羟甲芬太尼中间体的合成研究
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摘要
羟甲基芬太尼是中国科学院首次发现的一个新的强效麻醉性镇痛剂,镇痛活性是芬太尼的58倍、吗啡的6300倍。目前,羟甲基芬太尼作为一种强效镇痛性失能剂主要用于反恐武器和军事科学研究。20世纪60年代以后,恐怖主义活动日益频繁,恐怖主义活动严重威胁着国际社会的安全和秩序,许多国家纷纷采取对策。在2002年俄罗斯大剧院的人质事件中,俄罗斯特种部队行动小组在解救人质时就使用了芬太尼类强效镇痛性失能剂。俄罗斯特种部队之所以使用芬太尼类化合物,主要是因为芬太尼有特殊的药理作用。一方面芬太尼是一种强效能镇痛性,在解救人质的突袭事件中,可以使绑匪来不及反抗和做出反应伤害人质,保证人质安全;另一方面芬太尼及其衍生物有特效的解毒药,比如纳络酮等阿片受体拮抗剂,可以保护人质免予大量死亡。
20世纪60年代初比利时人Janssen首次报道了新型强效镇痛药芬太尼。芬太尼的问世,吸引了许多学者以芬太尼为先导物改变其结构,研究其构效关系,合成了一系列的芬太尼衍生物。羟甲基芬太尼(Ohmefentanyl)作为芬太尼(Fentanyl)一种衍生物,由于其具有高效镇痛性,对它的研究越来越受重视。
在参考大量文献的基础上,本文设计了羟甲基芬太尼合成路线,重点研究了合成羟甲基芬太尼的两个重要中间体1-苄基-3-甲基哌啶酮和N-[3-甲基-4-哌啶基]-N-丙酰苯胺的合成工艺。中间体1-苄基-3-甲基哌啶酮以以苄胺、甲基丙烯酸甲酯和丙烯酸甲酯为原料,经过经麦克尔(Michael)加成、狄克曼(Dieckmann)缩合、脱羧(Decarboxylation)反应等四步反应合成。本文对反应原料配比、反应温度、溶剂、催化剂等条件进行优化,探索出甲醇钠代替氢化钠作为缩合剂的反应条件,总收率由原来的60.65%提高到67%。中间体N-[3-甲基-4-哌啶基]-N-丙酰苯胺的合成以1-苄基-3-甲基哌啶酮为起始原料,经过与苯胺缩合反应,硼氢化钠还原,丙酰氯酰基化和钯碳催化脱苄基等四步反应。反应中选取N,N-二甲氨基吡啶(DMAP)作为酰化催化剂提高了丙酰氯的转化率,比原来产率提高50%,同时优化了其它反应的合成工艺,使反应条件更为合理。总之,通过对中间体的合成研究简化了合成工艺,节省了原料和成本,有利于工业生产。
本文根据羟甲芬太尼的镇痛构效关系,还提出了合成羟甲芬太尼醚类化合物的设计,展开合成。实验中中间体N-[3-甲基-4-哌啶基]-N-丙酰苯胺提纯分离方法尚存在一些不足,需要进一步探索改进;用钯碳脱苄基成本较高,需要寻找新型低廉的催化剂。
Ohmefentanyl is a new potent narcotic analgesic that was synthesized and investigated firstly by Chinese Academy of Sciences.Its analgesic activity is 58 times than that of fentanyl, and 6300 times than that of morphine.Recently,the ohmefentanyl is used widely as a potent analgesic agent of disability in anti-terrorism weapons and military scientific research.Since the 1960s,terrorist activities became a serious threat to international security and social order; many countries have to take actions.In the Russian Grand Theater's hostage event of 2002,the Russian special troop's action group used a strong effect analgesic fentanyl type of disability agent to rescue the hostage.A kind of fentanyl derivatives was used by Russian special troops, is mainly for the special pharmacological actions of fentanyl derivatives as follows:on the one hand,fentanyl is a kind of strong potent analgesia,can prevent the kidnapper from rebellion, ensuring security of hostages;On the other hand fentanyl and its the derivative have the special effect antidote,such as naloxone and other opioid receptor antagonists,may protect the hostage to exempt from the massive deaths.
In the early-1960s Belgian Janssen et al,reported the new potent analgesic fentanyl for the first time.As the advent of remifentanil,many scholars modified its structure,some of the fentanyl derivatives were synthesized to study its structure-activity relationships.As one kind of fentanyl derivatives,ohmefentanyl receives more and more attention for its efficient analgesia.
At the basis of massive literatures,synthetic routes of ohmefentanyl were designed in this paper,and the synthetic technology of two important N-(3-Methyl-piper-idin-4-yl)-N-phenyl-Propionamide intermediates have studied and synthesis as follows:1-benzyl-3-methyl-piperi -done was prepared with benylamine,methyl methacrylate and methylacrylate as raw materials via a series of 1,4-addition,Diekmann condensation and hydrolysis decarboxylation reactions.The material ratios,reaction temperature and catalyst were optimized.Reaction with sodium methoxide as condensation agent was investigated.The total yield was increased from 60.65%up to 66.75%.N-(3-Methyl-piperidin-4-yl)-N-phenyl-propionamide was synthesized with aniline,sodium borohydride,propionyl chloride and pd/c,via condensation reaction, reduction reaction,acylation reaction and debenzylation.To select N-dimethyl amino pyridine (DMAP) as an acylation catalyst enhanced the conversion rate of propionyl chlorides and raises the yield by 50%compared to the original production yield.At the same time,synthetic technology of other reactions was optimized,so that a more reasonable reaction conditions were reached.In general,through the synthesis research of intermediates,the synthesis process was simplified,materials and costs raw were saved and benefit for industrial production.
