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【结 构 式】 
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【分子编号】15575 【品名】(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-2-oxocyclohexyl]-2-azetanone 【CA登记号】 |
【 分 子 式 】C17H31NO3Si 【 分 子 量 】325.52358 【元素组成】C 62.73% H 9.6% N 4.3% O 14.74% Si 8.63% |
合成路线1
该中间体在本合成路线中的序号：(XVII)2) The condensation of the previously referenced azetidinone (III) with 1-(trimethylsilyloxy)cyclohexene (XVI) by means of trimethylsilyloxy trifluoromethanesulfonate in acetonitrile gives the corresponding addition product (XVII), which by reaction first with p-toluenesulfonyl hydrazide in acetic acid and then with lithium diisopropylamide in THF yields the cyclohexenyl derivative (XVIII). The regioselective epoxidation of (XVIII) with magnesium monoperoxyphthalate (MgMPP) in dichloromethane affords the epoxide (XIX), which is submitted to ring opening with methanol/p-toluenesulfonic acid and oxidation with sulfur trioxide and pyridine to give the methoxycyclohexylazetidinone (VIII) already described in Scheme 18359601a. 3) The condensation of the previously referenced azetidinone (III) with (2-cyclohexenyl)bis(trans-2-methylcyclohexyl)borane (XX) at room temperature in hexane/THF yields the cyclohexenyl-azetidinone derivative (XVIII) already described. 4) The enzymatic resolution of trans-2-methoxycyclohexanol (XX) with Pseudomonas fluorescens lipase or with Candida antarctica lipase in dry THF containing vinyl acetate and triethylamine gives the (S,S)-isomer (XXI), which is oxidized with oxalyl chloride in dichloromethane, or with CrO3/H2SO4, or with NaOCl or with N-bromoacetamide in acetone yielding 2(S)-methoxycyclohexanone (XXII). Finally, this compound is condensed with the previously referenced azetidinone (III) by means of SnCl4 in dichloromethane to afford the methoxycyclohexylazetidinone (VIII) already described. 5) The reaction of the previously described 2(S)-methoxycyclohexanone (XXII) with trimethylsilyl trifluoromethanesulfonate and triethylamine in THF gives the corresponding trimethylsilyl ether (XXIII), which is then condensed with the previously referenced azetidinone (III) by means of the SnCl4.S(Me)2 complex in dichloromethane yielding the previously described methoxycyclohexylazetidinone (VIII).
| 【1】 Rossi, T.; Zarantonello, P.; Thomas, J.R. (Glaxo SpA); Process for the preparation of cyclohexyl-azetidinones. WO 9526333 . |
| 【2】 Perboni, A.; Bismara, C.; Pentassuglia, G. (Glaxo SpA); Heterocyclic derivs. EP 0466509 . |
| 【3】 Bismara, C.; Di Fabio, R.; Donati, D.; Rossi, T.; Thomas, R.J.; The synthesis of a key intermediate of tricyclic beta-lactam antibiotics. Tetrahedron Lett 1995, 36, 24, 4283-6. |
| 【4】 Ngo, J.; Castaner, J.; Sanfetrinem cilexetil. Drugs Fut 1996, 21, 12, 1238. |
| 【5】 Rossi, T.; Biondi, S.; Contini, S.; Thomas, R.J.; Marchioro, C.; Novel amidoalkylation of 4-acetoxyazetidinones with allylic boranes. A stereoselective entry into the tribactams. J Am Chem Soc 1995, 117, 37, 9604-5. |
| 【6】 Ghiron, C.; Piga, E.; Rossi, T.; Tamburini, B.; Thomas; The stereoselective synthesis of a key intermediate of the trinem antibiotic sanfetrinem. Tetrahedron Lett 1996, 37, 22, 3891-4. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXa) | 15578 | 2-cyclohexen-1-yl[(1R,2R)-2-methylcyclohexyl][(1S,2S)-2-methylcyclohexyl]borane | C20H35B | 详情 | 详情 | |
| (XXb) | 64590 | (rac)-(1S,2S)-2-methoxycyclohexanol | C7H14O2 | 详情 | 详情 | |
| (VIII) | 15566 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,3S)-3-methoxy-2-oxocyclohexyl]-2-azetanone | C18H33NO4Si | 详情 | 详情 | |
| (XVI) | 15574 | 1-cyclohexen-1-yl trimethylsilyl ether; (1-cyclohexen-1-yloxy)(trimethyl)silane; 1-Cyclohexenyloxytrimethylsilane | 6651-36-1 | C9H18OSi | 详情 | 详情 |
| (XVII) | 15575 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-2-oxocyclohexyl]-2-azetanone | C17H31NO3Si | 详情 | 详情 | |
| (XVIII) | 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 | |
| (XIX) | 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 | |
| (XXI) | 15579 | (1S,2S)-2-methoxycyclohexanol | 7429-40-5 | C7H14O2 | 详情 | 详情 |
| (XXII) | 15581 | (2S)-2-methoxycyclohexanone | C7H12O2 | 详情 | 详情 | |
