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 -Drug Synthesis Database

【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 合成路线2

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.

参考文献中间体

合成目标

【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.

参考文献中间体

合成目标

【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