allyl (1S,5S,8aS,8bR)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】15586

【品名】allyl (1S,5S,8aS,8bR)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate

【CA登记号】

【分子式】C₂₃H₃₇NO₅Si

【分子量】435.63602

【元素组成】C 63.41% H 8.56% N 3.22% O 18.36% Si 6.45%

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：(XXVII)

6) The condensation of 2-methyl-2-cyclohexen-1-one (XXIV) with the previously described azetidinone (III) by means of lithium diisopropylamide in THF, followed by flash chromatography, gives the enantiomerically pure 3-methoxy-3-cyclohexenylazetidinone (XXV), which by reduction with H2 over Pd/C in ethyl acetate followed by chromatography yields the previously described azetidinone (VIII). The cyclization of (VIII) with allyloxyoxalyl chloride (XXVI) by means of K2CO3 in dichloromethane affords (4S,8S,9R,10S)-1-[1(R)-(tert-butyldimethylsilyloxy)ethyl-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid allyl ester (XXVII), which is treated with tetrabutylammonium fluoride in THF/acetic acid to eliminate the TBS group giving the 1-hydroxyethyl derivative (XXVIII). Finally, this compound is treated with triphenylphosphine and potassium 2-ethylhexanoate to afford the potassium salt (XIV), already described in Scheme 18359601a.

参考文献中间体

合成目标

【1】 Owen, M.R.; et al.; Efficiency by design: Optimisation in process research. Org Process Res Dev 2001, 5, 3, 308.
【2】 Tamburini, B.; Perboni, A.; Rossi, T.; Donati, D.; Andreotti, D.; Gaviraghi, G.; Carlesso, R.; Bismara, C. (Glaxo Wellcome plc); 10-(1-Hydroxyethyl)-11-oxo-1-azatricyclo[7.2.0.0.3,8]undec-2-ene-2-carboxylic acid derivs. AU 9162265; EP 0416953; US 5407931 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	11687	(2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate		C₁₃H₂₅NO₄Si	详情	详情
(VIII)	15566	(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,3S)-3-methoxy-2-oxocyclohexyl]-2-azetanone		C₁₈H₃₃NO₄Si	详情	详情
(XIV)	15572	potassium (1S,5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate		C₁₄H₁₈KNO₅	详情	详情
(XXIV)	15583	2-methoxy-2-cyclohexen-1-one	23740-37-6	C₇H₁₀O₂	详情	详情
(XXV)	15584	(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-3-methoxy-2-oxo-3-cyclohexen-1-yl]-2-azetanone		C₁₈H₃₁NO₄Si	详情	详情
(XXVI)	15585	allyl 2-chloro-2-oxoacetate		C₅H₅ClO₃	详情	详情
(XXVII)	15586	allyl (1S,5S,8aS,8bR)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate		C₂₃H₃₇NO₅Si	详情	详情
(XXVIII)	15587	allyl (1S,5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate		C₁₇H₂₃NO₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

A new synthesis of sanfetrinem has been published: The condensation of (3S,4R)-4-acetoxy-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (I) with 2-methoxy-2-cyclohexen-1-one (II) by means of lithium bis(trimethylsilyl)amide (LHMDA) in THF gives a mixture of diastereomers that are separated by flash chromatography yielding pure enantiomer (III). The hydrogenation of the double bond of (III) with H2 over Pd/C in ethyl acetate affords another mixture of diastereomers that are also separated by flash chromatography giving pure enantiomer (IV). The cyclization of (IV) with allyl acrylate (V) by means of triethylamine yields (4S,8S,9R,10S)-10-[1(R)-hydroxyethyl]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid allyl ester (VI), the silylated allyl ester of sanfetrinem. Finally, this compound is desilylated by treatment with tetrabutylammonium fluoride (TBAF)/acetic acid in THF, and saponified with potassium 2-ethylhexanoate (KEH).

参考文献中间体

合成目标

【1】 Owen, M.R.; et al.; Efficiency by design: Optimisation in process research. Org Process Res Dev 2001, 5, 3, 308.
【2】 Gaviraghi, G.; Marchioro, C.; Di Modugno, E.; Rossi, T.; Perboni, A.; Andreotti, D.; Donati, D.; Synthesis and antibacterial activity of 4- and 8-methoxy trinems. Bioorg Med Chem Lett 1996, 6, 4, 491.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IIIb)	23856	(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1S)-3-methoxy-2-oxo-3-cyclohexen-1-yl]-2-azetidinone		C₁₈H₃₁NO₄Si	详情	详情
(I)	11687	(2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate		C₁₃H₂₅NO₄Si	详情	详情
(II)	15583	2-methoxy-2-cyclohexen-1-one	23740-37-6	C₇H₁₀O₂	详情	详情
(III)	15584	(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-3-methoxy-2-oxo-3-cyclohexen-1-yl]-2-azetanone		C₁₈H₃₁NO₄Si	详情	详情
(IV)	15566	(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,3S)-3-methoxy-2-oxocyclohexyl]-2-azetanone		C₁₈H₃₃NO₄Si	详情	详情
(V)	15585	allyl 2-chloro-2-oxoacetate		C₅H₅ClO₃	详情	详情
(VI)	15586	allyl (1S,5S,8aS,8bR)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate		C₂₃H₃₇NO₅Si	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

A new synthesis of sanfetrinem has been puplished: The condensation of (3S,4R)-4-acetoxy-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (I) with 2-methoxy-2-cyclohexen-1-one (II) by means of lithium bis(trimethylsilyl)amide (LHMDA) in THF gives a mixture of diastereomers that are separated by flash chromatography yielding pure enantiomer (III). The hydrogenation of the double bond of (III) with H2 over Pd/C in ethyl acetate affords another mixture of diastereomers that are also separated by flash chromatography giving pure enantiomer (IV). The cyclization of (IV) with allyl acrylate (V) by means of triethylamine yields (4S,8S,9R,10S)-10-[1(R)-hydroxyethyl]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid allyl ester (VI), the silylated allyl ester of sanfetrinem. Finally, this compound is desilylated by treatment with tetrabutylammonium fluoride (TBAF)/acetic acid in THF, and saponified with potassium 2-ethylhexanoate (KEH).

参考文献中间体

合成目标

【1】 Owen, M.R.; et al.; Efficiency by design: Optimisation in process research. Org Process Res Dev 2001, 5, 3, 308.
【2】 Gaviraghi, G.; Marchioro, C.; Di Modugno, E.; Rossi, T.; Perboni, A.; Andreotti, D.; Donati, D.; Synthesis and antibacterial activity of 4- and 8-methoxy trinems. Bioorg Med Chem Lett 1996, 6, 4, 491.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IIIb)	23856	(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1S)-3-methoxy-2-oxo-3-cyclohexen-1-yl]-2-azetidinone		C₁₈H₃₁NO₄Si	详情	详情
(I)	11687	(2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate		C₁₃H₂₅NO₄Si	详情	详情
(II)	15583	2-methoxy-2-cyclohexen-1-one	23740-37-6	C₇H₁₀O₂	详情	详情
(III)	15584	(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-3-methoxy-2-oxo-3-cyclohexen-1-yl]-2-azetanone		C₁₈H₃₁NO₄Si	详情	详情
(IV)	15566	(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,3S)-3-methoxy-2-oxocyclohexyl]-2-azetanone		C₁₈H₃₃NO₄Si	详情	详情
(V)	15585	allyl 2-chloro-2-oxoacetate		C₅H₅ClO₃	详情	详情
(VI)	15586	allyl (1S,5S,8aS,8bR)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate		C₂₃H₃₇NO₅Si	详情	详情

Extended Information