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【结 构 式】 
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【分子编号】16074 【品名】Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate 【CA登记号】2524-64-3 |
【 分 子 式 】C12H10ClO3P 【 分 子 量 】268.636062 【元素组成】C 53.65% H 3.75% Cl 13.2% O 17.87% P 11.53% |
合成路线1
该中间体在本合成路线中的序号：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：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：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 |
合成路线4
该中间体在本合成路线中的序号：4) The reaction of phenyl thiobutyrate (XIX) with 9-borabicyclo[3.3.1]nonane (9-BBN) gives the enol ester (XX), which is condensed with the optically active imine (XXI) [prepared from 3-(trimethylsilyl)propynal (XXIII) and (S)-alpha-methylbenzylamine (XXII)] to afford the adduct (XXIV). The cyclization of (XXIV) by means of tert-butylmagnesium chloride in ether yields 3alpha-ethyl-1-(alpha-methylbenzyl)-4beta-[2-(trimethylsilyl)ethynyl]azetidin-2-one (XXV), which is deprotected with tetrabutylammonium fluoride giving the free acetylene derivative (XXVI). The partial reduction of (XXVI) with H2 over Pd-CaCO3-PbO yields the corresponding ethylene compound (XXVII), which is hydroxylated with disiamylborane (DSB) to give the 2-hydroxyethylazetidinone (XXVIII). The protection of (XXVIII) with tert-butyldimethylsilyl chloride yields the silylated compound (XXIX), which is treated with Na-NH3 to afford 3alpha-ethyl-4beta-[2-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (XXX). The protection of (XXX) with tert-butyldimethylsilyl chloride as before gives the fully silylated compound (XXXI), which is submitted to a controlled hydrolysis yielding 3alpha-ethyl-4beta-(2-hydroxyethyl)-1-(tert-butyldimethylsilyl)azetidin-2-one (XXXII). The oxidation of (XXXII) with CrO3 - pyridine gives the acetic acid derivative (XXXIII), which is deprotected to afford 2-(3alpha-ethyl-2-oxoazetidin-4beta-yl)acetic acid (XXXIV). The reaction of (XXXIV) with carbonyldiimidazole (XXXV) gives the corresponding imidazolide (XXXVI), which is condensed with magnesium 4-nitrobenzyl malonate (XXXVII) yielding 4-nitrobenzyl 4-(3alpha-ethyl-2-oxoazetidin-4beta-yl)-3-oxobutanoate (XXXVIII). The diazotation of (XXXVIII) with 4-azidobenzoic acid (XXXIX) gives the 2-diazo-3-oxobutanoate derivative (XL), which is finally cyclized to carbapen derivative (XII) in the presence of rhodium acetate. 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】 Shibasaki, M.; Ishida, Y.; Iwasaki, G.; Iimori, T.; Asymmetric synthesis of the carbapenem antibiotic (+)-PS-5. J Org Chem 1987, 52, 15, 3488-9. |
| 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 | ||
| (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 | |
| (XIX) | 20039 | S-phenyl butanethioate | C10H12OS | 详情 | 详情 | |
| (XX) | 20040 | (E)-1-(9-borabicyclo[3.3.1]non-9-yloxy)-1-butenyl phenyl sulfide; 9-[[(E)-1-(phenylsulfanyl)-1-butenyl]oxy]-9-borabicyclo[3.3.1]nonane | C18H25BOS | 详情 | 详情 | |
| (XXI) | 20041 | (1S)-1-phenyl-N-[(Z)-3-(trimethylsilyl)-2-propynylidene]-1-ethanamine; N-[(1S)-1-phenylethyl]-N-[(Z)-3-(trimethylsilyl)-2-propynylidene]amine | C14H19NSi | 详情 | 详情 | |
| (XXII) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (XXIII) | 20043 | 3-(trimethylsilyl)-2-propynal | C6H10OSi | 详情 | 详情 | |
| (XXIV) | 20044 | S-phenyl (2R,3S)-2-ethyl-3-[[(1S)-1-phenylethyl]amino]-5-(trimethylsilyl)-4-pentynethioate | C24H31NOSSi | 详情 | 详情 | |
| (XXV) | 20045 | (3R,4S)-3-ethyl-1-[(1S)-1-phenylethyl]-4-[2-(trimethylsilyl)ethynyl]-2-azetidinone | C18H25NOSi | 详情 | 详情 | |
| (XXVI) | 20046 | (3R,4S)-3-ethyl-4-ethynyl-1-[(1S)-1-phenylethyl]-2-azetidinone | C15H17NO | 详情 | 详情 | |
| (XXVII) | 20047 | (3R,4R)-3-ethyl-1-[(1S)-1-phenylethyl]-4-vinyl-2-azetidinone | C15H19NO | 详情 | 详情 | |
| (XXVIII) | 20048 | (3R,4R)-3-ethyl-4-(2-hydroxyethyl)-1-[(1S)-1-phenylethyl]-2-azetidinone | C15H21NO2 | 详情 | 详情 | |
| (XXIX) | 20049 | (3R,4R)-4-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-ethyl-1-[(1S)-1-phenylethyl]-2-azetidinone | C21H35NO2Si | 详情 | 详情 | |
