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有机化学
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有机化学 ›› 2014, Vol. 34 ›› Issue (5): 989-993.DOI: 10.6023/cjoc201312033 上一篇    下一篇

研究简报

利奈唑胺注射液中主要降解产物的合成

黄志雄a, 桑志培a, 曹海彦a, 晁若冰a, 邓勇a,b   

  1. a 四川大学华西药学院 成都 610041;
    b 靶向药物及释药系统教育部重点实验室 成都 610041
  • 收稿日期:2013-12-25 修回日期:2014-01-16 发布日期:2014-02-10
  • 通讯作者: 邓勇 E-mail:dengyongy@sohu.com
  • 基金资助:

    教育部博士点基金（No. 20110181110079）和国家科技重大专项（Nos. 2013ZX09301304-002，2013ZX09202002）资助项目.

Synthesis of Major Degradation Products of the Injection of Linezolid

Huang Zhixionga, Sang Zhipeia, Cao Haiyana, Chao Ruobinga, Deng Yonga,b   

  1. a Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041;
    b Key Laboratory of Drug Targeting and Drug Delivery System, Chengdu 610041
  • Received:2013-12-25 Revised:2014-01-16 Published:2014-02-10
  • Supported by:

    Project supported by the Research Fund for the Doctoral Program of Higher Education (No. 20110181110079) and the National Science and Technology Major Project (Nos. 2013ZX09301304-002, 2013ZX09202002).

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以利奈唑胺为起始原料，利用LiOH选择性水解利奈唑胺的酯键和酰胺键，得利奈唑胺注射液中的部分水解产物N-[（2R）-3-[[3-氟-4-（4-吗啉基）苯基]氨基]-2-羟基丙基]-乙酰胺（2）和完全水解杂质（2S）-1-氨基-3-[[3-氟-4-（4-吗啉基）苯基]氨基]-2-丙醇（4），收率分别为78.3%和86.6%；然后将化合物4的末端氨基用叔丁氧羰基保护，经N，O-双乙酰化后用氨水/甲醇脱除O-乙酰基，再利用饱和氯化氢乙醚溶液脱除叔丁氧羰基保护基，得N-[（2S）-3-氨基-2-羟基丙基]-N-[3-氟-4-（4-吗啉基）苯基]-乙酰胺（3）盐酸盐，五步总收率62.3%.

关键词: 噁唑烷酮类抗菌药, 利奈唑胺, 注射液, 降解产物, 杂质, 合成

The ester bond and amide bond of linezolid were selectively hydrolyzed by using LiOH to afford N-[(2R)-3-[[3-fluoro-4-(4-morpholino)phenyl]amino]-2-hydroxypropyl] acetamide (2) and (2S)-1-amino-3-[[3-fluoro-4-(4-morpholino)- phenyl]-amino]-2-propanol (4) with 78.3% and 86.6% yields respectively, which were the partially hydrolyzed impurity and fully hydrolyzed impurity of the injection of linezolid. The terminal amino group of compound 4 was then protected with tert-butyloxycarbonyl and subjected to N,O-diacetylation. Subsequently, N-[(2S)-3-amino-2-hydroxypropyl]-N-[3-fluoro-4-(4-morpholino)phenyl]acetamide (3) hydrochloride was synthesized by removal of O-acetyl with ammonia/methanol and then deprotection tert-butoxycarbonyl using saturated solution of hydrogen chloride in ether with 62.3% overall yield.

Key words: oxazolidinone antibacterial, linezolid, injection, degradation product, impurity, synthesis