benzyl 2-[4-(benzyloxy)phenyl]-3-chloro-3-oxopropanoate -Drug Synthesis Database

【结构式】

【分子编号】38602

【品名】benzyl 2-[4-(benzyloxy)phenyl]-3-chloro-3-oxopropanoate

【CA登记号】

【分子式】C₂₃H₁₉ClO₄

【分子量】394.85416

【元素组成】C 69.96% H 4.85% Cl 8.98% O 16.21%

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：(XXV)

The reaction of the amino group of (XIX) with 3,5-di-tert-butyl-4-hydroxybenzaldehyde (XX) gives the imine (XXI), which is dehydrogenated with nickel peroxide to the quinomethane (XXII). Addition of methanol to (XXII) yields the 7-alpha-amino compound (XXIII), which is treated with Girard reagent T to afford the 7-beta-amino-7-alpha-methoxyoxacepehem compound (XXIV). The acylation of the NH2 group of (XXIV) with 2-(benzyloxycarbonyl)-2-[4-benzyloxy)phenyl)acetyl chloride (XXV) (obtained by reaction of the corresponding acid (XXVI) with oxalyl chloride) gives the expected amide (XXVII), which is finally deprotected with TFA/anisole or AlCl3/anisole.

参考文献中间体

合成目标

【1】 Narisada, M.; et al.; Synthetic studies on beta-lactam antibiotics. Part 10. Synthesis of 7beta-[2-carboxy-2-(4-hydroxyphenyl)acetamido]-7alpha-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-1-oxa-1-dethia-3-cephem-4-carboxylic acid disodium salt (6059-S) and its related. J Med Chem 1979, 22, 7, 757.
【2】 Nagata, W.; Narisada, M. (Shionogi & Co. Ltd.); Arylmalonamido-1-oxadethiacephalosporins. US 4180571 .
【3】 Narisada, M.; Nagata, W. (Shionogi & Co. Ltd.); Arylmalonamido-1-oxadethiacephalosporins. DE 2713370; US 4138486 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIX)	38597	benzhydryl (6R,7S)-7-amino-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₂₃H₂₂N₆O₄S	详情	详情
(XX)	14875	3,5-Bis(1,1-dimethylethyl)-4-hydroxybenzaldehyde; 3,5-di(tert-butyl)-4-hydroxybenzaldehyde; 3,5-Di-tert-butyl-4-hydroxybenzaldehyde	1620-98-0	C₁₅H₂₂O₂	详情	详情
(XXI)	38598	benzhydryl (6R,7S)-7-([(E)-[3,5-di(tert-butyl)-4-hydroxyphenyl]methylidene]amino)-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₃₈H₄₂N₆O₅S	详情	详情
(XXII)	38599	benzhydryl (6R)-7-([[3,5-di(tert-butyl)-4-oxo-2,5-cyclohexadien-1-ylidene]methyl]imino)-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₃₈H₄₀N₆O₅S	详情	详情
(XXIII)	38600	benzhydryl (6R,7R)-7-([(E)-[3,5-di(tert-butyl)-4-hydroxyphenyl]methylidene]amino)-7-methoxy-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₃₉H₄₄N₆O₆S	详情	详情
(XXIV)	38601	benzhydryl (6R,7R)-7-amino-7-methoxy-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	66510-99-4	C₂₄H₂₄N₆O₅S	详情	详情
(XXV)	38602	benzyl 2-[4-(benzyloxy)phenyl]-3-chloro-3-oxopropanoate		C₂₃H₁₉ClO₄	详情	详情
(XXVI)	38603	3-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-oxopropionic acid		C₂₃H₂₀O₅	详情	详情
(XXVII)	38604	benzhydryl (6R,7R)-7-([3-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-oxopropanoyl]amino)-7-methoxy-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₄₇H₄₂N₆O₉S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

