4-nitrobenzyl 2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]acetate -Drug Synthesis Database

【结构式】

【分子编号】54842

【品名】4-nitrobenzyl 2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]acetate

【CA登记号】

【分子式】C₂₁H₃₂N₂O₆SSi

【分子量】468.64646

【元素组成】C 53.82% H 6.88% N 5.98% O 20.48% S 6.84% Si 5.99%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(IV)

The reaction of azetidinone (I) with sodium methyl mercaptan in acetonitrile gives the methylsulfanyl derivative (II), which is alkylated with para-methoxybenzyl 2-iodoacetate (III) by means of BuLi in THF to yield the azetidine-acetic acid derivative (IV). The acylation of (IV) with 5-azido-2,2-dimethylpentanoyl chloride (V) by means of LiHMDS affords the beta-oxopentanoate (VI), which is desilylated by means of TBAF and AcOH in THF to provide the 1-hydroxyethyl-azetidine (VII). The reaction of (VII) with chlorine or methyl sulphenyl chloride furnishes the chloroazetidine (VIII), which, without isolation, is cyclized by means of TEA in THF to give the precursor (IX). Finally, this compound is submitted to hydrogenation with H2 over Pd/C to provide the target aminoacid.

参考文献中间体

合成目标

【1】 Simpson, I.N.; et al.; Broad-spectrum beta-lactamase inhibitor AM-112: Synthesis and enhancement of the in vitro activity of ceftazidime and piperacillin. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-345.

中间体序号	中间体编号	品名	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)	61726	(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)	61727	5-azido-2,2-dimethylpentanoyl chloride	C₇H₁₂ClN₃O	详情	详情
(VI)	61728	4-nitrobenzyl 7-azido-2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxoheptanoate	C₂₈H₄₃N₅O₇SSi	详情	详情
(VII)	61729	4-nitrobenzyl 7-azido-2-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxoheptanoate	C₂₂H₂₉N₅O₇S	详情	详情
(VIII)	61730	4-nitrobenzyl 7-azido-2-{(3S)-2-chloro-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl}-4,4-dimethyl-3-oxoheptanoate	C₂₁H₂₆ClN₅O₇	详情	详情
(IX)	61731	4-nitrobenzyl (5R,6R)-3-(5-azido-1,1-dimethylpentyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₂₂H₂₇N₅O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

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.

参考文献中间体

合成目标

【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3

该中间体在本合成路线中的序号：(I)

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

Extended Information