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【结 构 式】 
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【分子编号】20031 【品名】(2R,3R)-2-Diazo-4-(3-ethyl-4-oxoazetidin-2-yl)-3-oxobutyric acid 4-nitrobenzyl ester 【CA登记号】 |
【 分 子 式 】C16H16N4O6 【 分 子 量 】360.3264 【元素组成】C 53.33% H 4.48% N 15.55% O 26.64% |
合成路线1
该中间体在本合成路线中的序号：(XI)1) The cyclization of ethyl 3(S)-hydroxybutanoate (I) with N-anisylcinnamylideneamine (II) gives 1-(4-anisyl)-3alpha-[1(S)-hydroxyethyl]-4-(2-phenylvinyl)azetidin-2-one (III), which is esterified with thiocarbonyldiimidazole (IV) yielding the thioester (V). The reduction of (V) with NaBH4 in hot DMSO affords 1-(4-anisyl)-3alpha-ethyl-4-(2-phenylvinyl)azetidin-2-one (VI), which is oxidized with KMnO4 - NaClO4, giving the carboxylic acid (VII). The oxidative decarboxylation of (VII) with lead tetraacetate yields 4-acetoxy-1-(4-anisyl)-3alpha-ethylazetidin-2-one (VIII), which is submitted to dearylation with ammonium cerium (IV) nitrate to afford 4-acetoxy-3alpha-ethylazetidin-2-one (IX). The condensation of (IX) with 4-nitrobenzyl 2-diazo-3-(tert-butyldimethylsilyloxy)-3-butenoate (X) gives the diazo keto ester (XI), which is cyclized yielding 4-nitrobenzyl 6-ethyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (XII). The reaction of (XII) with diphenyl chlorophosphate affords the enol phosphate (XIII), which is condensed with N-acetylcysteamine (XIV) to give 4-nitrobenzyl ester of PS-5 (XV). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C.
| 【1】 Georg, G.I.; Kant, J.; An asymmetric synthesis of carbapenem antibiotic (+)-PS-5 from ethyl 3-hydroxybutanoate. J Org Chem 1988, 53, 3, 692-5. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 | |
| 44204 | N,N-diethyl-2-propanamine; N,N-diethyl-N-isopropylamine | C7H17N | 详情 | 详情 | ||
| (I) | 20021 | (3S)-3-Hydroxybutanoic acid ethyl ester | 56816-01-4 | C6H12O3 | 详情 | 详情 |
| (II) | 20022 | 4-methoxy-N-[(Z,2E)-3-phenyl-2-propenylidene]aniline; N-(4-methoxyphenyl)-N-[(Z,2E)-3-phenyl-2-propenylidene]amine | C16H15NO | 详情 | 详情 | |
| (III) | 20023 | (3S)-3-(1-hydroxyethyl)-1-(4-methoxyphenyl)-4-[(E)-2-phenylethenyl]-2-azetidinone | C20H21NO3 | 详情 | 详情 | |
| (IV) | 11990 | Di(1H-imidazol-1-yl)methanethione; 1,1'-Thiocarbonyldiimidazole | 6160-65-2 | C7H6N4S | 详情 | 详情 |
| (V) | 20025 | O-(1-[(3S)-1-(4-methoxyphenyl)-2-oxo-4-[(E)-2-phenylethenyl]azetidinyl]ethyl) 1H-imidazole-1-carbothioate | C24H23N3O3S | 详情 | 详情 | |
| (VI) | 20026 | (3R)-3-ethyl-1-(4-methoxyphenyl)-4-[(E)-2-phenylethenyl]-2-azetidinone | C20H21NO2 | 详情 | 详情 | |
| (VII) | 20027 | (3R)-3-ethyl-1-(4-methoxyphenyl)-4-oxo-2-azetidinecarboxylic acid | C13H15NO4 | 详情 | 详情 | |
| (VIII) | 20028 | (3R)-3-ethyl-1-(4-methoxyphenyl)-4-oxoazetidinyl acetate | C14H17NO4 | 详情 | 详情 | |
| (IX) | 20029 | (3R)-3-ethyl-4-oxoazetidinyl acetate | C7H11NO3 | 详情 | 详情 | |
| (X) | 20030 | 2-Diazo-3-(tert-butyldimethylsilyloxy)-3-butenoic acid 4-nitrobenzyl ester | C17H23N3O5Si | 详情 | 详情 | |
| (XI) | 20031 | (2R,3R)-2-Diazo-4-(3-ethyl-4-oxoazetidin-2-yl)-3-oxobutyric acid 4-nitrobenzyl ester | C16H16N4O6 | 详情 | 详情 | |
| (XII) | 20032 | 4-nitrobenzyl (5R,6R)-6-ethyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C16H16N2O6 | 详情 | 详情 | |
| (XIII) | 20033 | 4-nitrobenzyl (5R,6R)-3-[(diphenoxyphosphoryl)oxy]-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C28H25N2O9P | 详情 | 详情 | |
| (XIV) | 20034 | N-(2-sulfanylethyl)acetamide | 1190-73-4 | C4H9NOS | 详情 | 详情 |
