% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The selective silylation of azetidine (I) with TBDMSCl and Et3N in CH2Cl2 gives the fully silylated azetidine (II), which is condensed with 1-(trimethylsilyloxy) cyclohexene (III) by means of SnCl4 in CH3CN to yield the adduct (IV). The N-silylation of (IV) with TBDMSCl and Et3N in DMF affords the disilylated compound (V), which is condensed with diethyl chlorophosphate by means of LiHMDS in THF providing the phosphate ester (VI). The reaction of (VI) with MCPBA in CH2Cl2 gives the epoxide (VII), which is treated with methylamine and K2CO3 in ethyl acetate to yield the secondary amine (VIII). The acylation of (VIII) with allyl chloroformate (IX) and Et3N in CH2Cl2 affords the carbamate (X), which is cyclized with allyl chlorooxalate (XI) and Et3N in CH2Cl2 providing the tricyclic compound (XII). The desilylation of (XII) with TBAF and HOAc in THF gives the hydroxy diallyl ester (XIII), which is treated with Pd(PPh3)4 and 5,5-dimethylcyclohexane-1,3-dione (DMCHE) to yield the tricyclic aminoacid (XIV). Finally this compound is treated with benzyloxy formimidate (XV) in a pH 8 buffer to afford the target N-methylformamidino compound.
| 【1】 Perboni, A.; Donati, D.; Tarzia, G. (Glaxo Wellcome plc); Antibacterial condensed carbapenems. EP 0502468; EP 0575375; JP 1994505018; US 5426104; WO 9215288; WO 9215586 . |
| 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) | 11687 | (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (II) | 41919 | (2R)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl acetate | C19H39NO4Si2 | 详情 | 详情 | |
| (III) | 15574 | 1-cyclohexen-1-yl trimethylsilyl ether; (1-cyclohexen-1-yloxy)(trimethyl)silane; 1-Cyclohexenyloxytrimethylsilane | 6651-36-1 | C9H18OSi | 详情 | 详情 |
| (IV) | 15575 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-2-oxocyclohexyl]-2-azetanone | C17H31NO3Si | 详情 | 详情 | |
| (V) | 41920 | (4R)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-2-oxocyclohexyl]-2-azetidinone | C23H45NO3Si2 | 详情 | 详情 | |
| (VI) | 41921 | (6R)-6-[(2R)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-1-cyclohexen-1-yl diethyl phosphate | C27H54NO6PSi2 | 详情 | 详情 | |
| (VII) | 41922 | (2R)-2-[(2R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-7-oxabicyclo[4.1.0]hept-1-yl diethyl phosphate | C21H40NO7PSi | 详情 | 详情 | |
| (VIII) | 41923 | (4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,3S)-3-(methylamino)-2-oxocyclohexyl]-2-azetidinone | C18H34N2O3Si | 详情 | 详情 | |
| (IX) | 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 |
| (X) | 41924 | allyl (1S,3R)-3-[(2R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-2-oxocyclohexyl(methyl)carbamate | C22H38N2O5Si | 详情 | 详情 | |
| (XI) | 15585 | allyl 2-chloro-2-oxoacetate | C5H5ClO3 | 详情 | 详情 | |
| (XII) | 41925 | allyl (5S,8aS,8bR)-5-[[(allyloxy)carbonyl](methyl)amino]-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate | C27H42N2O6Si | 详情 | 详情 | |
| (XIII) | 41926 | allyl (5S,8aS,8bR)-5-[[(allyloxy)carbonyl](methyl)amino]-1-[(1R)-1-hydroxyethyl]-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate | C21H28N2O6 | 详情 | 详情 | |
| (XIV) | 41927 | (5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-(methylamino)-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylic acid | C14H20N2O4 | 详情 | 详情 | |
| (XV) | 41928 | 1-[[amino(imino)methoxy]methyl]benzene | C8H10N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The condensation of azetidine (I) with B-2-cyclohexenyl(2-methylcyclohexyl)2 by means of Et2Zn gives the adduct (II), which is epoxidated with Mg monoperphthalic acid (MgPOPH) in CH2Cl2 to yield the epoxide (III). Opening of the epoxide (III) with methylamine and LiClO4 in CH3CN affords the methylamino derivative (IV), which is oxidated with oxalyl chloride and Et3N in DMSO/CH2Cl2 to provide the cyclohexanone derivative (V). The protection of the methylamino group of (V) with benzyl chloroformate (VI) and Et3N in CH2Cl2 gives the carbamate (VII), which is condensed with 9-fluorenyl chlorooxalate (VIII) by means of Et3N in toluene to yield the oxalamic ester (IX). The cyclization of (IX) by means of P(OEt)3 in refluxing toluene affords the tricyclic carboxylate (X), which is desilylated with Bu4NBr and KF in HOAc/THF providing the intermediate (XI). The deprotection of the ester and carbamate groups of (XI) with H2 over Pd/C in i-PrOH/H2O furnishes the tricyclic aminoacid (XII), which is finally treated with benzyloxy formimidate (XIII) over amberlyst IRA68 in CH3CN/H2O to afford the target N-methylformamidino compound.
| 【1】 Biondi, S.; et al.; Highly diastereoselective synthesis of 4-N-methylformamidino trinem (GV129606), a potent antibacterial agent. Tetrahedron 2000, 56, 31, 5649. |
| 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) | 11687 | (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (II) | 15576 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1S)-2-cyclohexen-1-yl]-2-azetanone | C17H31NO2Si | 详情 | 详情 | |
| (III) | 15577 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1S,2R,6R)-7-oxabicyclo[4.1.0]hept-2-yl]-2-azetidinone | C17H31NO3Si | 详情 | 详情 | |
| (IV) | 41929 | (4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,2S,3S)-2-hydroxy-3-(methylamino)cyclohexyl]-2-azetidinone | C18H36N2O3Si | 详情 | 详情 | |
| (V) | 41923 | (4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,3S)-3-(methylamino)-2-oxocyclohexyl]-2-azetidinone | C18H34N2O3Si | 详情 | 详情 | |
| (VI) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (VII) | 41930 | benzyl (1S,3R)-3-[(2R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-2-oxocyclohexyl(methyl)carbamate | C26H40N2O5Si | 详情 | 详情 | |
| (VIII) | 41931 | 2-(9H-fluoren-9-yloxy)-2-oxoacetyl chloride | C15H9ClO3 | 详情 | 详情 | |
| (IX) | 41932 | 9H-fluoren-9-yl 2-((2R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-[(1R,3S)-3-[(methoxycarbonyl)(methyl)amino]-2-oxocyclohexyl]-4-oxoazetidinyl)-2-oxoacetate | C35H44N2O8Si | 详情 | 详情 | |
| (X) | 41933 | 9H-fluoren-9-yl (5S,8aS,8bR)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-[(methoxycarbonyl)(methyl)amino]-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate | C35H44N2O6Si | 详情 | 详情 | |
| (XI) | 41934 | 9H-fluoren-9-yl (5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-[(methoxycarbonyl)(methyl)amino]-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate | C29H30N2O6 | 详情 | 详情 | |
| (XII) | 41927 | (5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-(methylamino)-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylic acid | C14H20N2O4 | 详情 | 详情 | |
| (XIII) | 41928 | 1-[[amino(imino)methoxy]methyl]benzene | C8H10N2O | 详情 | 详情 |