沙格列汀杂质的合成
Synthesis of Impurity in Saxagliptin
唐旭静 1蔡正贵 1张健青 1郭亚辉 1朱善良 1胡中元 1刘彦龙1
作者信息
- 1. 正大天晴药业集团股份有限公司研究院,江苏南京 210000
- 折叠
摘要
为有效控制沙格列汀原料药质量并建立质量标准,使用(S)-2-(金刚烷-1-基)-2-[(R)-2-羟基-1-苯乙基]氨基乙酸盐酸盐为起始原料,经Pd/C催化氢化脱苯乙醇后,与二碳酸二叔丁酯缩合,再经高锰酸钾氧化,最后与1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐进行重排反应制得沙格列汀杂质(S)-2-[1-(3-二甲基氨基丙基)-3-乙基脲基]-1-[(1R,3R,5R,7S)-3-羟基金刚烷-1-基]-2-氧代乙基氨基甲酸叔丁酯(5),其结构经1H NMR、13C NMR和HRMS确证.并对合成工艺进行了优化,优化条件下,杂质总收率为37.8％(以(S)-2-(金刚烷-1-基)-2-[(R)-2-羟基-1-苯乙基]氨基乙酸盐酸盐计),纯度98.9％(HPLC,归一法).合成工艺合理、原料易得、反应条件温和,制备的杂质纯度高,可作为沙格列汀杂质对照品用于质量研究.
Abstract
In order to effectively control the quality of Saxagliptin and establish its quality standards,(S)-2-(adamantan-1-yl)-2-((R)-2-hydroxy-1-phenylethyl)aminoacetic acid hydrochloride was used as the starting material.After Pd/C catalyzed hydrogenation,condensation with di-tert-butyl dicarbonate,oxidization by potassium permanganate,Saxagliptin impurity tert-butyl(S)-2-[1-(3-dimethylaminopropyl)-3-ethylureido]-1-[(1R,3R,5R,7S)-3-hydroxyadamantan-1-yl]-2-oxoethyl)carbamate(5)was synthesized from rearrangement reaction with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride,and purification with an overall yield of about 37.8% and a purity of 98.9% .Their structures were confirmed by 1H NMR,13C NMR and HRMS.The conditions for synthetic process were optimized.This synthesis process is reasonable and feasible,the reaction conditions are mild,and the purity is high.It can be used as the impurity reference substance for the quality control of Saxagliptin.
关键词
沙格列汀/(S)-2-(金刚烷-1-基)-2-[(R)-2-羟基-1-苯乙基]氨基乙酸盐酸盐/杂质Key words
Saxagliptin/(S)-2-(adamantan-1-yl)-2-((R)-2-hydroxy-1-phenylethyl)aminoacetic acid hydrochloride/impurity引用本文复制引用
出版年
2024
NETL
NSTL
万方数据