| (XXX) | 20050 | (3R,4R)-4-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-ethyl-2-azetidinone | C13H27NO2Si | 详情 | 详情 | |
| (XXXI) | 20051 | (3R,4R)-1-[tert-butyl(dimethyl)silyl]-4-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-ethyl-2-azetidinone | C19H41NO2Si2 | 详情 | 详情 | |
| (XXXII) | 20052 | (3R,4R)-1-[tert-butyl(dimethyl)silyl]-3-ethyl-4-(2-hydroxyethyl)-2-azetidinone | C13H27NO2Si | 详情 | 详情 | |
| (XXXIII) | 20053 | 2-[(2R,3R)-1-[tert-butyl(dimethyl)silyl]-3-ethyl-4-oxoazetidinyl]acetic acid | C13H25NO3Si | 详情 | 详情 | |
| (XXXIV) | 20054 | 2-[(2R,3R)-3-ethyl-4-oxoazetidinyl]acetic acid | C7H11NO3 | 详情 | 详情 | |
| (XXXV) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (XXXVI) | 20056 | (3R,4R)-3-ethyl-4-[2-(1H-imidazol-1-yl)-2-oxoethyl]-2-azetidinone | C10H13N3O2 | 详情 | 详情 | |
| (XXXVII) | 20057 | Malonic acid monoethyl ester magnesium salt | C20H16MgN2O12 | 详情 | 详情 | |
| (XXXVIII) | 20058 | 4-nitrobenzyl 4-[(2R,3R)-3-ethyl-4-oxoazetidinyl]-3-oxobutanoate | C16H18N2O6 | 详情 | 详情 | |
| (XXXIX) | 20059 | 4-azidobenzoic acid | 6427-66-3 | C7H5N3O2 | 详情 | 详情 |
| (XL) | 20060 | (2R,3R)-2-Diazo-4-(3-ethyl-4-oxoazetidin-2-yl)-3-oxobutyric acid 4-nitrobenzyl ester | C16H16N4O6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The reaction of (3R,5R,6S)-6-(1(R)-hydroxyethyl)-2-oxo-1-carbapenem-3-carboxylic acid p-nitrobenzyl ester (I) with diphenyl chlorophosphate by (II) means of DMAP and DIEA in DMA/dichloromethane gives the enol phosphate (III), which is condensed with 2-aminoethanethiol (IV) in DMA to yield the 2-aminoethylsulfanyl derivative (V). The reaction of (V) with benzyl formimidate (VI) by means of DIEA in DMA affords the intermediate p-nitrobenzyl ester (VII), which is finally hydrogenated with H2 over Pd/C in water/isopropanol/N-methylmorpholine to provide the target Imipemide.
| 【1】 Kumar, Y.; Tewari, N.; Rai, B.P. (Ranbaxy Laboratories Ltd.); Process for the preparation of imipenem. WO 0294828 . |
| 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) | 22686 | 4-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C16H16N2O7 | 详情 | 详情 | |
| (II) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
| (III) | 57095 | 4-nitrobenzyl (5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C28H25N2O10P | 详情 | 详情 | |
| (IV) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (V) | 57096 | 4-nitrobenzyl (5R,6S)-3-[(2-aminoethyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C18H21N3O6S | 详情 | 详情 | |
| (VI) | 57097 | benzyl iminoformate | C8H9NO | 详情 | 详情 | |
| (VII) | 57098 | 4-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-({2-[(iminomethyl)amino]ethyl}sulfanyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C19H22N4O6S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The condensation of (3R,4R)-4-acetoxy-3-[1(R)-(tert-butyldimethylsilylioxy)ethyl)azetidin-2-one (I) with benzyl 2-bromopropionate (II) by means of diethylaluminum chloride in hexane - THF gives the isomeric mixture (III), (IIIa), which is separated by column chrornatography and the correct isomer (III) is treated with tert-butyldimethylsilyl chloride to yield the silylated azetidine (IV). The reductive debenzylation of (IV) with H2 over Pd/C in methanol affords the protected free acid (V), which is condensed with magnesium 4-nitrobenzylmalonate (VI) by means of carbonyldiimidazole (CDI) in hot acetonitrile to give the protected ketoester (VII). Partial hydrolysis of (VII) with HCl in methanol affords the free ketoester (VIII), which is treated with p-toluenesulfonylazide in acetonitrile yielding the diazo compound (IX). The cyclization of (IX) by means of rhodium acetate in refluxing toluene gives 6alpha-[1(R)-hydroxyethyl)-1beta-methyl-2-oxo-1-dethia-1-carba-2-penem-3-car boxylic acid 4-nitrobenzyl ester (X), which is condensed with diphenyl chlorophosphate (XI) by means of diisopropylethylamine in acetonitrile, yielding the enol ester (XII).
