Synthesis of Amoxicillin Inpurity L

Received Date: 26 September 2016
Revised Date: 31 October 2016
Accepted Date: 5 December 2016

Fund Project: the National Natural Science Foundation of China 21402182Jilin Province and Chinese Academy of Sciences Cooperated High-tech Industrialization Special Fund Project 2017SYHZ0014

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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.
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