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【结 构 式】

【分子编号】54853

【品名】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

【CA登记号】

【 分 子 式 】C27H27N3O11

【 分 子 量 】569.525

【元素组成】C 56.94% H 4.78% N 7.38% O 30.9%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(Xa)

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

合成路线2

该中间体在本合成路线中的序号:(Xa),(XI)

The cis/trans mixture of bicyclic compounds (X) was separated either by column chromatography at low temperature or by fractional crystallization. The desired isomer (XI) was then subjected to catalytic hydrogenolysis of the p-nitrobenzyl ester groups, and the resultant carboxylic acid was then converted to the title potassium salt upon treatment with aqueous potassium bicarbonate. Recycling of the undesired isomer (XII) was possible because of slow isomerization of an EtOAc solution of (XII) at room temperature.

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
(Xa),(XI) 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),(XII) 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
Extended Information