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【结 构 式】

【分子编号】15566

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

【CA登记号】

【 分 子 式 】C18H33NO4Si

【 分 子 量 】355.54986

【元素组成】C 60.81% H 9.36% N 3.94% O 18% Si 7.9%

与该中间体有关的原料药合成路线共 7 条

合成路线1

该中间体在本合成路线中的序号:(VIII)

1) The reaction of 2-methoxycyclohexanone (I) with dialkyl carbonate by means of NaH/KH in THF gives 3-methoxy-2-oxocyclohexanecarboxylic acid allyl ester (II), which is condensed with (3R,4R)-4-acetoxy-3-[1(R)-tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (III) by means of NaH in THF yielding the condensation product (IV) as a mixture of the alpha- and beta-stereoisomers at the methoxy group. The protection of the NH group of (IV) with tert-butyldimethylsilyl (TBS) trifluoromethanesulfonate affords the bis-TBS-protected compound (V), which is stereospecifically decarboxylated with palladium acetate, formic acid and triphenylphosphine to the protected azetidinone (VI) also as alpha- and beta-isomers. The selective desilylation of (VI) with tetrabutylammonium fluoride (TBAF) in acetic acid gives the O-protected azetidinone (VII) also as a mixture, which is epimerized by sequential treatments with lithium diisopropylamide (LDA), with ZnBr2 and finally with diethyl malonate to afford the alpha-(S)-epimer (VIII). The acylation of (VIII) with benzyloxalyl chloride and pyridine in dichloromethane gives the N-benzyloxazyl derivative (IX), which is cyclized by means of triethyl phosphite in refluxing xylene yielding (4S,8S,9R,10S)-10-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid benzyl ester (X). The desilylation of (X) with TBAF in THF/acetic acid affords (XI) with a 1-hydroxyethyl group, which is hydrogenated with H2 over Pd/C in dioxane in the presence of 3,3,6,9,9-pentamethyl-2,10-diazabicyclo[4.4.0]dec-1-ene (XII) giving the addition salt (XIII). The treatment of (XIII) with potassium 2-ethylhexanoate yields the corresponding potassium salt (XIV) (1), which is finally esterified with 1-chloroethyl cyclohexyl carbonate (XV) by means of benzyltrimethylammonium chloride in DMF.

1 Owen, M.R.; et al.; Efficiency by design: Optimisation in process research. Org Process Res Dev 2001, 5, 3, 308.
2 Ngo, J.; Castaner, J.; Sanfetrinem cilexetil. Drugs Fut 1996, 21, 12, 1238.
3 Hanessian, S.; Rozema, M.J.; A highly stereoselective and practical total synthesis of the tricyclic beta-lactam antibiotic GV104326 (4-methoxytrinem). J Am Chem Soc 1996, 118, 41, 9884-91.
4 Perboni, A.; Rossi, T.; Gaviraghi, G.; Ursini, A.; Tarzia, G. (Glaxo Wellcome plc); 10(1-Hydroxyethyl-11-oxo-1-azatricyclo[7.2.0.0.3.8]undec-2-ene-2-carboxylic acid esters and a process for preparing thereof. JP 1993502044; US 5587374; WO 9203437 .
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) 15559 2-methoxycyclohexanone 7429-44-9 C7H12O2 详情 详情
(II) 15560 allyl 3-methoxy-2-oxocyclohexanecarboxylate C11H16O4 详情 详情
(III) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(IV) 15562 allyl 1-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl]-3-methoxy-2-oxocyclohexanecarboxylate C22H37NO6Si 详情 详情
(V) 15563 allyl 1-[(2S,3S)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-3-methoxy-2-oxocyclohexanecarboxylate C28H51NO6Si2 详情 详情
(VI) 15564 (3S,4R)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-3-methoxy-2-oxocyclohexyl]-2-azetanone C24H47NO4Si2 详情 详情
(VII) 15565 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-3-methoxy-2-oxocyclohexyl]-2-azetanone C18H33NO4Si 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
(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
(XII) 15570 2,2,4a,7,7-pentamethyl-1,2,3,4,4a,5,6,7-octahydro[1,8]naphthyridine; 3,3,6,9,9-pentamethyl-2,10-diazabicyclo[4.4.0]dec-1-ene 69340-58-5 C13H24N2 详情 详情
(XIII) 15571 (1S,5S,8aS,8bR)-1-(1(R)-Hydroxyethyl)-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[3,1-a]isoindole-4-carboxylic acid 2,2,4a,7,7-pentamethyl-2,3,4,4a,5,6,7,8-octahydro-1,8-naphthyridine salt C27H43N3O5 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
(XV) 15573 1-chloroethyl cyclohexyl carbonate C9H15ClO3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VIII)

