左氧氟沙星杂质N的全合成工艺
Total synthesis of levofloxacin impurity N
王洁利 1王凯 1罗艳娟 1商甜波 1陈彩萍 2章潮军 2沈华良 1沈润溥 1虞国棋3
作者信息
- 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. 浙江医药股份有限公司,浙江 绍兴 312000
- 3. 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;绍兴文理学院 药物制剂研究所,浙江 绍兴 312000
- 折叠
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.
Abstract
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-NO2,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-NH2.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Key words
levofloxacin/total synthesis/levofloxacin impurity N/diazotization引用本文复制引用
出版年
2024
国家科技期刊平台
NSTL
万方数据