磷酸西格列汀中间体的合成工艺改进  

Improvement of the Synthesis Process of Siagliptin Phosphate Intermediate

作　　者：张书晴 薛星星 薛浩天 梁明明 齐婷婷 苏为科[1] 周嘉第 ZHANG Shuqing;XUE Xingxing;XUE Haotian;LIANG Mingming;QI Tintin;SU Weike;ZHOU Jiadi(Zhejiang University of Technology,Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals,Hangzhou 310014)

机构地区：[1]浙江工业大学,长三角绿色制药协同创新中心,杭州310014

出　　处：《化工生产与技术》2023年第4期3-6,I0002,共5页Chemical Production and Technology

摘　　要：研究以1,2,4-三氟苯作为起始原料制备得到磷酸西格列汀的中间体4-(2,4,5-三氟苯基)-3-氧丁酸甲酯。结果表明,氯甲基化反应中,当1,2,4-三氟苯与多聚甲醛、浓硫酸、氯化钠及相转移催化剂的摩尔比为1∶2.5∶4∶3∶0.05,60℃反应5h可达最高收率85.2%;格氏反应中,当选用2-甲基四氢呋喃(2-MeTHF)为格氏试剂制备的溶剂,1,2,4-三氟苯与镁的摩尔比1∶5,在低温下制备格氏试剂后持续通入4h二氧化碳气体,最高收率可达88.6%;缩合反应及脱羧反应中,2,4,5-三氟苯乙酸在二环己基碳二亚胺及4-二甲氨基吡啶的作用下与麦氏酸缩合反应后在甲醇溶液中脱羧,缩合反应摩尔比为1∶1.2∶1.2∶1.2,脱羧温度为65℃时可达最高收率86%。3步反应总收率达64.9%。产物结构经NMR及熔点等数据确证。The intermediate methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate of sitagliptin phosphate was prepared from 1,2,4-trifluorobenzene as the starting material.The results showed that in the chloromethylation reaction,when the molar ratio of 1,2,4-trifluorobenzene to paraformaldehyde,concentrated sulfuric acid,sodium chloride and phase transfer catalyst was 1∶2.5∶4∶3∶0.05,the highest yield of 85.2%was obtained at 60℃for 5 h.In the Grignard reaction,when 2-methyltetrahydrofuran(2-MeTHF)was selected as the solvent prepared by the Grignard reagent,the molar ratio of 1,2,4-trifluorobenzene to magnesium was 1∶5,and the Grignard reagent was prepared at low temperature.After continuous introduction of carbon dioxide gas for 4 h,the highest yield can reach 88.6%;in the condensation reaction and decarboxylation reaction,2,4,5-trifluorophenylacetic acid was decarboxylated in methanol solution after condensation reaction with mai's acid under the action of dicyclohexylcarbodiimide and 4-dimethylaminopyridine.The molar ratio of condensation reaction was 1∶1.2∶1.2∶1.2,and the highest yield was 86%when the decarboxylation temperature was 65℃.The total yield of the three-step reaction was 64.9%.The structure of the product was confirmed by NMR and melting point data.

关 键 词：4-(2 4 5-三氟苯基)-3-氧丁酸甲酯 磷酸西格列汀 1 2 4-三氟苯 格氏反应 二氧化碳 

分 类 号：TQ225.241[化学工程—有机化工]