常山酮关键中间体的合成工艺研究  

Study on the Synthetic Process of the Key Intermediate of Halofuginone

作　　者：邓余[1] 黄升[1] 唐达[1] 伍涛[1] 李成洪[1] DENG Yu;HUANG Sheng;TANG Da;WU Tao;Li Chenghong(Institute of Veterinary Sciences & Pharmaceuticals, Chongqing Academy of Animal Sciences, Rongchang 402460, China)

机构地区：[1]重庆市畜牧科学院兽医兽药研究所,重庆荣昌402460

出　　处：《畜禽业》2020年第12期1-5,共5页Livestock and Poultry Industry

基　　金：重庆市技术创新与应用示范(社会民生)项目(cstc2018jscx-msybX0259);重庆市科研机构绩效激励引导专项(cstc2019jxjl80008)。

摘　　要：研究改进了常山酮关键中间体2-羟基-2-(7-溴-6氯-4-氧代-3(4H)-喹唑啉基)甲基六氢呋喃3,2-b吡啶-4(2H)-羧酸苄基酯(1)的合成工艺。1-苄基-3-羟基吡啶鎓盐氯化合物(2)与烯丙基溴在NaH的作用下反应、再经过硼氢化钠还原得到5-(烯丙氧基)-1-苄基-1,2,3,6-四氢吡啶(3),反应用N,N-二甲基甲酰胺(DMF)替换甲醇,降低了NaH的用量,提高3的收率至81%。将溶解于四氢呋喃(THF)的化合物3滴加到过量的氯甲酸苄酯(CbzCl)中反应,浓缩后的粗品与三氟化硼/乙醚(BF3·Et2O)进行克莱森重排,得到化合物2-烯丙基-3-氧代-1-哌啶甲酸苄酯(4)。该步反应通过改变氯甲酸苄酯的添加顺序,减少氯甲酸苄酯的用量;低温下通过添加路易斯酸进行重排反应,减少副产物的产生。化合物4经过还原、环化等反应得到中间体1。改进后的工艺总收率提升至32.0%。This study improved the synthetic process of the key intermediate of halofuginone,Benzyl 2-(Bromomethyl)hexahydrofuro[3,2-b]pyridine-4(2H)-carboxylate(1).1-Benzyl-3-hydroxypyridinium Chloride(2)reacted with allyl bromide mediated by NaH and the mixture processed to a reduction reaction via NaBH4 to give compound 5-(Allyloxy)-1-benzyl-1,2,3,6-tetrahydropyridine(3).DMF was employed as solvent to replace MeOH and thus reduced the amount of NaH as well as increased the yield of compound 3 to 81%.Compound 3 was dissolved in THF and added to benzyl chloroformate(CbzCl)dropwise and the resulting concentrated residue experienced the Claisen rearrangement in the existence of BF3·Et2O to provide benzyl 2-allyl-3-oxo-1-piperidinecarboxylate(4).Our improved method changed the adding order of material to reduce the amount of CbzCl and the later rearrangement reaction inhibit the byproduct by using Lewis acid.Compound 4 was then reduced and moved to a cyclization reaction to give the key intermediate 1.The yield of the optimized synthetic process was improved to 32.0%.

关 键 词：常山酮 中间体 合成 工艺改进 

分 类 号：O62[理学—有机化学]