Chinese Journal of Applied Chemistry ›› 2017, Vol. 34 ›› Issue (7): 768-773.DOI: 10.11944/j.issn.1000-0518.2017.07.160389

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Synthesis of Amoxicillin Inpurity L

YAO Feifeia,CUI Weib,XIAO Dehaia,ZHANG Jifenga*()   

  1. aGreen Chemistry and Process Laboratory; Key Laboratory of Synthetic Rubber,Chinese Academy of Sciences,Changchun Institute of Applied Chemistry,Changchun 100032,China
    bNortheast Dianli University,Jilin,Jilin 132000,China
  • Received:2016-09-26 Accepted:2016-12-05 Online:2017-07-04 Published:2017-07-04
  • Contact: ZHANG Jifeng
  • Supported by:
    Supported by the National Natural Science Foundation of China(No.21402182), Jilin Province and Chinese Academy of Sciences Cooperated High-tech Industrialization Special Fund Project(No.2017SYHZ0014)

Abstract:

Amoxicillin is a β-lactam antibiotic used for the treatment of a number of bacterial infections. It is on the World Health Organization's List of Essential Medicines, and one of the most important medications needed in a basic health system. The insufficient sources of its impurity L, i.e., (2S,5R,6R)-6-((2S,5R,6R)-6-((R)-2-amino-2-(4-hydroxyphenyl)acetamido)-3,3-dime-thyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxamido)-3,3-dimethyl-7-oxo-4-thia-1-azabicy-clo[3.2.0]heptane-2-carboxylic acid(6-APA amoxicilin amide), affect the quality control of the product. Herein, the first synthesis of amoxicillin impurity L, was reported by using a simple and efficient method. The starting materials of 6-aminopenicilanic acid and amoxycillin trihydrate were converted to intermediate compounds 3 and 6 through three-step and one-step reactions, respectively. By using benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP) as peptide coupling reagent, we successfully synthesized key intermediate 7 from compounds 3 and 6 in 76% yield, which was subsequently transformed to 6-APA amoxicillin amide by fully deprotection of benzyl and two carbobenzyloxy(Cbz) protecting groups. This method not only increases the source of the standard substance for quality control of amoxicillin, but also provides inspiration for novel β-lactam antibiotic and antiallergic research.

Key words: β-lactam, amoxicillin impurity L, peptide coupling reagent