阿莫西林杂质L的化学合成

doi:10.11944/j.issn.1000-0518.2017.07.160389

摘要/Abstract

摘要：

阿莫西林是一种最常用的β-内酰胺抗生素,作为基本医疗系统中最重要药物之一被世界卫生组织基本药物标准清单收录。其杂质L,即:(2S,5R,6R)-6-((2S,5R,6R)-6-((R)-2-氨基-2-(4-羟基苯基)乙酰氨基)-3,3-二甲基-7-氧代-4-硫杂-1-氮杂双环[3.2.0]庚烷-2-甲酰胺)-3,3-二甲基-7-氧代-4-硫杂-1-氮杂双环[3.2.0]庚烷-2-甲酸(6-APA amoxicillin amide),由于含量少难以获取成为影响产品质量的因素之一,因此,我们以6-氨基青霉素烷酸和阿莫西林三水合物为原料,分别通过3步和1步转化为相应的中间体化合物3和6,并使用酰胺缩合试剂六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(PyBOP)以76%的收率实现了化合物3和6的脱水缩合,得到的关键中间体化合物7在Pd/C催化条件下一步脱除苄基及两个苄氧羰基保护基,首次通过化学方法合成了β-内酰胺化合物阿莫西林杂质L,反应使用简单易得的原料,温和的反应条件,无需复杂的分离纯化处理,对以阿莫西林为代表的β-内酰胺类抗生素的过敏研究以及新型β-内酰胺抗生素的开发和作用机制研究等有着参考和借鉴意义。

关键词: β-内酰胺, 阿莫西林杂质L, 酰胺缩合试剂

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

姚飞飞, 崔巍, 肖德海, 张吉凤. 阿莫西林杂质L的化学合成[J]. 应用化学, 2017, 34(7): 768-773.

YAO Feifei, CUI Wei, XIAO Dehai, ZHANG Jifeng. Synthesis of Amoxicillin Inpurity L[J]. Chinese Journal of Applied Chemistry, 2017, 34(7): 768-773.

参考文献

[1]	CHEN Qiaoyun,ZHOU Xiaodong,YUAN Li,et al.Retrospective Analysis on the Adverse Reactions of Amoxicillin Based on Domestic Literatures[J]. Anti-Infect Pharm,2007,4(1):31-35(in Chinese). 陈巧云,周晓东,袁力,等. 阿莫西林不良反应国内文献回顾性分析[J]. 抗感染药学,2007,4(1):31-35.
[2]	TIAN Xin,QIAO Hailing. The Structural Basis of β-Lactam Antibiotics That Caused Cross Allergic Reactions[J]. Chinese Pharm J,2009,44(8):564-566(in Chinese). 田鑫,乔海灵. β-内酰胺类抗生素交叉过敏反应的结构基础[J]. 中国药学杂志,2009,44(8):564-566.
[3]	TIAN Guiying. GelChromatography Applications in the Determination of β-Lactam Antibiotics Polymer[J]. Tianjin Pharm,2010,22(3):65-67(in Chinese). 田桂英. 凝胶色谱分析法在测定β-内酰胺类抗生素高分子聚合物中的应用[J]. 天津药学,2010,22(3):65-67.
[4]	YI Dawei,ZHANG Yajie,WANG Lu,et al.Determination of Polymer in Amoxicillin Sodium for Injection and Related Substances by HPLC[J]. Pract Pharm Clin Remed,2005,8:49-50(in Chinese). 易大为,张亚杰,王璐,等. 高效液相色谱法测定注射用阿莫西林舒巴坦钠中高聚物以及有关物质[J]. 实用药物与临床,2005,8:49-50.
[5]	CAI Shanying,HU Changqin. Analysis Method Progress of Separating Polymer in the β-Lactam Antibiotics[J]. J Guangdong Pharm Coll,2002,18(2):138-142(in Chinese). 蔡姗英,胡昌勤. β-内酰胺类抗生素中高分子聚合物的分离分析方法研究进展[J]. 广东药学院学报,2002,18(2):138-142.
[6]	Takagi S,Nobuhara Y,Nakanishi Y. Formation of Penicillin Polymers and Determination of Molecular Weight[J]. J Chromatogr A,1983,258:262-266.
[7]	MAO Xinzhu,LI Zhi. Relationship Between β-Lactam Antibiotics Allergic Reaction and Its Chemical Structures[J]. Pract J Med Pharm,2007,24(7):865-866(in Chinese). 毛竹叶,李志. β-酰胺类抗生素的化学结构与其过敏反应的关系[J]. 实用医药杂志,2007,24(7):865-866.
[8]	Roets E,Poureq P D,Toppet S,et al.Isolation and Structure Elucidation of Ampicillin and Amoxicillin Oligomers[J]. J Chromatogr A,1984,303(1):117-129.
[9]	ZHU Ke,WANG Yanyan,DING Haiping,et al.Study on Preparation of Amoxicillin by Enzymatic Method[J]. Chinese J Antibiot,2011,36(1):44-47(in Chinese). 朱科,王艳艳,丁海平,等. 酶法制备阿莫西林的工艺优化研究[J]. 中国抗生素杂志,2011,36(1):44-47.
[10]	NIU Changqun,ZHU Shiqing. LC-MS Analysis of Related Substances in Ampicillin and Amoxicillin[J]. Acta Pharm Sin,2001,36(10):758-761(in Chinese). 牛长群,祝仕清. 氨苄西林、阿莫西林中相关物质的LC-MS分析[J]. 药学学报,2001,36(10):758-761.
[11]	Hamilton C S,Yasuhara A,Baldwin J E,et al.Contrasting Fates for 6-Α-Methylpenicillin N Upon Oxidation by Deacetoxycephalosporin C Synthase(DAOCS) and Deacetoxy/Deacetylcephalosporin C Synthase(DAOC/DACS)[J]. Biorg Med Chem Lett,2001,11(18):2511-2514.