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【结 构 式】 
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【分子编号】15568 【品名】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 【CA登记号】 |
【 分 子 式 】C27H39NO5Si 【 分 子 量 】485.6959 【元素组成】C 66.77% H 8.09% N 2.88% O 16.47% Si 5.78% |
合成路线1
该中间体在本合成路线中的序号：(X)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：(X)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 |