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【结 构 式】 
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【分子编号】23856 【品名】(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1S)-3-methoxy-2-oxo-3-cyclohexen-1-yl]-2-azetidinone 【CA登记号】 |
【 分 子 式 】C18H31NO4Si 【 分 子 量 】353.53398 【元素组成】C 61.15% H 8.84% N 3.96% O 18.1% Si 7.94% |
合成路线1
该中间体在本合成路线中的序号：(IIIb)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2
该中间体在本合成路线中的序号：(IIIb)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 |