马来酸罗格列酮合成研究进展

罗格列酮(RSG)是一种噻唑烷二酮类胰岛素增敏剂,1999年5月马来酸罗格列酮(RSGM)被美国食品与药物管理局批准上市,用于非胰岛素依赖型(NIDDM型/Ⅱ型)糖尿病的治疗.国内外文献中报道的RSG和RSGM的合成方法较多,根据不同的起始原料及合成工艺RSG和RSGM及其关键中间体的合成路线主要有:以2,5-二溴吡啶为原料经4步反应可制备RSG,RSG与马来酸成盐即得RSGM,该法反应条件温和,但是原料价格较贵,且反应的原子经济性不高;以2-溴吡啶或2-氯吡啶为原料的合成工艺有多条,以4-羟甲基苯酚为原料的合成路线因试剂毒性大、价格高,不适于工业化;以4-羟基苯甲醛为原料的合成路线有两条,其中一条中的醚化反应要用到N,N’-二环己基碳二亚胺,成本较高,第二条路线复杂冗长,操作繁琐,亦不理想;以对氟苯甲醛为原料的合成路线因原料价格较贵,缺乏竞争力;其中以2-氯吡啶为原料、4-2-(甲基-2-吡啶基氨基)-乙氧基]-苯甲醛为关键中间体的合成路线最具吸引力.

Advance on synthesis of Rosiglitazone Maleate

Rosiglitazone（RSG）is a thiazolidinedione insulin sensitizer,which was approved by American Food and Drug Administration（FDA）in the form of Rosiglitazone Maleate（RSGM）for the treatment of non-insulin-dependent diabetes mellitus（NIDDM）or diabetes mellitus type II.At present,many synthetic methods of RSG and RSGM were reported.Base on different starting materials and synthetic technology,the synthetic routes of RSG and RSGM as well as their key intermediates were reviewed as follows：The reaction conditions of preparing RSG from 2,5-dibromopyridine via 4step reactions are mild but with expensive starting materials and low atom economy;most of the synthetic routes of RSGM are from the starting material 2-bromopyridine or 2-chloropyridine,among which the synthetic route of RSGM with 2-chloropyridine as starting material and 4-（2-（methyl（pyridin-2-yl）amino）ethoxy）benzaldehyde as key intermediate is the most attractive one;the synthetic route of RSGM from 4-hydroxymethylphenol is not suitable for industrialization due to the high toxicity and high price of reaction reagents;one of the two synthetic routes from 4hydroxybenzaldehyde is high-cost due to the use of NN＇Dicyclohexylcarbodie in the etherification reaction,and the other route is tedious and non-ideal;the two routes of preparing RSGM from pfluorobenzaldehyde are less competitive due to the expensive starting material.