The epoxidation of alpha-(3beta-benzamido-4beta-allyloxy-2-oxoazetidin-1-yl)-alpha-isopropylilideneacetic acid diphenylmethyl ester (I) with a peracid gives the corresponding epoxide in the allyl group (II), which is chlorinated with tert-butyl hypochlorite affording the chloro epoxide (III). The methoxylation of (III) with lithium methoxide yields the 3beta-benzamido-3alpha-methoxy derivative (IV), which is condensed with lithium 1-methyltetrazol-5-ylmercaptide (V) to afford the tetrazol derivative (VI). The oxidation of (VI) with CrO3 affords the ketonic compound (VII), which is debenzoylated by treatment with PCl5, MeOH and triethylamine giving alpha-[3beta-amino-3alpha-methoxy-4beta-[3-(1-methyltetrazol-5-yl)thiomethyl-2-oxopropoxy]-2-oxoazetidine-1-yl]-alpha-isopropylidieneacetic acid diphenylmethyl ester (VIII). The condensation of (VIII) with alpha-(p-benzyloxyphenyl)-alpha-(benzyloxycarbonyl)acetyl chloride (IX) by means of triethylamine affords the 3beta-[alpha-(benzyloxyphenyl)-alpha-(benzyloxycarbonyl)acetamido] derivative (XX).

参考文献中间体

合成目标

【1】 Serradell, M.N.; Blancafort, P.; Castaner, J.; S-6059. Drugs Fut 1979, 4, 9, 667.
【2】 Narisada, M.; Nagata, W. (Shionogi & Co. Ltd.); Arylmalonamido-1-oxadethiacephalosporins. DE 2713370; US 4138486 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	39541	benzhydryl 2-[(2R,3S)-2-(allyloxy)-3-(benzoylamino)-4-oxoazetidinyl]-3-methyl-2-butenoate	C₃₁H₃₀N₂O₅	详情	详情
(II)	39542	benzhydryl 2-[(2R,3S)-3-(benzoylamino)-2-(2-oxiranylmethoxy)-4-oxoazetidinyl]-3-methyl-2-butenoate	C₃₁H₃₀N₂O₆	详情	详情
(III)	39543	benzhydryl 2-[(2R,3R)-3-(benzoylamino)-3-chloro-2-(2-oxiranylmethoxy)-4-oxoazetidinyl]-3-methyl-2-butenoate	C₃₁H₂₉ClN₂O₆	详情	详情
(IV)	39544	benzhydryl 2-[(2R,3R)-3-(benzoylamino)-3-methoxy-2-(2-oxiranylmethoxy)-4-oxoazetidinyl]-3-methyl-2-butenoate	C₃₂H₃₂N₂O₇	详情	详情
(V)	39545		C₂H₄LiN₄S	详情	详情
(VI)	39546	benzhydryl 2-((2R,3R)-3-(benzoylamino)-2-[2-hydroxy-3-[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]propoxy]-3-methoxy-4-oxoazetidinyl)-3-methyl-2-butenoate	C₃₄H₃₆N₆O₇S	详情	详情
(VII)	39547	benzhydryl 2-((2R,3R)-3-(benzoylamino)-3-methoxy-2-[3-[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]-2-oxopropoxy]-4-oxoazetidinyl)-3-methyl-2-butenoate	C₃₄H₃₄N₆O₇S	详情	详情
(VIII)	39548	benzhydryl 2-((2R,3R)-3-amino-3-methoxy-2-[3-[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]-2-oxopropoxy]-4-oxoazetidinyl)-3-methyl-2-butenoate	C₂₇H₃₀N₆O₆S	详情	详情
(IX)	38602	benzyl 2-[4-(benzyloxy)phenyl]-3-chloro-3-oxopropanoate	C₂₃H₁₉ClO₄	详情	详情
(X)	39549	benzhydryl 2-((2R,3R)-3-([3-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-oxopropanoyl]amino)-3-methoxy-2-[3-[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]-2-oxopropoxy]-4-oxoazetidinyl)-3-methyl-2-butenoate	C₅₀H₄₈N₆O₁₀S	详情	详情

Extended Information