西他列汀关键中间体的合成研究
Study on the Synthesis of Key Intermediate for Preparing Sitagliptin
邢冰梅 1徐鹤 1谷少华 2姜玉钦3
作者信息
- 1. 天方药业有限公司,河南 驻马店463000
- 2. 新乡市中心医院,河南 新乡451191
- 3. 河南师范大学 化学化工学院,河南 新乡453007
- 折叠
摘要
3-氧代-4-(2,4,5-三氟苯基)-丁酸甲酯是合成二肽基肽酶-IV抑制剂类药物磷酸西他列汀的关键中间体.以2,3,5-三氟苯胺为原料,先经过重氮化反应得到1,2,4-三氟苯,再在溴素和三氯化铝的作用下发生亲电取代,得到2,4,5-三氟溴苯;然后与丙二酸二乙酯缩合,再经氢氧化钠水解、盐酸酸化、加热脱羧得到纯品2,4,5-三氟苯乙酸,最后与2,2-二甲基-1,3-二恶烷-4,6-二酮缩合后水解得到3-氧代-4-(2,4,5-三氟苯基)-丁酸甲酯,总收率达到61.9%.产品经核磁氢谱和核磁碳谱表征.该路线能有效减少副产物,适合工业化生产.
Abstract
3-Chloro-4-(2,4,5-trifluorophenyl)-methyl butyrate is a key intermediate in the synthesis of dipeptidyl peptidase-IV inhibitor cetaxidine phosphate. In this paper, 1,2,4-trifluorobenzene was synthesized from 2,3,5-trifluoroaniline by diazotization, then 2,4,5-trifluorobromobenzene was obtained by electrophilic substitution with bromine and aluminum trichloride,and then 2,4,5-trifluorophenylacetic acid was obtained via condensation reaction with diethyl malonate, hydrolysis by sodium hydroxide, acidification by hydrochloric acid and decarboxylation by heating. Finally, methyl 3-oxo-4(- 2,4,5-trifluorophenyl)-butyrate was synthesized by condensation with 2,2-dimethyl-1,3-dioxane-4,6-dione and hydrolysis with a total yield of 61.9%. The products were characterized by 1H NMR and 1H NMR. This route can effectively reduce by-products and is suitable for industrial production.
关键词
3-氧代-4-(2,4,5-三氟苯基)-丁酸甲酯/2,3,5-三氟苯胺/工业化生产Key words
3-chloro-4-(2,4,5- three fluorophenyl)-methyl butyrate/2,3,5-trifluoroaniline/Industrial production引用本文复制引用
基金项目
河南省重点科技攻关计划(2015)(152102210285)
出版年
2019
NETL
NSTL
维普
万方数据