莫西沙星是第四代氟喹诺酮类抗菌药物,能有效地治疗多种细菌引起的感染,也可用于材料的防腐。(S,S)—6—苄基—八氢—吡咯并[3,4-b]吡啶是莫西沙星的一种重要中间体。本文主要是以吡啶酸酐为原料,与苄胺反应生成6—苄基—吡咯并[3,4-b]吡啶—5,7—二酮,再在四氢呋哺体系中,用Pd/C作催化剂,加氢还原后,用烷基金属还原剂Synhydrid还原,得到6—苄基—八氢-吡咯并[3,4-b]吡啶,经过手性拆分以后得到目标产物。 在查阅了相关的文献资料和对(S,S)—6—苄基—八氢-吡咯并[3,4-b]吡啶的几种合成路线综合比较的基础上,对原有的合成路线进行了改进。 首先,由吡啶酸酐和苄胺加热至130℃下回流,反应生成酰胺,不经分离直接加入乙酸酐脱水环合,冷却(10℃以下)结晶,过滤后,滤饼用乙醇洗涤得到6—苄基—吡咯并[3,4-b]吡啶—5,7—二酮,收率达到70.1%,产品经IR和GC-MS检测,结构正确。 然后Pd/C催化下,在四氢呋喃溶剂中加氢至8MPa,加热至85℃还原14h,该方法利用了四氢呋喃的溶剂效应,抑制了副反应的发生,可以在较为强烈的条件下一步反应得到6—苄基—六氢—吡咯并[3,4-b]吡啶—5,7—二酮,比文献报道的用两种催化剂分两步催化加氢的工艺路线简便,缩短了反应时间。 对酮的还原,我们使用常压法,为了降低了成本,选择了一条避开使用价格昂贵的氢化锂铝,而是使用相对较便宜的还原剂的工艺路线。本文采用烷基金属还原剂Synhydrid,此工艺路线原料简单易得,成本大为节省,适用于工业化生产,此方法在国内外文献中未见报道。 同时在手性拆分的实验部分,对影响实验结果的不同因素进行考察,改进了工艺条件。通过用质谱,红外光谱,核磁共振谱对产品进行表征,确认其分子结构。 通过实验,得到一条工业上经济可行的合成抗菌药物莫西沙星的关键中间体(S,S)—6—苄基—八氢-吡咯并[3,4-b]吡啶的方法,收率稳定,原料廉价易得,大大降低了生产成本,其总收率达到55.5%,具有较好的工业化应用前浙江大学硕士学位论文药物莫西沙星中间体的合成研究景。关键词:氟喳诺酮改进,催化加氢,一口比咯并[3,4一b〕毗陡抗菌药物,莫西沙星,合成烷基金属还原剂,手性拆分, 中间体,环合,工艺(S,S)一6一节基一八氢AbstraCt Moxifloxacin,one of newly marketed fluoroquinolones drugs,isanantimierobial eomPound useful as a medieament for humans,animals,助dfishes and an antimicrobial agent eontaining the same.(s,s)一6一BenzyloetabydroPurrolo[3,4一b]P州dine 15 an intermediate ofmoxifloxacin. A novel synthesis route was ProPosed based on literatures and eomPrehensiveeomP丽son.(s,s)一6一BenZyloetahydroPurrolo[3,4一b]Pyridine was synthesized withsome imProvements. First,the Proeess eomPrising reacting the reaetion Product ofP州dinedicarboxylie acid anhydride and benZylamine without solvent to givetheintermediate6一BenZyl一5,7一dihydro一5,7一dioxoPyrr01o[3,4一b]P州dine. This Intermediate was added THF and a Palladium一on一earbon eatalyst,助dhydrogenation,was eonducted under a Pressurized勿drogen gas atmosPhereatssoc and 5 kg/e扩ro:14 hours.The eatalyst was removed by nltration,andthefiltrate was eoneentrated,6一BenZyl一5,7一dioxo一oetahydroP拼010[3,4一b]Pyridine wasobtained.This Proeess 15 more eeonomieal. AmethodatatmosPheiePressurewasobtaintoredueeoxoeomPound.InthisProeess,Synhydrid,a new kind of reduced reagent,was used.A solution of6一Benzyl一5,7一dioxo一octahydroPyrrolo[3,4一b]Pyridine in ariliydrous THF was addeddroPwise to a solution of Synhydrid in anhydrous THF,then the miXture wasstired for 1 0 hours in reflux eonditions.The reaction、vas terminate by sodiumhydroxide solution.The reaction mixture was filtrated and the filtrate、vas dried