| 【1】 Fukasawa, M.; Inoue, T.; Kato, M.; Matsumura, H.; Sunagawa, M. (Sumitomo Pharmaceuticals Co., Ltd.); Thiopyrrolidinyl-beta-lactam derivs.. EP 0126587; ES 8600305; JP 1985001186; JP 1985019787; JP 1991041066; US 4933333; US 4943569; US 5122604 . |
| 【2】 Prous, J.; Castaner, J.; SM-7338. Drugs Fut 1988, 13, 6, 534. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 22568 | benzyl (2S)-2-[(2S,3S)-3-(1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propanoate | C21H33NO4Si | 详情 | 详情 | |
| (I) | 22565 | methyl (2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxo-2-azetidinecarboxylate | C13H25NO4Si | 详情 | 详情 | |
| (II) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
| (II) | 22566 | benzyl 2-bromopropanoate | 3017-53-6 | C10H11BrO2 | 详情 | 详情 |
| (III) | 22567 | benzyl 2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propanoate | C21H33NO4Si | 详情 | 详情 | |
| (IV) | 22569 | benzyl 2-[(2S,3S)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propanoate | C27H47NO4Si2 | 详情 | 详情 | |
| (V) | 22570 | 2-[(2S,3S)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid | C20H41NO4Si2 | 详情 | 详情 | |
| (VI) | 22571 | 3-[(4-nitrobenzyl)oxy]-3-oxopropanoate | C10H8MgNO6 | 详情 | 详情 | |
| (VII) | 22572 | 4-nitrobenzyl 4-[(2R,3S)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-3-oxopentanoate | C29H48N2O7Si2 | 详情 | 详情 | |
| (VIII) | 22573 | 4-nitrobenzyl 4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate | C17H20N2O7 | 详情 | 详情 | |
| (IX) | 30150 | (3S,4R)-3-((1R)-1-Hydroxyethyl)-4[(1R)-1-methyl-3-diazo-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one | 137391-68-5 | C17H18N4O7 | 详情 | 详情 |
| (X) | 22575 | 4-nitrobenzyl (2R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C17H18N2O7 | 详情 | 详情 | |
| (XII) | 22577 | 4-nitrobenzyl (5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C29H27N2O10P | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)The reaction of (1R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylic acid 4-methoxybenzyl ester (I) with diphenyl chlorophosphate (II) and ethyl diisopropylamine in acetonitrile gives the corresponding penem diphenylphosphate (III), which is condensed with 1-(tert-butoxycarbonyl)-2(S)-sulfamoylaminomethyl)pyrrolidine-4(S)-thio l (IV) by means of ethyl diisopropylamine in the same solvent, yielding compound (V), which is finally treated with AlCl3 to eliminate the protecting groups to obtain S-4661.
| 【1】 Sendo, Y.; Kii, M.; Nishitani, Y.; Irie, T.; Nishino, Y. (Shionogi & Co., Ltd.); A production method for sulfamide. EP 0557122 . |
| 【2】 Castaner, J.; Mealy, N.; Rabasseda, X.; S-4661. Drugs Fut 1995, 20, 4, 367. |
| 【3】 Nishitani, Y.; Irie, T.; Nishino, Y. (Shionogi & Co. Ltd.); A pyrrolidylthiocarbapenem derivative. EP 0528678; JP 1993294970; US 5317016 . |
| 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) | 16073 | 4-methoxybenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C18H21NO6 | 详情 | 详情 | |
| (II) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
| (III) | 16075 | 4-methoxybenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C30H30NO9P | 详情 | 详情 | |
| (IV) | 16076 | tert-butyl (2S,4S)-2-[[(aminosulfonyl)amino]methyl]-4-sulfanyltetrahydro-1H-pyrrole-1-carboxylate | C10H21N3O4S2 | 详情 | 详情 | |
| (V) | 16077 | 4-methoxybenzyl (4R,5S,6S)-3-[[(3S,5S)-5-[[(aminosulfonyl)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 | C28H40N4O9S2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XXI)The reaction of 4(R)-hydroxy-L-proline (I) with allyl chloroformate (II) and NaOH gives the protected proline (III), which is esterified with MeOH and sulfuric acid to yield the methyl prolinate (IV). The reaction of (IV) with Ms-Cl and TEA affords the mesylate (V), which is reduced with NaBH4 to provide the prolinol derivative (VI). The Swern oxidation of alcohol (VI) gives the carbaldehyde (VII), which is condensed with the phosphorane (VIII) by means of NaOMe, yielding the acrylate (IX). The reduction of (IX) with DIBAL affords the substituted allyl alcohol (X), which is condensed with phthalimide (XI) by means of PPh3 and DIAD to provide the adduct (XII). The cleavage of the phthalimido group of (XII) with hydrazine gives the amino derivative (XIII), which is treated with Ms-Cl and TEA to yield the sulfonamide (XIV). The reaction of (XIV) with potassium thioacetate affords the acetylsulfanyl pyrrolidine (XV), which is hydrolyzed with HCl to provide the thiol (XVI). The condensation of the thiol (XVI) with the carbapenem derivative (XVII) by means of DIEA gives the protected adduct (XVIII), which is finally treated with Pd(II) and Bu3SnH in order to eliminate the allyl protecting groups. The intermediate carbapenem derivative (XVII) has been obtained from azetidinone (XIX) by known methods as indicated in the scheme.