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3

该中间体在本合成路线中的序号:(VIII)

6) The condensation of 2-methyl-2-cyclohexen-1-one (XXIV) with the previously described azetidinone (III) by means of lithium diisopropylamide in THF, followed by flash chromatography, gives the enantiomerically pure 3-methoxy-3-cyclohexenylazetidinone (XXV), which by reduction with H2 over Pd/C in ethyl acetate followed by chromatography yields the previously described azetidinone (VIII). The cyclization of (VIII) with allyloxyoxalyl chloride (XXVI) by means of K2CO3 in dichloromethane affords (4S,8S,9R,10S)-1-[1(R)-(tert-butyldimethylsilyloxy)ethyl-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid allyl ester (XXVII), which is treated with tetrabutylammonium fluoride in THF/acetic acid to eliminate the TBS group giving the 1-hydroxyethyl derivative (XXVIII). Finally, this compound is treated with triphenylphosphine and potassium 2-ethylhexanoate to afford the potassium salt (XIV), already described in Scheme 18359601a.

1 Owen, M.R.; et al.; Efficiency by design: Optimisation in process research. Org Process Res Dev 2001, 5, 3, 308.
2 Tamburini, B.; Perboni, A.; Rossi, T.; Donati, D.; Andreotti, D.; Gaviraghi, G.; Carlesso, R.; Bismara, C. (Glaxo Wellcome plc); 10-(1-Hydroxyethyl)-11-oxo-1-azatricyclo[7.2.0.0.3,8]undec-2-ene-2-carboxylic acid derivs. AU 9162265; EP 0416953; US 5407931 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 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
(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
(XXIV) 15583 2-methoxy-2-cyclohexen-1-one 23740-37-6 C7H10O2 详情 详情
(XXV) 15584 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-3-methoxy-2-oxo-3-cyclohexen-1-yl]-2-azetanone C18H31NO4Si 详情 详情
(XXVI) 15585 allyl 2-chloro-2-oxoacetate C5H5ClO3 详情 详情
(XXVII) 15586 allyl (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 C23H37NO5Si 详情 详情
(XXVIII) 15587 allyl (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 C17H23NO5 详情 详情

合成路线4

该中间体在本合成路线中的序号:(VIII)

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5

该中间体在本合成路线中的序号:(VIII)

A new method of synthesis for the key intermediate (3S,4R)-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-4-[3(R)-methoxy-2-ox o-1(R)-cyclohexyl]azetidin-2-one ([VIII] in original monograph) of sanfetrinem has been described: The oxidation of (1S,2S)-2-methoxycyclohexanol (I) with CrO3/H2SO4 in water gives 2(S)-methoxycyclohexanone (II), which is then condensed with the comercially available (3S,4R)-4-acetoxy-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (III) by means of SnCl4 and diisopropylethylamine or triisobutylamine in dichloromethane or chlorobenzene to afford intermediate (VIII) after crystallization of the isomeric mixture.

