罗格列酮的工业化合成工艺研究  

Study on the industrial synthetic process of rosiglitazone

作　　者：邹磊 吴成军 孙铁民[1] ZOU lei;WU Chengjun;SUN Tiemin(School of Pharmaceutical Engineering,Shenyang Pharmaceutical University,Shenyang 110016,China;Jiangsu Hansoh Pharmaceutical Group Co.,Ltd.,Lianyungang 222069,China)

机构地区：[1]沈阳药科大学制药工程学院,辽宁沈阳110016 [2]江苏豪森药业集团有限公司,江苏连云港222069

出　　处：《中国药物化学杂志》2024年第5期382-387,共6页Chinese Journal of Medicinal Chemistry

摘　　要：目的研究罗格列酮的合成工艺,解决中试级别规模化生产中的工艺问题,从而得到适合罗格列酮工业化生产的合成工艺。方法以2-氯吡啶和2-甲氨基乙醇为起始原料,经取代反应生成2-[N-甲基-N-(2-吡啶基)氨基]乙醇(2),2在氢氧化钾为缚酸剂条件下与4-氟苯甲醛通过成醚反应生成4-[2-(甲基-2-吡啶氨基)乙氧基]苯甲醛(3),3在哌啶催化下与2,4-噻唑烷二酮经缩合反应生成5-{4-[2-(甲基-2-吡啶基氨基)乙氧基]苯基亚甲基}-2,4-噻唑二酮(4),4在六水合氯化钴、丁二酮肟催化下,经硼氢化钠还原生成罗格列酮粗品,该粗品在无水乙醇、氢氧化钠体系下制备成钠盐,再通过乙酸水溶液游离,获得最终目标产物罗格列酮(1)。结果与结论本合成工艺解决了罗格列酮在放大至中试级别规模化生产中的各项工艺问题,具有一定的现实意义。This article aims to study the synthetic process of rosiglitazone,solve the scale-up problems of technical process,and obtain a suitable synthetic process for the industrialization of rosiglitazone.2-Chloropyridine and 2-methylaminoethanol were used as starting materials to undergo a substitution reaction to generate 2-[N-methyl-N-(2-pyridyl)amino]ethanol(2).Under the condition of potassium hydroxide as an acid binding agent,compound 2 underwent an etherification reaction with 4-fluorobenzaldehyde to generate 4-[2-(methyl-2-pyridylamino)ethoxy]benzaldehyde(3).Under the catalysis of piperidine,compound 3 underment condensation reaction with 2,4-thiazolidinedione to generate 5-{4-[2-(methyl-2-pyridylamino)ethoxy]phenylmethylene}-2,4-thiazolidinedione(4).Under the catalytic conditions of cobalt chloride hexahydrate and dimethylglyoxime succinate,compound 4 underwent a reduction reaction with sodium borohydride to obtain the crude product of rosiglitazone.The crude product of 1 was prepared into a sodium salt in an anhydrous ethanol and sodium hydroxide system,which was then dissociated into the final target product of rosiglitazone(1)through acetic acid aqueous solution.This synthetic process solves various problems in the large-scale production of rosiglitazone.It has certain practical significance.

关 键 词：罗格列酮 噻唑二酮类药物 工业化生产 合成工艺 优化 2型糖尿病 

分 类 号：R914[医药卫生—药物化学]