| (XV) | 20035 | 4-nitrobenzyl (5R,6R)-3-[[2-(acetamido)ethyl]sulfanyl]-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C20H23N3O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)2) The hydroxyethylazetidinone (III) is esterified with p-toluenesulfonyl chloride to the corresponding tosylate (XVI), which is reduced with NaBH4 to the ethylazetidinone (VI), which is oxidized with KMnO4 - NaClO4, giving the carboxylic acid (VII). The oxidative decarboxylation of (VII) with lead tetraacetate yields 4-acetoxy-1-(4-anisyl)-3alpha-ethylazetidin-2-one (VIII), which is submitted to dearylation with ammonium cerium (IV) nitrate to afford 4-acetoxy-3alpha-ethylazetidin-2-one (IX). The condensation of (IX) with 4-nitrobenzyl 2-diazo-3-(tert-butyldimethylsilyloxy)-3-butenoate (X) gives the diazo keto ester (XI), which is cyclized yielding 4-nitrobenzyl 6-ethyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (XII). The reaction of (XII) with diphenyl chlorophosphate affords the enol phosphate (XIII), which is condensed with N-acetylcysteamine (XIV) to give 4-nitrobenzyl ester of PS-5 (XV). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C.
| 【1】 Georg, G.I.; Kant, J.; An asymmetric synthesis of carbapenem antibiotic (+)-PS-5 from ethyl 3-hydroxybutanoate. J Org Chem 1988, 53, 3, 692-5. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 | |
| 44204 | N,N-diethyl-2-propanamine; N,N-diethyl-N-isopropylamine | C7H17N | 详情 | 详情 | ||
| (I) | 20021 | (3S)-3-Hydroxybutanoic acid ethyl ester | 56816-01-4 | C6H12O3 | 详情 | 详情 |
| (II) | 20022 | 4-methoxy-N-[(Z,2E)-3-phenyl-2-propenylidene]aniline; N-(4-methoxyphenyl)-N-[(Z,2E)-3-phenyl-2-propenylidene]amine | C16H15NO | 详情 | 详情 | |
| (III) | 20023 | (3S)-3-(1-hydroxyethyl)-1-(4-methoxyphenyl)-4-[(E)-2-phenylethenyl]-2-azetidinone | C20H21NO3 | 详情 | 详情 | |
| (VI) | 20026 | (3R)-3-ethyl-1-(4-methoxyphenyl)-4-[(E)-2-phenylethenyl]-2-azetidinone | C20H21NO2 | 详情 | 详情 | |
| (VII) | 20027 | (3R)-3-ethyl-1-(4-methoxyphenyl)-4-oxo-2-azetidinecarboxylic acid | C13H15NO4 | 详情 | 详情 | |
| (VIII) | 20028 | (3R)-3-ethyl-1-(4-methoxyphenyl)-4-oxoazetidinyl acetate | C14H17NO4 | 详情 | 详情 | |
| (IX) | 20029 | (3R)-3-ethyl-4-oxoazetidinyl acetate | C7H11NO3 | 详情 | 详情 | |
| (X) | 20030 | 2-Diazo-3-(tert-butyldimethylsilyloxy)-3-butenoic acid 4-nitrobenzyl ester | C17H23N3O5Si | 详情 | 详情 | |
| (XI) | 20031 | (2R,3R)-2-Diazo-4-(3-ethyl-4-oxoazetidin-2-yl)-3-oxobutyric acid 4-nitrobenzyl ester | C16H16N4O6 | 详情 | 详情 | |
| (XII) | 20032 | 4-nitrobenzyl (5R,6R)-6-ethyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C16H16N2O6 | 详情 | 详情 | |
| (XIII) | 20033 | 4-nitrobenzyl (5R,6R)-3-[(diphenoxyphosphoryl)oxy]-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C28H25N2O9P | 详情 | 详情 | |
| (XIV) | 20034 | N-(2-sulfanylethyl)acetamide | 1190-73-4 | C4H9NOS | 详情 | 详情 |
| (XV) | 20035 | 4-nitrobenzyl (5R,6R)-3-[[2-(acetamido)ethyl]sulfanyl]-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C20H23N3O6S | 详情 | 详情 | |
| (XVI) | 20036 | 1-[(3S)-1-(4-methoxyphenyl)-2-oxo-4-[(E)-2-phenylethenyl]azetidinyl]ethyl 4-methylbenzenesulfonate | C27H27NO5S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)3) The reduction of (III) to (VI) can also be performed by treatment of (III) with methanesulfonyl chloride giving mesylate (XVII), which is treated with NaI to yield iodo derivative (XVIII). This compound is reduced to (VI) with NaBH4, which is oxidized with KMnO4 - NaClO4, giving the carboxylic acid (VII). The oxidative decarboxylation of (VII) with lead tetraacetate yields 4-acetoxy-1-(4-anisyl)-3alpha-ethylazetidin-2-one (VIII), which is submitted to dearylation with ammonium cerium (IV) nitrate to afford 4-acetoxy-3alpha-ethylazetidin-2-one (IX). The condensation of (IX) with 4-nitrobenzyl 2-diazo-3-(tert-butyldimethylsilyloxy)-3-butenoate (X) gives the diazo keto ester (XI), which is cyclized yielding 4-nitrobenzyl 6-ethyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (XII). The reaction of (XII) with diphenyl chlorophosphate affords the enol phosphate (XIII), which is condensed with N-acetylcysteamine (XIV) to give 4-nitrobenzyl ester of PS-5 (XV). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C.