| 【1】 Kwon, J.W.; Kim, W.B.; Kim, S.H.; Lee, M.G.; DA-1131. Drugs Fut 2001, 26, 11, 1040. |
| 【2】 Shin, H.C.; Kim, J.Y.; Kim, G.W.; Lee, C.W.; Lim, J.I.; Chang, M.S.; Kim, N.S.; Kim, D.S.; Im, W.B.; Rhee, J.K. (Dong-A Pharmaceutical Co., Ltd.); Carbapenem derivs. and processes for preparing the same. WO 9514692 . |
| 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) | 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 |
| (III) | 47730 | (2S,4R)-1-[(allyloxy)carbonyl]-4-hydroxy-2-pyrrolidinecarboxylic acid | C9H13NO5 | 详情 | 详情 | |
| (IV) | 42200 | 1-allyl 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | C10H15NO5 | 详情 | 详情 | |
| (V) | 42201 | 1-allyl 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]-1,2-pyrrolidinedicarboxylate | C11H17NO7S | 详情 | 详情 | |
| (VI) | 42202 | allyl (2S,4R)-2-(hydroxymethyl)-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C10H17NO6S | 详情 | 详情 | |
| (VII) | 49446 | allyl (2S,4R)-2-formyl-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C10H15NO6S | 详情 | 详情 | |
| (VIII) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (IX) | 49447 | allyl (2S,4R)-2-[(E)-3-methoxy-3-oxo-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C13H19NO7S | 详情 | 详情 | |
| (X) | 49448 | allyl (2S,4R)-2-[(E)-3-hydroxy-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C12H19NO6S | 详情 | 详情 | |
| (XI) | 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 |
| (XII) | 49449 | allyl (2S,4R)-2-[(E)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C20H22N2O7S | 详情 | 详情 | |
| (XIII) | 49450 | allyl (2S,4R)-2-[(E)-3-amino-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C12H20N2O5S | 详情 | 详情 | |
| (XIV) | 50598 | allyl (2S,4R)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C13H22N2O7S2 | 详情 | 详情 | |
| (XV) | 49451 | allyl (2S,4S)-4-(acetylsulfanyl)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate | C14H22N2O5S2 | 详情 | 详情 | |
| (XVI) | 49452 | allyl (2S,4S)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C12H20N2O4S2 | 详情 | 详情 | |
| (XVII) | 32617 | allyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C25H26NO8P | 详情 | 详情 | |
| (XVIII) | 49454 | allyl (4R,5S,6S)-3-[((3S,5S)-1-[(allyloxy)carbonyl]-5-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C25H35N3O8S2 | 详情 | 详情 | |
| (XIX) | 11687 | (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (XX) | 50599 | C17H27N3O6Si | 详情 | 详情 | ||
| (XXI) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(III)MK-0826 can be synthesized as follows: The cyclization of 2-diazo-4-[3-(1-hydroxyethyl)-4-oxoazetidin-2-yl]-3-oxopentanoic acid allyl ester (I) by means of rhodium octanoate gives the 2-oxocarbapenam derivative (II), which by reaction with chlorophosphoric acid diphenyl ester (III) and DIEA in acetonitrile yields the enol phosphate (IV). Condensation of (IV) with the sulfanylpyrrolidine (V) by means of DIEA in acetonitrile affords the corresponding addition compound MK-0826 diallyl ester (VI), which is finally deprotected by means of Meldrum's acid and Pd(PPh3)4 in DMF/THF and converted to the sodium salt.
