【结 构 式】 |
【分子编号】15563 【品名】allyl 1-[(2S,3S)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-3-methoxy-2-oxocyclohexanecarboxylate 【CA登记号】 |
【 分 子 式 】C28H51NO6Si2 【 分 子 量 】553.88708 【元素组成】C 60.72% H 9.28% N 2.53% O 17.33% Si 10.14% |
合成路线1
该中间体在本合成路线中的序号:(V)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 |