沙格列汀杂质的合成  

Synthesis of Impurity in Saxagliptin

作　　者：唐旭静 蔡正贵 张健青 郭亚辉 朱善良 胡中元 刘彦龙 TANG Xu-jing;CAI Zheng-gui;ZHANG Jian-qing;GUO Ya-hui;ZHU Shan-liang;HU Zhong-yuan;LIU Yanlong(Research Institute of Chia Tai Tianqing Pharmaceutical Group Limited by Share Ltd.,Nanjing 210000,China)

机构地区：[1]正大天晴药业集团股份有限公司研究院,江苏南京210000

出　　处：《精细化工中间体》2024年第3期44-47,共4页Fine Chemical Intermediates

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^(1)H NMR、^(13)C 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。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'-ethylcarbodimide hydrochloride,and purification with an overall yield of about 37.8%and a purity of 98.9%.Their structures were confirmed by ^(1)H NMR,^(13)C 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 

分 类 号：TQ460[化学工程—制药化工]