| 【1】 Betts, M.J.; Davies, G.M.; Swain, M.L. (AstraZeneca plc); Carbapenems containing a carboxy substd. phenyl group, processes for their preparation, intermediates and use as antibiotics. EP 0579826; JP 1994506704; US 5478820; US 5652233; US 5856321; WO 9315078 . |
| 【2】 Leeson, P.A.; Rabasseda, X.; Castañer, J.; Sorbera, L.A.; MK-0826. Drugs Fut 2000, 25, 8, 795. |
| 【3】 Houghton, P.; Williams, J.M.; Skerlj, R.; Brands, K.M.J. (Merck & Co., Inc.); Process for synthesizing carbapenem antibiotics. WO 9945010 . |
| 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) | 39645 | allyl (4R)-2-diazo-4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate | C13H17N3O5 | 详情 | 详情 | |
| (II) | 32616 | allyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C13H17NO5 | 详情 | 详情 | |
| (III) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
| (IV) | 32617 | allyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C25H26NO8P | 详情 | 详情 | |
| (V) | 39646 | allyl (2S,4S)-2-([3-[(allyloxy)carbonyl]anilino]carbonyl)-4-sulfanyl-1-pyrrolidinecarboxylate | C19H22N2O5S | 详情 | 详情 | |
| (VI) | 39647 | allyl (4R,5S,6S)-3-[[(3S,5S)-1-[(allyloxy)carbonyl]-5-([3-[(allyloxy)carbonyl]anilino]carbonyl)pyrrolidinyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C32H37N3O9S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XIV)The intermediate, the glucopyranosyl bromide (I) has been obtained as follows: The reaction of 2-(trimethylsilylethyl)-2-amino-2-deoxy-4,6-O-isopropylidene-beta-D-glucopyranoside (VII) with Troc-Cl and NaHCO3 gives the N-protected glucoside (VIII), which is acylated with the tetradecanoic acid (IX) by means of EDC and 4-(1-pyrrolidinyl)pyridine in dichloromethane to yield the 3-O-acylated glucoside (X). The hydrolysis of the isopropylidene group of (X) with AcOH affords the diol (XI), which is selectively protected at the primary OH group with 2,2,2-trichloro-1,1-dimethylethyl chloroformate (XII) in pyridine to provide (XIII). The phosphorylation of the remaining OH group of (XIII) with diphenyl chlorophosphate (XIV) by means of DIEA in dichloromethane gives the phosphoric ester (XV), which is finally desilylated and hydrolyzed with TFA in dichloromethane, and treated with oxalyl bromide in dichloromethane/DMF to furnish the target glucopyranosyl bromide (I).
| 【1】 Johnson, D.A.; Sowell, C.G. (Corixa Corp.); Aminoalkyl glucosamine phosphate cpds. and their use as adjuvants and immunoeffectors. EP 0983286; US 6113918; WO 9850399 . |
| 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) | 38211 | (2R,3R,4R,5S,6R)-2-bromo-5-[(diphenoxyphosphoryl)oxy]-6-([[(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl]oxy]methyl)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]tetrahydro-2H-pyran-4-yl (3R)-3-(decanoyloxy)tetradecanoate | C50H71BrCl6NO14P | 详情 | 详情 | |
| (VII) | 38217 | (4aR,6S,7R,8R,8aS)-7-amino-2,2-dimethyl-6-[2-(trimethylsilyl)ethoxy]hexahydropyrano[3,2-d][1,3]dioxin-8-ol | C14H29NO5Si | 详情 | 详情 | |
| (VIII) | 38218 | 2,2,2-trichloroethyl (4aR,6S,7R,8R,8aS)-8-hydroxy-2,2-dimethyl-6-[2-(trimethylsilyl)ethoxy]hexahydropyrano[3,2-d][1,3]dioxin-7-ylcarbamate | C17H30Cl3NO7Si | 详情 | 详情 | |
| (IX) | 38215 | (3R)-3-(decanoyloxy)tetradecanoic acid | C24H46O4 | 详情 | 详情 | |
| (X) | 38219 | (4aR,6S,7R,8R,8aR)-2,2-dimethyl-7-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]hexahydropyrano[3,2-d][1,3]dioxin-8-yl (3R)-3-(decanoyloxy)tetradecanoate | C41H74Cl3NO10Si | 详情 | 详情 | |
| (XI) | 38220 | (2R,3R,4R,5R,6S)-3-hydroxy-2-(hydroxymethyl)-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]tetrahydro-2H-pyran-4-yl (3R)-3-(decanoyloxy)tetradecanoate | C38H70Cl3NO10Si | 详情 | 详情 | |
| (XII) | 38221 | 1,1,1-trichloro-2-[(chlorocarbonyl)oxy]-2-methylpropane | C5H6Cl4O2 | 详情 | 详情 | |
| (XIII) | 38222 | (2R,3R,4R,5R,6S)-3-hydroxy-2-([[(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl]oxy]methyl)-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]tetrahydro-2H-pyran-4-yl (3R)-3-(decanoyloxy)tetradecanoate | C43H75Cl6NO12Si | 详情 | 详情 | |
| (XIV) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
| (XV) | 38223 | (2R,3R,4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-2-([[(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl]oxy]methyl)-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]tetrahydro-2H-pyran-4-yl (3R)-3-(decanoyloxy)tetradecanoate | C55H84Cl6NO15PSi | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(XIV)The intermediate, the glucopyranosyl bromide (I) has been obtained as follows: The reaction of 2-(trimethylsilylethyl) 2-amino-2-deoxy-4,6-O-isopropylidene-beta-D-glucopyranoside (VII) with Troc-Cl and NaHCO3 gives the N-protected glucoside (VIII), which is acylated with the tetradecanoic acid (IX) by means of EDC and 4-(1-pyrrolidinyl)pyridine in dichloromethane to yield the 3-O-acylated glucoside (X). The hydrolysis of the isopropylidene group of (X) with AcOH affords the diol (XI), which is selectively protected at the primary OH group with 2,2,2-trichloro-1,1-dimethylethyl chloroformate (XII) in pyridine to provide (XIII). The phosphorylation of the remaining OH group of (XIII) with diphenyl chlorophosphate (XIV) by means of DIEA in dichloromethane gives the phosphoric ester (XV), which is finally desilylated and hydrolyzed with TFA in dichloromethane, and treated with oxalyl bromide in dichloromethane/DMF to furnish the target glucopyranosyl bromide (I).
