benzhydryl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】16100

【品名】benzhydryl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

【CA登记号】

【分子式】C₃₅H₃₂NO₈P

【分子量】625.614782

【元素组成】C 67.2% H 5.16% N 2.24% O 20.46% P 4.95%

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：(VIII)

A new synthesis of S-4661 has been reported: The protection of trans-4-hydroxy-L-proline with tert-butoxycarbonyl anhydride gives N-(tert-butoxycarbonyl)-4(R)-hydroxy-L-proline (II), which is successively treated with ethyl chloroformate, mesylated with mesyl chloride and reduced with NaBH4 yielding (2S,4R)-1-(tert-butoxycarbonyl)-2-(hydroxymethyl)-4-(methanesulfonyloxy)pyrrolidine (III). The reaction of (III) with potassium thioacetate affords Compound (IV), which is condensed with N-(tert-butoxycarbonyl)sulfamide (V) by means of diethyl azodicarboxylate and triphenylphosphine to give the protected pyrrolidinesulfamide (VI). The deacetylation of (VI) with sodium methoxide yields (2S,4S)-1-(tert-butoxycarbonyl)-2-[N-(tert-butoxycarbonyl)-N-sulfamoylaminomethyl]-4-sulfanylpyrrolidine (VII), which is then condensed with (1R,5S,6S)-2-(diphenoxyphosphoryloxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid diphenylmethyl ester (VIII) by means of diisopropylethylamine to afford the protected final product (IX). Finally, this compound is deprotected with AlCl3 in anisole.

参考文献中间体

合成目标

【1】 Motokawa, K.; Nishitani, Y.; Iso, Y.; Kii, M.; Irie, T.; Sendo, Y.; Iwaki, T.; Synthesis and modification of a novel 1beta-methyl carbapenem antibiotic, S-4661. J Antibiot 1996, 49, 5, 478.

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)	14489	(2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline	51-35-4	C₅H₉NO₃	详情	详情
(II)	16094	(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid;1-(tert-butoxycarbonyl)-4®-hydroxy-L-proline;(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid	16094	C₁₀H₁₇NO₅	详情	详情
(III)	16095	tert-butyl (2S,4R)-2-(hydroxymethyl)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1-carboxylate		C₁₁H₂₁NO₆S	详情	详情
(IV)	16096	tert-butyl (2S,4S)-4-(acetylsulfanyl)-2-(hydroxymethyl)tetrahydro-1H-pyrrole-1-carboxylate		C₁₂H₂₁NO₄S	详情	详情
(V)	16097	tert-butyl 2,2-dioxo-2lambda(6)-diazathiane-1-carboxylate	148017-28-1	C₅H₁₂N₂O₄S	详情	详情
(VI)	16098	tert-butyl (2S,4S)-4-(acetylsulfanyl)-2-[[(aminosulfonyl)(tert-butoxycarbonyl)amino]methyl]tetrahydro-1H-pyrrole-1-carboxylate		C₁₇H₃₁N₃O₇S₂	详情	详情
(VII)	16099	tert-butyl (2S,4S)-2-[[(aminosulfonyl)(tert-butoxycarbonyl)amino]methyl]-4-sulfanyltetrahydro-1H-pyrrole-1-carboxylate		C₁₅H₂₉N₃O₆S₂	详情	详情
(VIII)	16100	benzhydryl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₃₅H₃₂NO₈P	详情	详情
(IX)	16101	benzhydryl (4R,5S,6S)-3-[[(3S,5S)-5-[[(aminosulfonyl)(tert-butoxycarbonyl)amino]methyl]-1-(tert-butoxycarbonyl)pyrrolidinyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₃₈H₅₀N₄O₁₀S₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

参考文献中间体

合成目标

【1】 Zhang AY, Zhu XY, Yuan ZD.2006.Synthesis of doripenem. Chin J Pharmaceuticals, 37: 361～363

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(III)	67084	(4S)-1-tert-butyl 2-methyl 4-((methylsulfonyl)oxy)pyrrolidine-1,2-dicarboxylate	C₁₂H₂₁NO₇S	详情	详情
(I)	67082	(4S)-4-hydroxypyrrolidine-2-carboxylic acid	C₅H₉NO₃	详情	详情
(II)	67083	(4S)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride	C₆H₁₁NO₃.HCl	详情	详情
(IV)	16095	tert-butyl (2S,4R)-2-(hydroxymethyl)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1-carboxylate	C₁₁H₂₁NO₆S	详情	详情
(V)	16096	tert-butyl (2S,4S)-4-(acetylsulfanyl)-2-(hydroxymethyl)tetrahydro-1H-pyrrole-1-carboxylate	C₁₂H₂₁NO₄S	详情	详情
(VI)	16098	tert-butyl (2S,4S)-4-(acetylsulfanyl)-2-[[(aminosulfonyl)(tert-butoxycarbonyl)amino]methyl]tetrahydro-1H-pyrrole-1-carboxylate	C₁₇H₃₁N₃O₇S₂	详情	详情
(VII)	16099	tert-butyl (2S,4S)-2-[[(aminosulfonyl)(tert-butoxycarbonyl)amino]methyl]-4-sulfanyltetrahydro-1H-pyrrole-1-carboxylate	C₁₅H₂₉N₃O₆S₂	详情	详情
(VIII)	16100	benzhydryl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₃₅H₃₂NO₈P	详情	详情
(IX)	16101	benzhydryl (4R,5S,6S)-3-[[(3S,5S)-5-[[(aminosulfonyl)(tert-butoxycarbonyl)amino]methyl]-1-(tert-butoxycarbonyl)pyrrolidinyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₃₈H₅₀N₄O₁₀S₂	详情	详情
(X)	67085	4-nitrobenzyl 6-(1-hydroxyethyl)-4-methyl-7-oxo-3-((5-((sulfamoylamino)methyl)pyrrolidin-3-yl)thio)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₂₂H₂₉N₅O₈S₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

参考文献中间体

合成目标

【1】 Xu DY, Tang Y, Zhou WC, et al.2007. Preparation of pyrrolidine derivatives as doripenem intermediates. CN 1896057 A.

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)	67093	4-Nitrobenzyl alcohol;p-Nitrobenzyl alcohol	619-73-8	C₇H₇NO₃	详情	详情
(II)	67094	4-nitrobenzyl 2-sulfamoylacetate		C₉H₁₀N₂O₆S	详情	详情
(III)	67095	4-nitrobenzyl 4-(acetylthio)-2-(hydroxymethyl)pyrrolidine-1-carboxylate		C₁₅H₁₈N₂O₆S	详情	详情
(IV)	67096	4-nitrobenzyl 4-(acetylthio)-2-(((((4-nitrobenzyl)oxy)carbonyl)(sulfamoyl)amino)methyl)pyrrolidine-1-carboxylate		C₂₃H₂₅N₅O₁₁S₂	详情	详情
(V)	67097	4-nitrobenzyl 4-mercapto-2-(((((4-nitrobenzyl)oxy)carbonyl)(sulfamoyl)amino)methyl)pyrrolidine-1-carboxylate		C₂₁H₂₃N₅O₁₀S₂	详情	详情
(VI)	16100	benzhydryl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₃₅H₃₂NO₈P	详情	详情
(VII)	67098	nitro(phenyl)methyl 6-(1-hydroxyethyl)-4-methyl-3-((1-(((4-nitrobenzyl)oxy)carbonyl)-5-(((((4-nitrobenzyl)oxy)carbonyl)(sulfamoyl)amino)methyl)pyrrolidin-3-yl)thio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₃₈H₃₉N₇O₁₆S₂	详情	详情

Extended Information