多尼培南一水合物合成工艺改进  

Process Improvement of Doripenem Hydrate

作　　者：白文钦 宋传玲 肖友亮 唐贞波 张贵民 BAI Wenqin;SONG Chuanling;XIAO Youliang;TANG Zhenbo;ZHANG Guimin(National Chiral Pharmaceuticals Engineering and Technology Research Center, Lunan Pharmaceutical Group Co., Ltd., Linyi 273400)

机构地区：[1]鲁南制药集团股份有限公司国家手性制药工程技术研究中心

出　　处：《中国医药工业杂志》2019年第7期728-731,共4页Chinese Journal of Pharmaceuticals

摘　　要：(2S,4S)-1-对硝基苄氧羰基-2-(N-叔丁氧羰基-N-氨基磺酰胺甲基)-4-乙酰硫基吡咯烷(2)经硫酸脱除叔丁氧羰基保护后,与1β-甲基碳青霉烯双环母核(MAP)经缩合反应得(4R,5S,6S)-3-[[(3S,5S)-1-对硝基苄氧羰基-5-(氨基磺酰胺甲基)-3-吡咯烷]硫]-6-[(1R)-1-羟乙基]-4-甲基-7-氧代-1-氮杂双环[3.2.0]庚-2-烯-2-羧酸对硝基苄酯(5), 5 再经催化氢化脱保护得多尼培南一水合物(1),总收率77%,纯度99.7%。最后一步中,本研究用乙酸乙酯-水代替 THF-水作溶剂,避免了氯化镁的使用,解决了后处理抽滤难和成品灼残超标的问题;用钯炭代替雷尼镍和锌粉作催化剂,钯炭过滤后可循环套用,降低生产成本,且反应时间由6 h 缩短为3 h。优化后的工艺反应条件更温和,操作简捷,更适合工业化生产。An improved kilo-scale process of doripenem hydrate (1) was reported.(2S,4S)-1-(4- Nitrobenzyloxycarbonyl)-2-[N-(tert-butoxycarbonyl)-N-[[(sulfamoyl)amino]methyl]]-4-(acetylthio)pyrrolidine (2) was used as the starting material. After a deprotection of 2 with H2SO4, the corresponding product reacted with MAP via condensation to give 4-nitrobenzyl (4R,5S,6S)-3-[[(3S,5S)-1-[[(4-nitrobenzyl)oxy]carbonyl]-5-[[(sulfamoyl)amino]- methyl]pyrrolidin-3-yl]thio]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (5), which was followed by a deprotection via catalytic hydrogenation to afford the target compound in a total yield of 77%, and a purity of 99.2%. In the last step, ethyl acetate-water was used as the solvent instead of THF-water to avoid the use of magnesium chloride and to solve the difficulty of filtration and excessive inorganic residue of products. In addition, palladium-carbon was used instead of Raney nickel and zinc powder as the catalyst, which could be recycled after filtration, so that the production costs were reduced and the reaction time was shorted from 6 h to 3 h.

关 键 词：多尼培南 广谱抗菌药 碳青霉烯类 多相反应 

分 类 号：R978.1[医药卫生—药品] R914.5[医药卫生—药学]