XOB, AM-114, -Drug Synthesis Database

【结构式】

【药物名称】XOB, AM-114

【化学名称】(5R,6R)-2-tert-Butyl-6-[1(S)-hydroxyethyl]-1-oxa-2-penem-3-carboxylic acid potassium salt

【CA登记号】150407-29-7, 150407-34-4 (diastereomer), 155899-36-8 (diastereomer)

【分子式】C₁₂H₁₆KNO₅

【分子量】293.36702

【开发单位】Amura (Originator)

【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, beta-Lactam Enhancers, beta-Lactamase Inhibitors, Penems

合成路线1 合成路线2 合成路线3

合成路线1

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

【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

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

【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

合成路线3

In an alternative route, intermediate (VI) was prepared from the previously reported azetidinone (XIII), possessing the adequate alcohol group configuration. Displacement of the acetoxy group of (XIII) with sodium methanethiolate gave sulfide (XIV). The azetidinone N was then alkylated with p-nitrobenzyl iodoacetate (XV) to afford azetidineacetate (XVI). Acylation of the lithium enolate of ester (XVI) by pivaloyl chloride (II) provided keto ester (XVII). Intermediate (VI) was then obtained by desilylation of (XVII) with tetrabutylammonium fluoride.

参考文献中间体

【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
(II)	13597	2,2-Dimethylpropanoyl chloride; Pivaloyl chloride	3282-30-2	C₅H₉ClO	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
(XIII)	54855	(2R,3R)-3-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidinyl acetate		C₁₃H₂₅NO₄Si	详情	详情
(XIV)	54856	(3S,4R)-3-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(methylsulfanyl)-2-azetidinone		C₁₂H₂₅NO₂SSi	详情	详情
(XV)	54841	4-nitrobenzyl 2-iodoacetate		C₉H₈INO₄	详情	详情
(XVI)	54857	4-nitrobenzyl 2-[(2R,3S)-3-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]acetate		C₂₁H₃₂N₂O₆SSi	详情	详情
(XVII)	54858	4-nitrobenzyl 2-[(2R,3S)-3-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxopentanoate		C₂₆H₄₀N₂O₇SSi	详情	详情

Extended Information