| (XXIII) | 15582 | [[(6S)-6-methoxy-1-cyclohexen-1-yl]methyl](trimethyl)silane; methyl (1S)-2-[(trimethylsilyl)methyl]-2-cyclohexen-1-yl ether | C11H22OSi | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVII)7) The potassium salt (XIV), immediate precursor of sanfetrinem cilexetil can also be obtained as an enantiomeric mixture by the following sequence: The reduction of 2-oxocyclohexanecarboxylic acid ethyl ester (XXIX) with H2 over PtO2 in ethanol gives a mixture of the cis- and trans-2-hydroxycyclohexane (XXX), which is separated by distillation and treated with tert-butyldimethylsilyl chloride and imidazole in THF to yield cis-2-(tert-butyldimethylsilyloxy)cyclohexanecarboxylic acid ethyl ester (XXXI) as an enantiomeric mixture cis-(S,R)/cis-(R,S) (for the sake of clarity only one of the enantiomers is presented). The reduction of (XXXI) with diisobutylaluminum hydride (DIBAL) in ether affords the corresponding aldehyde (XXXII), which is treated with lithium trimethylsilylamide in THF to give the silylated imine (XXXIII). The cyclization of (XXXIII) with lithium tert-butyl acetate (XXXIV) in THF yields the silylated azetidinone (XXXV), which is deprotected by treatment with tetrabutylammonium fluoride (TBAF) in THF affording the hydroxyazetidinone (XXXVI). The reaction of (XXXVI) with 2,2-dimethoxypropane (XXXVII) and BF3 ethearate in dichloromethane gives the acetonide (XXXVIII), which is condensed with acetyltrimethylsilane (XXXIX) by means of lithium diisopropylamide (LDA) and potassium tert-butoxide (in order to introduce the 1-hydroxyethyl group) yielding the alkylated acetonide (XL). The trimethylsilyl protection of (XL) was removed and substituted with a more stable tert-butyldimethylsilyl (TBS) group affording (XLI), which is treated with pyridine chlorochromate (PCC) to give the previously reported 2-oxocyclohexylazetidinone (XVII) (Scheme 2), but as an enantiomeric mixture. The reaction sequence was continued (XVII) -> (XVIII) -> (XIX) -> (VIII) as in Scheme 2, and (VIII) -> (IX) -> (X) -> (XI) -> potassium salt (XIV) (all the compounds as enantiomeric mixtures). Note that if the starting compound is 2-oxocyclohexane-1(S)-carboxylic acid ethyl ester, instead of the racemic compound (XXIX), the potassium salt (XIV) can be obtained in enantiomerically pure form.
| 【1】 Camerini, R.; Panunzio, M.; Bonanomi, G.; Donati, D.; Perboni, A.; Highly stereocontrolled synthesis of a novel tribactam by reaction of an ester enolate with a N-trimethylsilylimine. Tetrahedron Lett 1996, 37, 14, 2467-70. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 15566 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,3S)-3-methoxy-2-oxocyclohexyl]-2-azetanone | C18H33NO4Si | 详情 | 详情 | |
| (IX) | 15567 | benzyl 2-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-[(1R,3S)-3-methoxy-2-oxocyclohexyl]-4-oxoazetidinyl]-2-oxoacetate | C27H39NO7Si | 详情 | 详情 | |
| (X) | 15568 | benzyl (1S,5S,8aS,8bR)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate | C27H39NO5Si | 详情 | 详情 | |
| (XI) | 15569 | benzyl (1S,5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate | C21H25NO5 | 详情 | 详情 | |
| (XIV) | 15572 | potassium (1S,5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate | C14H18KNO5 | 详情 | 详情 | |
| (XVII) | 15575 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-2-oxocyclohexyl]-2-azetanone | C17H31NO3Si | 详情 | 详情 | |
| (XVIII) | 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 | |
| (XIX) | 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 | |
| (XXIX) | 11889 | ethyl 2-oxocyclohexanecarboxylate; Ethyl 2-cyclohexanonecarboxylate | 1655-07-8 | C9H14O3 | 详情 | 详情 |
| (XXX) | 15589 | ethyl 2-hydroxycyclohexanecarboxylate; Ethyl cis-2-hydroxy-1-cyclohexanecarboxylate | 6149-52-6 | C9H16O3 | 详情 | 详情 |
| (XXXI) | 15590 | ethyl (1S,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]cyclohexanecarboxylate | C15H30O3Si | 详情 | 详情 | |
| (XXXII) | 15591 | (1S,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]cyclohexanecarbaldehyde | C13H26O2Si | 详情 | 详情 | |
| (XXXIII) | 15592 | N-[(E)-((1R,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]cyclohexyl)methylidene](trimethyl)silanamine; N-[(E)-((1R,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]cyclohexyl)methylidene]-N-(trimethylsilyl)amine | C16H35NOSi2 | 详情 | 详情 | |
| (XXXIV) | 15593 | [2-(tert-butoxy)-2-oxoethyl]lithium | C6H11LiO2 | 详情 | 详情 | |
| (XXXV) | 15594 | (4S)-4-((1R,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]cyclohexyl)-2-azetanone | C15H29NO2Si | 详情 | 详情 | |
| (XXXVI) | 15595 | (4S)-4-[(1R,2R)-2-hydroxycyclohexyl]-2-azetanone | C9H15NO2 | 详情 | 详情 | |
| (XXXVII) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XXXVIII) | 15597 | (5aR,9aR,9bS)-4,4-dimethyloctahydro-2H-azeto[1,2-c][1,3]benzoxazin-2-one | C12H19NO2 | 详情 | 详情 | |
| (XXXIX) | 15598 | 1-(trimethylsilyl)-1-ethanone | 13411-48-8 | C5H12OSi | 详情 | 详情 |
| (XL) | 15599 | (1R,5aR,9aR,9bR)-4,4-dimethyl-1-[(1R)-1-methyl-2-(trimethylsilyl)ethyl]octahydro-2H-azeto[1,2-c][1,3]benzoxazin-2-one | C18H33NO2Si | 详情 | 详情 | |
| (XLI) | 15600 | (1S,5aR,9aR,9bR)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4,4-dimethyloctahydro-2H-azeto[1,2-c][1,3]benzoxazin-2-one | C20H37NO3Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)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 |