| 【1】 Georg, G.I.; Kant, J.; An asymmetric synthesis of carbapenem antibiotic (+)-PS-5 from ethyl 3-hydroxybutanoate. J Org Chem 1988, 53, 3, 692-5. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 | |
| 44204 | N,N-diethyl-2-propanamine; N,N-diethyl-N-isopropylamine | C7H17N | 详情 | 详情 | ||
| (I) | 20021 | (3S)-3-Hydroxybutanoic acid ethyl ester | 56816-01-4 | C6H12O3 | 详情 | 详情 |
| (II) | 20022 | 4-methoxy-N-[(Z,2E)-3-phenyl-2-propenylidene]aniline; N-(4-methoxyphenyl)-N-[(Z,2E)-3-phenyl-2-propenylidene]amine | C16H15NO | 详情 | 详情 | |
| (III) | 20023 | (3S)-3-(1-hydroxyethyl)-1-(4-methoxyphenyl)-4-[(E)-2-phenylethenyl]-2-azetidinone | C20H21NO3 | 详情 | 详情 | |
| (VI) | 20026 | (3R)-3-ethyl-1-(4-methoxyphenyl)-4-[(E)-2-phenylethenyl]-2-azetidinone | C20H21NO2 | 详情 | 详情 | |
| (VII) | 20027 | (3R)-3-ethyl-1-(4-methoxyphenyl)-4-oxo-2-azetidinecarboxylic acid | C13H15NO4 | 详情 | 详情 | |
| (VIII) | 20028 | (3R)-3-ethyl-1-(4-methoxyphenyl)-4-oxoazetidinyl acetate | C14H17NO4 | 详情 | 详情 | |
| (IX) | 20029 | (3R)-3-ethyl-4-oxoazetidinyl acetate | C7H11NO3 | 详情 | 详情 | |
| (X) | 20030 | 2-Diazo-3-(tert-butyldimethylsilyloxy)-3-butenoic acid 4-nitrobenzyl ester | C17H23N3O5Si | 详情 | 详情 | |
| (XI) | 20031 | (2R,3R)-2-Diazo-4-(3-ethyl-4-oxoazetidin-2-yl)-3-oxobutyric acid 4-nitrobenzyl ester | C16H16N4O6 | 详情 | 详情 | |
| (XII) | 20032 | 4-nitrobenzyl (5R,6R)-6-ethyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C16H16N2O6 | 详情 | 详情 | |
| (XIII) | 20033 | 4-nitrobenzyl (5R,6R)-3-[(diphenoxyphosphoryl)oxy]-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C28H25N2O9P | 详情 | 详情 | |
| (XIV) | 20034 | N-(2-sulfanylethyl)acetamide | 1190-73-4 | C4H9NOS | 详情 | 详情 |
| (XV) | 20035 | 4-nitrobenzyl (5R,6R)-3-[[2-(acetamido)ethyl]sulfanyl]-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C20H23N3O6S | 详情 | 详情 | |
| (XVII) | 20037 | (3S)-1-(4-methoxyphenyl)-3-(1-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]ethyl)-4-[(E)-2-phenylethenyl]-2-azetidinone | C23H27NO3S | 详情 | 详情 | |
| (XVIII) | 20038 | (3R)-3-(1-iodoethyl)-1-(4-methoxyphenyl)-4-[(E)-2-phenylethenyl]-2-azetidinone | C20H20INO2 | 详情 | 详情 |