In this paper,a synthetic compound ethers hydroxymethyl fentanyl was designed firstly and start to synthesis,based on analgesia structure-activity relationship of Ohmefentanyl.In the ex -periment,purification method for isolation of N-(3-Methyl-piper-idin-4-yl)-N-Phenylpropio-namide has a number of deficiencies,needing a further exploration.Debenzylation with palla -dium carbon was high costly,so it is necessary to seek cheap catalyst of new model.
20世纪60年代初比利时人Janssen首次报道了新型强效镇痛药芬太尼。芬太尼的问世,吸引了许多学者以芬太尼为先导物改变其结构,研究其构效关系,合成了一系列的芬太尼衍生物。羟甲基芬太尼(Ohmefentanyl)作为芬太尼(Fentanyl)一种衍生物,由于其具有高效镇痛性,对它的研究越来越受重视。
在参考大量文献的基础上,本文设计了羟甲基芬太尼合成路线,重点研究了合成羟甲基芬太尼的两个重要中间体1-苄基-3-甲基哌啶酮和N-[3-甲基-4-哌啶基]-N-丙酰苯胺的合成工艺。中间体1-苄基-3-甲基哌啶酮以以苄胺、甲基丙烯酸甲酯和丙烯酸甲酯为原料,经过经麦克尔(Michael)加成、狄克曼(Dieckmann)缩合、脱羧(Decarboxylation)反应等四步反应合成。本文对反应原料配比、反应温度、溶剂、催化剂等条件进行优化,探索出甲醇钠代替氢化钠作为缩合剂的反应条件,总收率由原来的60.65%提高到67%。中间体N-[3-甲基-4-哌啶基]-N-丙酰苯胺的合成以1-苄基-3-甲基哌啶酮为起始原料,经过与苯胺缩合反应,硼氢化钠还原,丙酰氯酰基化和钯碳催化脱苄基等四步反应。反应中选取N,N-二甲氨基吡啶(DMAP)作为酰化催化剂提高了丙酰氯的转化率,比原来产率提高50%,同时优化了其它反应的合成工艺,使反应条件更为合理。总之,通过对中间体的合成研究简化了合成工艺,节省了原料和成本,有利于工业生产。
本文根据羟甲芬太尼的镇痛构效关系,还提出了合成羟甲芬太尼醚类化合物的设计,展开合成。实验中中间体N-[3-甲基-4-哌啶基]-N-丙酰苯胺提纯分离方法尚存在一些不足,需要进一步探索改进;用钯碳脱苄基成本较高,需要寻找新型低廉的催化剂。
Ohmefentanyl is a new potent narcotic analgesic that was synthesized and investigated firstly by Chinese Academy of Sciences.Its analgesic activity is 58 times than that of fentanyl, and 6300 times than that of morphine.Recently,the ohmefentanyl is used widely as a potent analgesic agent of disability in anti-terrorism weapons and military scientific research.Since the 1960s,terrorist activities became a serious threat to international security and social order; many countries have to take actions.In the Russian Grand Theater's hostage event of 2002,the Russian special troop's action group used a strong effect analgesic fentanyl type of disability agent to rescue the hostage.A kind of fentanyl derivatives was used by Russian special troops, is mainly for the special pharmacological actions of fentanyl derivatives as follows:on the one hand,fentanyl is a kind of strong potent analgesia,can prevent the kidnapper from rebellion, ensuring security of hostages;On the other hand fentanyl and its the derivative have the special effect antidote,such as naloxone and other opioid receptor antagonists,may protect the hostage to exempt from the massive deaths.
In the early-1960s Belgian Janssen et al,reported the new potent analgesic fentanyl for the first time.As the advent of remifentanil,many scholars modified its structure,some of the fentanyl derivatives were synthesized to study its structure-activity relationships.As one kind of fentanyl derivatives,ohmefentanyl receives more and more attention for its efficient analgesia.
At the basis of massive literatures,synthetic routes of ohmefentanyl were designed in this paper,and the synthetic technology of two important N-(3-Methyl-piper-idin-4-yl)-N-phenyl-Propionamide intermediates have studied and synthesis as follows:1-benzyl-3-methyl-piperi -done was prepared with benylamine,methyl methacrylate and methylacrylate as raw materials via a series of 1,4-addition,Diekmann condensation and hydrolysis decarboxylation reactions.The material ratios,reaction temperature and catalyst were optimized.Reaction with sodium methoxide as condensation agent was investigated.The total yield was increased from 60.65%up to 66.75%.N-(3-Methyl-piperidin-4-yl)-N-phenyl-propionamide was synthesized with aniline,sodium borohydride,propionyl chloride and pd/c,via condensation reaction, reduction reaction,acylation reaction and debenzylation.To select N-dimethyl amino pyridine (DMAP) as an acylation catalyst enhanced the conversion rate of propionyl chlorides and raises the yield by 50%compared to the original production yield.At the same time,synthetic technology of other reactions was optimized,so that a more reasonable reaction conditions were reached.In general,through the synthesis research of intermediates,the synthesis process was simplified,materials and costs raw were saved and benefit for industrial production.
In this paper,a synthetic compound ethers hydroxymethyl fentanyl was designed firstly and start to synthesis,based on analgesia structure-activity relationship of Ohmefentanyl.In the ex -periment,purification method for isolation of N-(3-Methyl-piper-idin-4-yl)-N-Phenylpropio-namide has a number of deficiencies,needing a further exploration.Debenzylation with palla -dium carbon was high costly,so it is necessary to seek cheap catalyst of new model.
引文
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