| 【1】 Johnson, D.A.; Sowell, C.G. (Corixa Corp.); Aminoalkyl glucosamine phosphate cpds. and their use as adjuvants and immunoeffectors. EP 0983286; US 6113918; WO 9850399 . |
| 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) | 38211 | (2R,3R,4R,5S,6R)-2-bromo-5-[(diphenoxyphosphoryl)oxy]-6-([[(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl]oxy]methyl)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]tetrahydro-2H-pyran-4-yl (3R)-3-(decanoyloxy)tetradecanoate | C50H71BrCl6NO14P | 详情 | 详情 | |
| (VII) | 38217 | (4aR,6S,7R,8R,8aS)-7-amino-2,2-dimethyl-6-[2-(trimethylsilyl)ethoxy]hexahydropyrano[3,2-d][1,3]dioxin-8-ol | C14H29NO5Si | 详情 | 详情 | |
| (VIII) | 38218 | 2,2,2-trichloroethyl (4aR,6S,7R,8R,8aS)-8-hydroxy-2,2-dimethyl-6-[2-(trimethylsilyl)ethoxy]hexahydropyrano[3,2-d][1,3]dioxin-7-ylcarbamate | C17H30Cl3NO7Si | 详情 | 详情 | |
| (IX) | 38215 | (3R)-3-(decanoyloxy)tetradecanoic acid | C24H46O4 | 详情 | 详情 | |
| (X) | 38219 | (4aR,6S,7R,8R,8aR)-2,2-dimethyl-7-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]hexahydropyrano[3,2-d][1,3]dioxin-8-yl (3R)-3-(decanoyloxy)tetradecanoate | C41H74Cl3NO10Si | 详情 | 详情 | |
| (XI) | 38220 | (2R,3R,4R,5R,6S)-3-hydroxy-2-(hydroxymethyl)-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]tetrahydro-2H-pyran-4-yl (3R)-3-(decanoyloxy)tetradecanoate | C38H70Cl3NO10Si | 详情 | 详情 | |
| (XII) | 38221 | 1,1,1-trichloro-2-[(chlorocarbonyl)oxy]-2-methylpropane | C5H6Cl4O2 | 详情 | 详情 | |
| (XIII) | 38222 | (2R,3R,4R,5R,6S)-3-hydroxy-2-([[(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl]oxy]methyl)-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]tetrahydro-2H-pyran-4-yl (3R)-3-(decanoyloxy)tetradecanoate | C43H75Cl6NO12Si | 详情 | 详情 | |
| (XIV) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
| (XV) | 38223 | (2R,3R,4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-2-([[(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl]oxy]methyl)-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]tetrahydro-2H-pyran-4-yl (3R)-3-(decanoyloxy)tetradecanoate | C55H84Cl6NO15PSi | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(B)Protection of alcohol (I) with TBDMSCl and imidazole gives silyl compound (II) which is N-methylated by means of NaH and MeI and then deprotected with HCl to yield derivative (III). Mesylation of (III) with MsCl in presence of Et3N followed by thioacetylation with AcSK (A) affords thioacetate (IV) which is then hydrolyzed with NaOMe to yield (V). Treatment of (VI) with diphenylphosphoryl chloride (B) and DIEA in acetonitrile yields (VII), which is then condensed with mercaptan (V) by means of DIEA in the same solvent to provide carbapenem (VIII). Deprotection of the carboxyl moiety of (VIII) by hydrogenation with H2 over Pd/C affords carboxylate (IX), which is finally esterified with pivaloyloxymethyl iodide (X) in N,N-dimethylacetamide or DMF.
