【作者】 蒋瑶；

【导师】 胡艾希；

【作者基本信息】 湖南大学 ， 应用化学， 2006， 硕士

【摘要】 盐酸罗哌卡因和盐酸布比卡因是一类新型的酰胺类局部麻醉药。本文以2-哌啶甲酸为原料合成盐酸罗哌卡因和盐酸布比卡因,并通过拆分外消旋原料2-哌啶甲酸得到高纯度的（S）-（–）-哌啶甲酸,进一步合成具有光学活性的（S）-（–）-盐酸布比卡因。（1）盐酸罗哌卡因的合成:①以2-哌啶甲酸为原料,经酸化成盐,与SOCl₂发生氯化反应得到2-哌啶酰氯,再与2,6-二甲基苯胺进行酰胺化反应得到中间体1-N-（2,6-二甲苯基）-2-哌啶甲酰胺,与溴丙烷进行丙基化反应,酸化成盐合成罗哌卡因。采用单因素法考察1-N-（2,6-二甲苯基）-2-哌啶甲酰胺中间体合成反应中溶剂、温度、反应时间、2,6-二甲基苯胺和SOCl₂加入量等因素的影响,优化了反应条件,中间体收率60%;丙基化反应中用由N,N-二甲基甲酰胺代替异丙醇作为反应溶剂,反应时间由8 h缩短到1.5 h,收率为54%,总收率32.4%。②在此基础上,首次以三光气[二（三氯甲基）碳酸酯]替换二氯亚砜作为氯化剂,由2-哌啶甲酸经酸化成盐,氯化,酰胺化,丙基化,酸化成盐合成盐酸罗哌卡因。单因素影响法考察此路线中间体1-N-（2,6-二甲苯基）-2-哌啶甲酰胺合成中反应的时间、三光气加入量、滴加时间等因素的影响,优化反应条件,中间体1-N-（2,6-二甲苯基）-2-哌啶甲酰胺收率为55%,总收率30%。（2）盐酸布比卡因的合成:①2-哌啶甲酸为原料与溴丁烷反应得到中间体1-丁基-N-哌啶甲酸丁酯,后者在氢化钠作用下与2,6-二甲基苯胺得到布比卡因,酸化成盐合成盐酸布比卡因。单纯形优化法寻找最佳反应条件,丁基化反应收率92%,酰胺化反应收率55%,总收率50%。②在罗哌卡因合成方法基础上,以中间体1-N-（2,6-二甲苯基）-2-哌啶甲酰胺为原料,与溴丁烷发生丁基化,反应收率93.5%;酸化成盐得到盐酸布比卡因,反应收率91.6%。对盐酸布比卡因的合成路线进行综合比较。（3）（RS）-哌啶甲酸的拆分及（S）-（–）-盐酸布比卡因的合成:以（2S,3S）-酒石酸为拆分剂,拆分外消旋原料2-哌啶甲酸制备（S）-（–）-哌啶甲酸,首次以（S）-（–）-哌啶甲酸为原料经三光气氯化,与2,6-二甲基苯胺发生酰胺化,最后加入溴丁烷丁基化,成盐得到（S）-（–）-盐酸布比卡因[a]²⁵_D=12.2°[文献值:[a]²⁵_D=-12.3°（c=2,H₂O）],总收率47.1%,光学纯度99%,符合光学给药趋势,具有一定的工业应用价值。外消旋原料2-哌啶甲酸的拆分步骤包括复盐（S）-哌啶甲酸-（2S,3S）-酒石酸盐的制备与氨水处理复盐获得（S）-（–）-哌啶甲酸。成盐:化学直接成盐法收率48%更多还原

【Abstract】 Ropivacine Hydrochloride and Bupivacaine Hydrochloride are well-known local anaesthetics. The invention related to the processes for the manufacture of Ropivacine Hydrochloride and Bupivacaine Hydrochloride from 2-pipecolic acid. （S）-（-）-Bupivacaine Hydrochloride was prepared from （S）-（-）-pipecolic acid with highly purity, which was abtained by resolving racemic 2-pipecolic acid.（1） Synthesis of Ropivacine Hydrochloride:①With 2-pipecolic acid as starting material, by chlorination with SOCl₂ to give 2-pipecolic chloride, the latter amidated by 2,6-dimethylaniline to form intermediate 1-N-pipecolic acid-2,6-xylidide, the intermediate reacted with 1-propyl bromide to give Ropivacaine Hydrochloride . The best reaction conditions were found out via investagation on singlet effective factor in the prepaping 1-N-pipecolic acid-2,6-xylidide, such as solvent, temperature, reaction time, the quantity of 2,6-dimethylaniline and SOCl₂, the yield of imtermediate was 60%, in propylation the solvent isopropanol was substituted by DMF, the time of reaction was 8h reduce to 1.5h with a yield was 54%, the overall yield was 32.4%.②Ropivacaine Hydrochloride was also first prepared by chlorination that SOCl2 was substituted by triphosgene[Bis（Trichloromethyl）Carbonate], amidation, propylation and acidification from 2-pipecolic acid. Optimizaion the conditions for prepaing the intermediate 1-N-pipecolic acid-2,6-xylidide and affecting factors on reaction such as temperature, he time of reacion, the quantity of triphosgene and the time of triphosgene added were studied, the yield of imtermediate was 55%, the overall yield 30%.（2） Preparing for Bupivacaine Hydrochloride:①2-pipecolic acid was reacted with 1-butyl bromide to give 1-butyl-N-butyl-pipecolate, the latter amidated with 2,6-dimethylaniline that used NaH to form bupivacaine, bupivacaine was reacted with HCl aqueous to give Bupivacaine Hydrochloride. The best reaction conditions were found out by singlet optimization., the yield of butylation was 92%, amidation with a yield of 55% and the total yield was 50%.②Bupivacaine Hydrochloride was synthesized from the intermediate1-N-pipecolic acid-2,6-xylidide which prepared by the route for Ropivacaine reacted with 1-butyl bromide enduring the butylation with a yield 93..5%, acidification with a yield 91.6%. Concluded the advantages of every route for synthesis of Bupivacaine Hydrochloride.（3）Preparing for （S）-（-）-pipecolic acid and （S）-（-）-Bupivacaine Hydrochloride: By using （2S,3S）-tartrate acid as resolving agent, the pure isomer local anaesthetics （S）-（-）-Bupivacaine Hydrochloride [a]²⁵_D=-12.2°was prepared from （S）-（-）-pipecolic acid with highly purity which was abtained by resolving racemic 2-pipecolic acid via chlorination with triphosgene, amidation更多还原