立体选择性合成α-细辛脑的工艺研究

0要α-细辛脑是中药石菖蒲中提取出的有效成分。通过对大量文献调查研究，作者发现α-细辛脑具有多方面的作用。自上世纪60年代起，国内外对α-细辛脑即进行了广泛的研究，已证实其在止咳、祛痰、镇静、抗惊厥等方面具有广泛的生物学活性。而中草药资源有限，关于α-细辛脑的立体选择性合成问题越来越受到关注。在此基础上，本文对立体选择性合成α-细辛脑的反应条件进行了深入考察。本文以1,2,4-三甲氧基苯为原料，经Vilsmeier反应制得2,4,5-三甲氧基苯甲醛。首先研究了利用Wittig反应合成α-细辛脑，结果表明产率和立体选择性都较低。然后研究了Grignard反应合成α-细辛脑，利用2,4,5-三甲氧基苯甲醛与乙基溴化镁反应制得相应的中间体醇，考察了该醇脱水时不同脱水剂对产率和立体选择性的影响。结果表明采用硫酸铜催化，甲苯恒沸脱水，合成α-细辛脑（2-((E)-1-丙烯基)-1,4,5-三甲氧基苯），立体选择性93.3%，总产率80.26%（以醛计）。由α-细辛脑的合成路线可知，在合成的α-细辛脑中伴有少量的其顺反异构体β-细辛脑，其结构与α-细辛脑相似，但β-细辛脑具有很强的毒性。根据中国药典02000年版）要求，在合成的α-细辛脑中β-细辛脑的含量应小于1%。作者分别采用了HPLC法和GC法对α-细辛脑的含量进行了测定。对比发现，GC法较HPLC法简便迅速。测定结果表明α-细辛脑的含量符合药典要求。该方法为α-细辛脑的工业生产提供了一种高效简便的方法。关键词：α-细辛脑、无水硫酸铜、立体选择性、合成、HPLC法、GC法Abstractα-AsaroneistheeffectiveingredienttakedoutfromAcorusgramineussoland.Theα-Asaroneisveryusefulindifferentfieldsafterreadinganumberofliteratures.Internalandoverseasscientistshavestudiedonα-Asaroneintheearly1960s.Itisfoundthatα-Asaroneplayanessentialroleinrelievingacough,removingthephlegm,calmless,resistingconvulsion.BecauseChinesetraditionalmedicineislimited,studiesonstereoselectivesynthesisofα-Asaronehavebeenpaidmoreandmoreattentionto.Thispaperwillstudytheconditionofstereoselectivesynthesisofα-Asarone.2,4,5-trimethoxybenzaldehydewassynthesizedfrom1,2,4-trimethoxybenzenebytheVilsmeierreaction.First,synthesisofα-AsaronebyWittigreactionwasstudied,theresultshowedthattheyieldandstereoselectivitytosynthesizeα-Asaroneislower.Thensynthesisofα-AsaronebyGrignardreactionwasstudied.Theintermediatearomaticalcoholwaspreparedbythereactionofmagnesiumethylbromidewith2,4,5-trimethoxybenzaldehyde,thecatalysisofdifferentdehydrantwasevaluatedfortheyieldandstereoselectivitytosynthesizeα-Asarone.Theresultsshowedthatα-AsaronewasstereoselectivelyobtainedwithdominantE-stereoselectivity(93.3%)undercatalysisofcupricsulfateindrytoluene,theyieldwas80.2%(basedonthearomaticaldehyde).Fromthesyntheticrouteofα-Asarone,afewβ-Asaronewillbemakedwithα-Asarone.β-Asaronewhosestructurelikeα-Asaronehasstrongtoxicity.Thecontentofβ-Asaroneshouldn’tachieve1%accordingtotherequirementofChinesepharmacopoeia(2000).Thecontentofα-AsaronewasmensuratedbythemethodofHPLCandGC.ComparingthetwomethodsGCismoresimpleandconvenientthanHPLC.Theresultshowedthatthecontentofα-Asaronereachedtherequirementofpharmacopoeia.Anewsimpleandefficientprocesfortheindustrialproductionofα-Asaronewasprovided.KeyWords:α-Asarone、cupricsulfate、stereoselectivity、Synthesis、HPLC、GCauthorhasfoundthat0录第1章绪论····································································································11.1α-细辛脑简介··································································································11.2α-细辛脑的研究进展············································································21.2.1体内代谢································································································21.2.2药理作用································································································41.2.3临床应用································································································51.3本论文的选题背景及目的··············································································9第2章2,4,5-三甲氧基苯甲醛的合成及利用Wittig反应合成α-细辛脑·········112.1引言··············································································································112.22,4,5-三甲氧基苯甲醛的合成········································································122.2.1合成方法研究·························································································112.2.2实验部分·······························································································142.2.3小结·······································································································112.3利用Wittig反应合成α-细辛脑····································································152.3.1合成方法研究·························································································122.3.2实验部分·······························································································122.4小结··············································································································17第3章1-(2,4,5-三甲氧基苯)-1-丙醇的合成及合成α-细辛脑的脱水剂选择···183.1引言··············································································································183.2仪器与药品···································································································193.2.1THF的精制····························································································193.2.2溴乙烷的精制························································································203.2.3无水甲苯的精制····················································································203.31-(2,4,5-三甲氧基苯)-1-丙醇的合成······························································203.3.1合成方法研究························································································203.3.2实验部分·······························································································203