| 【1】 Miyauchi, M.; Ohya, S.; Kawamoto, I.; Shibayama, T.; Kanno, O.; Synthesis and biological evaluation of new oral carbapenems with 1-methyl-5-oxopyrrolidin-3-ylthio moiety. J Antibiot 1999, 52, 10, 900. |
| 【2】 Kawamoto, I.; Tanaka, T.; Endo, R.; Miyauchi, M.; Iwata, M. (Sankyo Co., Ltd.); 2-(Heterocyclylthio)carbapenem derivs. their preparation and their use as antibiotics. AU 8932386; EP 0337637; EP 0597821; JP 1990028180; JP 1990049783; US 5104867; US 5242914 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
| (A) | 17190 | potassium ethanethioate | 10387-40-3 | C2H3KOS | 详情 | 详情 |
| (I) | 17188 | (S)-4-hydroxy-2-pyrrolidone; (4S)-4-hydroxytetrahydro-2H-pyrrol-2-one; (S)-4-hydroxypyrrolidone | 68108-18-9 | C4H7NO2 | 详情 | 详情 |
| (II) | 41640 | (4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-pyrrolidinone | C10H21NO2Si | 详情 | 详情 | |
| (III) | 41641 | (4S)-4-hydroxy-1-methyl-2-pyrrolidinone | C5H9NO2 | 详情 | 详情 | |
| (IV) | 41642 | S-[(3R)-1-methyl-5-oxopyrrolidinyl] ethanethioate | C7H11NO2S | 详情 | 详情 | |
| (V) | 41643 | (4R)-1-methyl-4-sulfanyl-2-pyrrolidinone | C5H9NOS | 详情 | 详情 | |
| (VI) | 37720 | 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C17H18N2O7 | 详情 | 详情 | |
| (VII) | 13224 | 4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | 90776-59-3 | C29H27N2O10P | 详情 | 详情 |
| (VIII) | 41644 | 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[[(3R)-1-methyl-5-oxopyrrolidinyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C22H25N3O7S | 详情 | 详情 | |
| (IX) | 41645 | sodium (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[[(3R)-1-methyl-5-oxopyrrolidinyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C15H19N2NaO5S | 详情 | 详情 | |
| (X) | 11159 | iodomethyl pivalate | C6H11IO2 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(B)Alcohol (I) is protected with TBDMSCl and imidazole to give silyl compound (II), which is N-methylated by means of NaH and MeI and then deprotected with HCl to yield derivative (III). Mitsunobu reaction of (III) with 4-nitrobenzoic acid in presence of PPh3 and DEAD, followed by ester hydrolysis with K2CO3, provides alcohol (IV). Mesylation of (IV) with MsCl in presence of Et3N, followed by thioacetylation with AcSK (A), affords thioacetate (V), which is then hydrolyzed with NaOMe to yield (VI). Treatment of (VII) with diphenylphosphoryl chloride (B) in CH3CN and DIEA in CH3CN yields (VIII), which is then condensed with mercaptan (VI) by means of DIEA in the same solvent to provide carbapenem (IX). Deprotection of the carboxyl moiety of (IX) by hydrogenation with H2 over Pd/C affords carboxylate (X), which is finally esterified with pivaloyloxymethyl iodide (XI) in N,N-dimethylacetamide or DMF.