1 Thomas, R.J.; Marchioro, C.; Zarantonello, P.; Paio, A.; Rossi, T.; Stereoselective synthesis of a key intermediate of sanfetrinem by means of a chelated tin(IV) enolate. J Org Chem 1997, 62, 6, 1653.
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) 15579 (1S,2S)-2-methoxycyclohexanol 7429-40-5 C7H14O2 详情 详情
(II) 15581 (2S)-2-methoxycyclohexanone C7H12O2 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

合成路线6

该中间体在本合成路线中的序号:(IV)

A new synthesis of sanfetrinem has been published: The condensation of (3S,4R)-4-acetoxy-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (I) with 2-methoxy-2-cyclohexen-1-one (II) by means of lithium bis(trimethylsilyl)amide (LHMDA) in THF gives a mixture of diastereomers that are separated by flash chromatography yielding pure enantiomer (III). The hydrogenation of the double bond of (III) with H2 over Pd/C in ethyl acetate affords another mixture of diastereomers that are also separated by flash chromatography giving pure enantiomer (IV). The cyclization of (IV) with allyl acrylate (V) by means of triethylamine yields (4S,8S,9R,10S)-10-[1(R)-hydroxyethyl]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid allyl ester (VI), the silylated allyl ester of sanfetrinem. Finally, this compound is desilylated by treatment with tetrabutylammonium fluoride (TBAF)/acetic acid in THF, and saponified with potassium 2-ethylhexanoate (KEH).

1 Owen, M.R.; et al.; Efficiency by design: Optimisation in process research. Org Process Res Dev 2001, 5, 3, 308.
2 Gaviraghi, G.; Marchioro, C.; Di Modugno, E.; Rossi, T.; Perboni, A.; Andreotti, D.; Donati, D.; Synthesis and antibacterial activity of 4- and 8-methoxy trinems. Bioorg Med Chem Lett 1996, 6, 4, 491.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IIIb) 23856 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1S)-3-methoxy-2-oxo-3-cyclohexen-1-yl]-2-azetidinone C18H31NO4Si 详情 详情
(I) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(II) 15583 2-methoxy-2-cyclohexen-1-one 23740-37-6 C7H10O2 详情 详情
(III) 15584 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-3-methoxy-2-oxo-3-cyclohexen-1-yl]-2-azetanone C18H31NO4Si 详情 详情
(IV) 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
(V) 15585 allyl 2-chloro-2-oxoacetate C5H5ClO3 详情 详情
(VI) 15586 allyl (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 C23H37NO5Si 详情 详情

合成路线7

该中间体在本合成路线中的序号:(IV)

A new synthesis of sanfetrinem has been puplished: The condensation of (3S,4R)-4-acetoxy-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (I) with 2-methoxy-2-cyclohexen-1-one (II) by means of lithium bis(trimethylsilyl)amide (LHMDA) in THF gives a mixture of diastereomers that are separated by flash chromatography yielding pure enantiomer (III). The hydrogenation of the double bond of (III) with H2 over Pd/C in ethyl acetate affords another mixture of diastereomers that are also separated by flash chromatography giving pure enantiomer (IV). The cyclization of (IV) with allyl acrylate (V) by means of triethylamine yields (4S,8S,9R,10S)-10-[1(R)-hydroxyethyl]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid allyl ester (VI), the silylated allyl ester of sanfetrinem. Finally, this compound is desilylated by treatment with tetrabutylammonium fluoride (TBAF)/acetic acid in THF, and saponified with potassium 2-ethylhexanoate (KEH).

1 Owen, M.R.; et al.; Efficiency by design: Optimisation in process research. Org Process Res Dev 2001, 5, 3, 308.
2 Gaviraghi, G.; Marchioro, C.; Di Modugno, E.; Rossi, T.; Perboni, A.; Andreotti, D.; Donati, D.; Synthesis and antibacterial activity of 4- and 8-methoxy trinems. Bioorg Med Chem Lett 1996, 6, 4, 491.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IIIb) 23856 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1S)-3-methoxy-2-oxo-3-cyclohexen-1-yl]-2-azetidinone C18H31NO4Si 详情 详情
(I) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(II) 15583 2-methoxy-2-cyclohexen-1-one 23740-37-6 C7H10O2 详情 详情
(III) 15584 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-3-methoxy-2-oxo-3-cyclohexen-1-yl]-2-azetanone C18H31NO4Si 详情 详情
(IV) 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
(V) 15585 allyl 2-chloro-2-oxoacetate C5H5ClO3 详情 详情
(VI) 15586 allyl (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 C23H37NO5Si 详情 详情
Extended Information