6-(2,6-二氟苯基)-5-氟吡啶甲酸合成工艺  

Synthesis of 6-(2,6-difluorophenyl)-5-fluoropicolinic acid

作　　者：程超[1,2,3] 吴萍萍 申屠宝卿 CHENG Chao;WU Ping-ping;SHENTU Bao-qing(State Key Lab of Chemical Engineering,College of Chemical and Biological Engineering,Zhejiang University,Hangzhou 310027,China;Zhejiang Zhongcheng Packing Material Co.Ltd.,Jiashan 314100,China;Zhejiang Zhongli Synthetic Material Technology Co.Ltd.,Pinghu 314200,China)

机构地区：[1]化学工程联合国家重点实验室(浙江大学),浙江大学化学工程与生物工程学院,浙江杭州310027 [2]浙江众成包装材料股份有限公司,浙江嘉善314100 [3]浙江众立合成材料科技股份有限公司,浙江平湖314200

出　　处：《高校化学工程学报》2021年第2期324-330,共7页Journal of Chemical Engineering of Chinese Universities

摘　　要：为了解决N-(4-((1R,3S,5S)-3-氨基-5-甲基环己基)吡啶-3-基)-6-(2,6-二氟苯基)-5-氟吡啶酰胺(PIM447)中间体6-(2,6-二氟苯基)-5-氟吡啶-2-甲酸(化合物1)的放大工艺问题,以5-氟吡啶-2-甲酸(化合物2)为原料,经氧化、氯代、卤素交换、酯化、Suzuki偶联、水解反应制备了化合物1。化合物2与H_(2)O2的氧化反应生成2-羧酸-5-氟吡啶-N-氧化物(化合物3)。化合物3与POCl3氯代反应得到6-氯-5-氟吡啶-2-甲酸(化合物4),在HBr-HOAc溶液中,化合物4发生卤素交换反应得到6-溴-5-氟吡啶-2-甲酸(化合物5)。化合物5与MeOH酯化反应生成6-溴-5-氟吡啶-2-甲酸甲酯(化合物6)。化合物6与2,6-二氟苯硼酸发生Suzuki偶联反应得到6-(2,6-二氟苯基)-5-氟吡啶-2-甲酸甲酯(化合物7)。最后,化合物7在NaOH/MeOH溶液中水解生成目标化合物1,总收率达到58.7%。A synthetic process was proposed to obtain 6-(2,6-difluorophenyl)-5-fluoropicolinic acid(compound 1),the intermediate of N-(4-((1 R,3 S,5 S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(PIM447),from 5-fluoropicolinic acid(compound 2)through oxidation,chlorination,halo-exchange,esterification,Suzuki coupling,hydrolysis reactions.2-Carboxy-5-fluoropyridineN-oxide(compound 3)was prepared by the oxidation reaction of compound 2 with H2 O2,6-chloro-5-fluoropicolinic acid(compound 4)by chlorination reaction of compound 3 with POCl3,6-bromo-5-fluoropicolinic acid(compound 5)by halo-exchange reaction of compound 4 in HBr-HOAc solution,methyl 6-bromo-5-fluoropicolinate(compound 6)by the esterification of compound 5 with MeOH,and methyl 6-(2,6-difluorophenyl)-5-fluoropicolinate(compound 7)by Suzuki cross-coupling between compound 6 and(2,6-difluorophenyl)boronic acid.Compound 1 was finally synthesized by hydrolysis of compound 7 with Na OH/Me OH solution with a total yield of 58.7%.

关 键 词：N-(4-((1R 3S 5S)-3-氨基-5-甲基环己基)吡啶-3-基)-6-(2 6-二氟苯基)-5-氟吡啶酰胺 6-(2 6-二氟苯基)-5-氟吡啶甲酸 5-氟吡啶-2-甲酸 SUZUKI偶联 

分 类 号：TQ465.92[化学工程—制药化工]