替比培南匹伏酯的合成工艺研究

Improved synthesis of tebipenem pivoxil

目的改进替比培南匹伏酯的合成工艺,提高反应收率及产品纯度,以适合工业化生产。方法以培南类抗生素β-内酰胺母核6-MAP为起始原料,与替比培南侧链(3S,4S)-1-羧甲基-4-[(1R)-1-(对氯苯硫羰基)乙基]-3-[(1R)-1-羟乙基]-2-氧氮杂环丁酮缩合,催化氢化脱除对硝基苄基保护基后,再与特戊酸碘甲酯进行酯化,精制后得到终产品替比培南匹伏酯。结果与结论目标化合物替比培南匹伏酯经MS、1H-NNR和13C-NM R进行结构确证,总收率达到36. 3%,终产品纯度大于99. 8%,该工艺可操作性高,适合工业化生产。

Tebipenem pivoxil is a new oral carbapenem broad-spectrum antibiotics developed by Wyeth Rieter Company. Based on the literatures and patents,a synthetic route of tebipenem pivoxil was established and optimized thoroughly. Starting from 4-nitrobenzyl ( 4R,5R,6S) -3-( ( diphenoxyphosphoryl) oxy ) 6- ( ( R) -1-hydroxyethyl) -4-methyl-7-oxo-1-azabicyclo[3. 2. 0]hept-2-ene-2-carboxylate ( 6-MAP) ,and 1- ( 4,5-dihydrothiazol-2-yl ) azetidine-3-thiol hydrochloride,tebipenem pivoxil was synthesized via condensation,hydrogenative deprotection,esterification and recrystallization reaction. The total yield was 35. 3%( calculated by 6-MAP) and the purity of the final production was 99. 87%. The structure of tebipenem pivoxil was confirmed by MS,1H-NMR and 13C-NMR,and the structure of some intermediates were confirmed by MS and 1H-NMR. The purity of compounds were determined by HPLC.