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【结 构 式】

【分子编号】15576

【品名】(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1S)-2-cyclohexen-1-yl]-2-azetanone

【CA登记号】

【 分 子 式 】C17H31NO2Si

【 分 子 量 】309.52418

【元素组成】C 65.97% H 10.09% N 4.53% O 10.34% Si 9.07%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(XVIII)

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:(XVIII)

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:(II)

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
Extended Information