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【结 构 式】 
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【分子编号】54843 【品名】4-nitrobenzyl 2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxopentanoate 【CA登记号】 |
【 分 子 式 】C26H40N2O7SSi 【 分 子 量 】552.76438 【元素组成】C 56.5% H 7.29% N 5.07% O 20.26% S 5.8% Si 5.08% |
合成路线1
该中间体在本合成路线中的序号：(VI)Azetidinone acetate (I) was treated with sodium methanethiolate to produce thioether (II). Lactam (II) N-alkylation with p-nitrobenzyl iodoacetate (III) furnished the azetidineacetate (IV). The lithium enolate of ester (IV) was subsequently acylated with pivaloyl chloride (V) at low temperature to afford keto ester (VI). The silyl protecting group of (VI) was then removed by treatment with tetrabutylammonium fluoride, yielding alcohol (VII). Chlorination of (VII) with concomitant oxidative cleavage of the methylthio group at -78 C gave rise to the chloroazetidine (VIII). Cyclization of (VIII) to the key oxapenem bicyclic system was accomplished by treatment with triethylamine in cold THF. Chromatographic separation of the resultant mixture of cis/trans bicyclic compounds afforded the desired isomer (IX). After hydrogenolysis of the p-nitrobenzyl ester group of (IX), the resultant carboxylic acid was converted to the required potassium salt by treatment with aqueous potassium bicarbonate.
| 【1】 Pfaendler, H.R.; Weisner, F.; Synthesis and antibacterial activity of 1'R,5R,6R)-2-tert-butyl-6-(1'hydroxyethyl)oxapenem-3-carboxylic acid. Bioorg Med Chem Lett 1993, 3, 11, 2211. |
| 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) | 54840 | (3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(methylsulfanyl)-2-azetidinone | C12H25NO2SSi | 详情 | 详情 | |
| (III) | 54841 | 4-nitrobenzyl 2-iodoacetate | C9H8INO4 | 详情 | 详情 | |
| (IV) | 54842 | 4-nitrobenzyl 2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]acetate | C21H32N2O6SSi | 详情 | 详情 | |
| (V) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (VI) | 54843 | 4-nitrobenzyl 2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxopentanoate | C26H40N2O7SSi | 详情 | 详情 | |
| (VII) | 54844 | 4-nitrobenzyl 2-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxopentanoate | C20H26N2O7S | 详情 | 详情 | |
| (VIII) | 54845 | 4-nitrobenzyl 2-{(2R,3S)-2-chloro-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl}-4,4-dimethyl-3-oxopentanoate | C19H23ClN2O7 | 详情 | 详情 | |
| (IX) | 54846 | 4-nitrobenzyl 2-{(2S,3S)-2-chloro-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl}-4,4-dimethyl-3-oxopentanoate | C19H23ClN2O7 | 详情 | 详情 | |
| (X) | 54847 | 4-nitrobenzyl (5R,6R)-3-(tert-butyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C19H22N2O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The title compound has been prepared starting from the known azetidinone (I). The lithium enolate of ester (I) was acylated with pivaloyl chloride (II) at low temperature to afford keto ester (III). The silyl protecting group of (III) was then removed by treatment with tetrabutylammonium fluoride, yielding alcohol (IV). Inversion of the configuration of alcohol (IV) was accomplished by Mitsunobu coupling with formic acid to produce the formate ester (V), which was subsequently hydrolyzed to the desired alcohol (VI) under acidic conditions. Protection of alcohol (VI) with p-nitrobenzyl chloroformate (VII) gave carbonate (VIII). Chlorination of (VIII) with concomitant oxidative cleavage of the methylthio group at -40 C led to the chloroazetidine (IX). Cyclization of (IX) to the key oxapenem bicyclic system (X) was then performed by treatment with potassium tert-butoxide in cold t-BuOH/THF.
| 【1】 Pfaendler, H.R. (Eli Lilly and Company); (1'S)-Hydroxyalkyloxapenem-3-carboxylic acids and their use as beta-lactamase inhibitors. DE 4142423; EP 0548790 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IXa) | 54851 | 4-nitrobenzyl 2-{(2R,3S)-2-chloro-3-[(1S)-1-({[(4-nitrobenzyl)oxy]carbonyl}oxy)ethyl]-4-oxoazetidinyl}-4,4-dimethyl-3-oxopentanoate | C27H28ClN3O11 | 详情 | 详情 | |
| (IXb) | 54852 | 4-nitrobenzyl 2-{(2S,3S)-2-chloro-3-[(1S)-1-({[(4-nitrobenzyl)oxy]carbonyl}oxy)ethyl]-4-oxoazetidinyl}-4,4-dimethyl-3-oxopentanoate | C27H28ClN3O11 | 详情 | 详情 | |
| (Xa) | 54853 | 4-nitrobenzyl (5R,6R)-3-(tert-butyl)-6-[(1S)-1-({[(4-nitrobenzyl)oxy]carbonyl}oxy)ethyl]-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C27H27N3O11 | 详情 | 详情 | |
| (Xb) | 54854 | 4-nitrobenzyl (5S,6R)-3-(tert-butyl)-6-[(1S)-1-({[(4-nitrobenzyl)oxy]carbonyl}oxy)ethyl]-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C27H27N3O11 | 详情 | 详情 | |
| (I) | 54842 | 4-nitrobenzyl 2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]acetate | C21H32N2O6SSi | 详情 | 详情 | |
| (II) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (III) | 54843 | 4-nitrobenzyl 2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxopentanoate | C26H40N2O7SSi | 详情 | 详情 | |
| (IV) | 54844 | 4-nitrobenzyl 2-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxopentanoate | C20H26N2O7S | 详情 | 详情 | |
| (V) | 54848 | 4-nitrobenzyl 2-[(2R,3S)-3-[(1S)-1-(formyloxy)ethyl]-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxopentanoate | C21H26N2O8S | 详情 | 详情 | |
| (VI) | 54849 | 4-nitrobenzyl 2-[(2R,3S)-3-[(1S)-1-hydroxyethyl]-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxopentanoate | C20H26N2O7S | 详情 | 详情 | |
| (VII) | 33055 | 1-[[(chlorocarbonyl)oxy]methyl]-4-nitrobenzene | 4457-32-3 | C8H6ClNO4 | 详情 | 详情 |
| (VIII) | 54850 | 4-nitrobenzyl 4,4-dimethyl-2-{(2R,3S)-2-(methylsulfanyl)-3-[(1S)-1-({[(4-nitrobenzyl)oxy]carbonyl}oxy)ethyl]-4-oxoazetidinyl}-3-oxopentanoate | C28H31N3O11S | 详情 | 详情 |