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【结 构 式】 
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【药物名称】Imipenem, Imipemide(former USAN), MK-0787, Tienam 【化学名称】[5R-[5alpha,6alpha(R*)]]-6-(1-Hydroxyethyl)-3-[[2-[(iminomethyl)amino]ethyl]thio]-7-oxo-1-azabicyclo[3.2.O]hept-2-ene-2-carboxylic acid monohydrate 【CA登记号】74431-23-5, 64221-86-9 (anhydrous) 【 分 子 式 】C12H19N3O5S 【 分 子 量 】317.36633 |
【开发单位】Merck & Co. (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Carbapenems |
合成路线1
The condensation of 7-oxo-6-(1-hydroxyethyl)-3-(diphenoxyphosphate)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitrophenyl ester (I) with the bis(trimethylsilyl) derivative of 2-(iminomethylamino)ethanethiol (II) in the presence of base gives p-nitrophenyl ester of MK-0787, protected with a trimethylsilyl group (III), which is finally deprotected by hydrogenolysis.
| 【1】 Reamer, R.a.; Sletzinger, M.; Hartner, F.W.; Liu, T.; Shinkai, I.; A direct transformation of bicyclic keto esters to N-formimidoyl thienamycin. Tetrahedron Lett 1982, 23, 47, 4903. |
| 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) | 30377 | 4-nitrophenyl (5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C27H23N2O10P | 详情 | 详情 | |
| (II) | 30378 | N'-(trimethylsilyl)-N-[2-[(trimethylsilyl)sulfanyl]ethyl]iminoformamide | C9H24N2SSi2 | 详情 | 详情 | |
| (III) | 30379 | 4-nitrophenyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[2-([[(trimethylsilyl)imino]methyl]amino)ethyl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C21H28N4O6SSi | 详情 | 详情 |
合成路线2
By reaction of thienamycin (I) with methyl formimidate (II) by means of NaOH in water.
| 【1】 Christensen, B.G.; et al. (Merck & Co., Inc.); Derivatives of thienamycin and its isomers. DE 2652679; FR 2332012; GB 1570990; NL 7612939 . |
| 【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; MK-0787. Drugs Fut 1980, 5, 3, 136. |
合成路线3
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 |