| 【1】 Miyauchi, M.; Ohya, S.; Kawamoto, I.; Shibayama, T.; Kanno, O.; Synthesis and biological evaluation of new oral carbapenems with 1-methyl-5-oxopyrrolidin-3-ylthio moiety. J Antibiot 1999, 52, 10, 900. |
| 【2】 Kawamoto, I.; Tanaka, T.; Endo, R.; Miyauchi, M.; Iwata, M. (Sankyo Co., Ltd.); 2-(Heterocyclylthio)carbapenem derivs. their preparation and their use as antibiotics. AU 8932386; EP 0337637; EP 0597821; JP 1990028180; JP 1990049783; US 5104867; US 5242914 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
| (A) | 17190 | potassium ethanethioate | 10387-40-3 | C2H3KOS | 详情 | 详情 |
| (I) | 17188 | (S)-4-hydroxy-2-pyrrolidone; (4S)-4-hydroxytetrahydro-2H-pyrrol-2-one; (S)-4-hydroxypyrrolidone | 68108-18-9 | C4H7NO2 | 详情 | 详情 |
| (II) | 41640 | (4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-pyrrolidinone | C10H21NO2Si | 详情 | 详情 | |
| (III) | 41641 | (4S)-4-hydroxy-1-methyl-2-pyrrolidinone | C5H9NO2 | 详情 | 详情 | |
| (IV) | 41648 | (4R)-4-hydroxy-1-methyl-2-pyrrolidinone | C5H9NO2 | 详情 | 详情 | |
| (V) | 41649 | S-[(3S)-1-methyl-5-oxopyrrolidinyl] ethanethioate | C7H11NO2S | 详情 | 详情 | |
| (VI) | 41650 | (4S)-1-methyl-4-sulfanyl-2-pyrrolidinone | C5H9NOS | 详情 | 详情 | |
| (VII) | 37720 | 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C17H18N2O7 | 详情 | 详情 | |
| (VIII) | 13224 | 4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | 90776-59-3 | C29H27N2O10P | 详情 | 详情 |
| (IX) | 41646 | 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[[(3S)-1-methyl-5-oxopyrrolidinyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C22H25N3O7S | 详情 | 详情 | |
| (X) | 41647 | sodium (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[[(3S)-1-methyl-5-oxopyrrolidinyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C15H19N2NaO5S | 详情 | 详情 | |
| (XI) | 11159 | iodomethyl pivalate | C6H11IO2 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(D)N-Protection of amino alcohol (VI) under Schotten-Baumann conditions with 2,2,2-trichloroethyl chloroformate (B) aforded carbamate (VII). Subsequent esterification of (VII) with acid (II) provided (VIII), which was followed by acetonide hydrolysis to give diol (IX). Selective protection of the primary hydroxyl of (IX) with 1,1-dimethyl-2,2,2-trichloroethyl chloroformate (C) furnished carbonate (X). Further phosphorylation of the free secondary hydroxyl of (X) with diphenylphosphoryl chloride (D) produced phosphate ester (XI). Conversion of the trimethylsily-ethyl glycoside (XI) into the desired glycosyl chloride (XII) was then accomplished by treatment with alpha,alpha-dichloromethyl methyl ether and ZnCl2.
| 【1】 Sowell, C.G.; Johnson, D.A.; Keegan, D.S.; et al.; 3-O-Desacyl monophosphoryl lipid A derivatives: Synthesis and immunostimulant activities. J Med Chem 1999, 42, 22, 4640. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 13664 | 1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate | 17341-93-4 | C3H2Cl4O2 | 详情 | 详情 |
| (D) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
| (II) | 40612 | (3R)-3-(tetradecanoyloxy)tetradecanoic acid | C28H54O4 | 详情 | 详情 | |
| (VI) | 39769 | (4aR,6R,7R,8R,8aS)-7-amino-2,2-dimethyl-6-[2-(trimethylsilyl)ethoxy]hexahydropyrano[3,2-d][1,3]dioxin-8-ol | C14H29NO5Si | 详情 | 详情 | |
| (VII) | 39770 | 2,2,2-trichloroethyl (4aR,6R,7R,8R,8aS)-8-hydroxy-2,2-dimethyl-6-[2-(trimethylsilyl)ethoxy]hexahydropyrano[3,2-d][1,3]dioxin-7-ylcarbamate | C17H30Cl3NO7Si | 详情 | 详情 | |
| (VIII) | 39772 | (4aR,6R,7R,8R,8aR)-2,2-dimethyl-7-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]hexahydropyrano[3,2-d][1,3]dioxin-8-yl (3R)-3-(tetradecanoyloxy)tetradecanoate | C45H82Cl3NO10Si | 详情 | 详情 | |
| (IX) | 39773 | (2R,3R,4R,5R,6R)-3-hydroxy-2-(hydroxymethyl)-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]tetrahydro-2H-pyran-4-yl (3R)-3-(tetradecanoyloxy)tetradecanoate | C42H78Cl3NO10Si | 详情 | 详情 | |
| (X) | 39774 | (2R,3R,4R,5R,6R)-3-hydroxy-2-([[(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl]oxy]methyl)-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]tetrahydro-2H-pyran-4-yl (3R)-3-(tetradecanoyloxy)tetradecanoate | C47H83Cl6NO12Si | 详情 | 详情 | |
| (XI) | 39775 | (2R,3R,4R,5R,6R)-3-[(diphenoxyphosphoryl)oxy]-2-([[(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl]oxy]methyl)-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]tetrahydro-2H-pyran-4-yl (3R)-3-(tetradecanoyloxy)tetradecanoate | C59H92Cl6NO15PSi | 详情 | 详情 | |
| (XII) | 40616 | (2R,3R,4R,5S,6R)-2-chloro-5-[(diphenoxyphosphoryl)oxy]-6-([[(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl]oxy]methyl)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]tetrahydro-2H-pyran-4-yl (3R)-3-(tetradecanoyloxy)tetradecanoate | C54H79Cl7NO14P | 详情 | 详情 | |
| (C) | 38221 | 1,1,1-trichloro-2-[(chlorocarbonyl)oxy]-2-methylpropane | C5H6Cl4O2 | 详情 | 详情 |