左氧氟沙星杂质N的全合成工艺  

Total synthesis of levofloxacin impurity N

作　　者：王洁利 王凯[1] 罗艳娟 商甜波 陈彩萍 章潮军 沈华良 沈润溥[1] 虞国棋[1,2] WANG Jieli;WANG Kai;LUO Yanjuan;SHANG Tianbo;CHEN Caiping;ZHANG Chaojun;SHEN Hualiang;SHEN Runpu;YU Guoqi(Zhejiang Engineering Research Center of Fat-soluble Vitamin,Shaoxing University,Shaoxing 312000,China;Center for Drug Delivery System Research,Shaoxing University,Shaoxing 312000,China;Zhejiang Pharmaceutical Co.Ltd.,Shaoxing 312000,China)

机构地区：[1]绍兴文理学院脂溶性维生素浙江省工程研究中心,浙江绍兴312000 [2]绍兴文理学院药物制剂研究所,浙江绍兴312000 [3]浙江医药股份有限公司,浙江绍兴312000

出　　处：《高校化学工程学报》2024年第3期468-474,共7页Journal of Chemical Engineering of Chinese Universities

基　　金：国家自然科学基金(22278270)。

摘　　要：化合物((S)-(-)-2,3-二氢-3-甲基-9,10-双(4-甲基-1-哌嗪基)-7-氧代-7H-吡啶并[1,2,3-de][1,4]苯并噁嗪-6-羧酸)是抗菌药左氧氟沙星的杂质N,可作为左氧氟沙星生产过程中的杂质对照品。针对其合成难度大的问题,设计了左氧氟沙星杂质N(6)的合成工艺。以左氧氟沙星中间体环合酯((S)-(-)-2,3-二氢-3-甲基-9,10-二氟-7-氧代-7H-吡啶并[1,2,3-de][1,4]苯并噁嗪-6-羧酸乙酯)(1)为原料,先在8位引入硝基,经N-甲基哌嗪的亲核取代反应得到化合物(3),再在氢氧化钠作用下水解、铁粉/氯化铵体系还原、重氮化脱除8-氨基得到目标化合物。该工艺原料易得,反应条件温和,总收率约为35.8%,解决了缺少左氧氟沙星相关研究中杂质N对照品的难题。The compound((S)-(-)-2,3-dihydro-3-methyl-9,10-bis(4-methyl-1-piperazinyl)-7-oxo-7H-pyridino[1,2,3-de][1,4]benzoxazin-6-carboxylic acid)is the impurity N of the antibacterial drug levofloxacin,which is used as the reference substance during the preparation of levofloxacin and hard to synthesize.A novel total synthesis of levofloxacin impurity N(6)was proposed.The intermediate of levofloxacin((S)-(-)-2,3-dihydro-3-methyl-9,10-difluoro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate ethyl ester)(1)was used to introduce 8-NO_(2),and the compound(3)was obtained by nucleophilic substitution of N-methyl piperazine.The compound(6)was obtained by hydrolyzing under the action of sodium hydroxide,reducing with iron powder/ammonium chloride,and diazotizing to remove 8-NH_(2).The raw materials of the synthesis process are easily available,reaction conditions are temperate,and the levofloxacin impurity N is obtained with the overall yield of about 35.8%and can be applied as the reference substance in levofloxacin-related research.

关 键 词：左氧氟沙星 全合成 左氧氟沙星杂质N 重氮化反应 

分 类 号：O622.6[理学—有机化学]