4-甲氧羰基芬太尼类化合物的合成及其磷酰化反应的探索研究
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摘要
自20世纪90年代以来,恐怖主义的势力急剧扩张,日益猖獗,尤其是9.11事件的发生,标志着恐怖主义和反恐斗争进入一个新的发展阶段。发生在2002年莫斯科轴承厂文化宫的人质事件,最终导致100多人丧生,俄罗斯政府在解救人质时使用的就是芬太尼的衍生物。芬太尼是60年代初报道的一个新型强效麻醉性镇痛剂,由于其镇痛活性强和结构独特,受到了普遍关注,这类药物属于医疗药品,并且有其解药纳洛酮,因此可以保护人质免予大量死亡。
一些4-位取代的芬太尼的衍生物中,4-甲氧羰基芬太尼类化合物是镇痛活性最强类型之一,因此对于芬太尼尤其是4-甲氧羰基芬太尼类化合物的合成研究,无论是对于临床医疗还是用于反恐都有着非常重要的价值。
磷不但是构成人体的重要元素之一,而且参与生命活动中非常重要的代谢过程,磷酰基的转移反应与生命过程息息相关,而4-甲氧羰基芬太尼4-N-酰基的存在对于产生强效镇痛活性有重要的作用,目前研究的都是4-N-丙酰基,还没有发现有4-N-磷酰基的情况,因此我们对4-甲氧羰基芬太尼的磷酰化反应的合成路径进行了探索研究。
我们在参考文献的基础上,设计了合成路线,以1-苯乙基-4-哌啶酮为原料,经过Strecker反应、两步水解、酯化反应,最终合成了4-N-苯基和4-N-环己基的4-甲氧羰基芬太尼类化合物的中间体,并且借助Atheron-Todd反应对N-苯基-4-甲氧羰基芬太尼磷酰化反应的合成路径进行了探索,以相似结构苯胺和N-甲基苯胺为模型,成功合成了其磷酰化产物,但是由于空间位阻的原因,4-甲氧羰基芬太尼的磷酰化反应很难通过Atheron-Todd反应直接实现。于是,我们又希望通过合成一关键中间体,达到目标产物的实现,在合成中间体的实验中,通过LC-Ms分析发现,这一中间体可能生成,但是由于产率太低,故实验条件处于摸索阶段中。
我们采用微波催化合成的方法,对部分实验进行了工艺条件的改进,结果表明提高了产率,缩短了反应时间。
另外,我们计算了4-甲氧羰基芬太尼类化合物的HOMO、LUMO以及电荷密度图,并对其活性部位进行了预测。
The force of terrorism has been outspread rapidly and rampant increasingly since 1990s, especially 9.11 events occurred. It indicated that the terrorism and the anti-terrorism were entering a recent stage of development. In 2002, the hostages were held by armed militants in the theater of Moscow axletree factory, this finally led to more than 100 hostages to be death. Russian government used the fentanyl derivatives to rescue hostages. It was reported that fentanyl is a kind of powerful effect analgesic medicine in the beginning of 1960s. Because of its high analgesia intensity and particular structure, many investigators have interest in it. This kind of medicine belongs to something that cures, and its derivatives have the relevant alexipharmic noloxone, this alexipharmic can protect the hostages from being injured.
Some 4-substituent fentanyl derivatives, for instance, 4-methoxycarbonyl fentanyl is one of strongest types of analgesia activities. Therefore, it is important to research fentanyl for both clinic study and anti-terrorism, especially 4-methoxycarbonyl fentanyl.
Phosphore is one of important elements of bodys, and it participates in crucial metabolis -m activity of lives. Phosphorylation transfer reaction and life process are closely bound up. 4-N-acyl is very important to produce strong narcotic analgesic activities in the molecular structure of 4-methoxycarbonyl fentanyl. So far, 4-N-posphoracyl has not been reported, only 4-N-propionyl is well-informed. So we explored the synthesis path of phosphorylation reactio -n about 4-methoxycarbonyl fentanyl.
In this paper, the intermediates of 4-methoxycarbonyl fentanyl about 4-N-phenyl and 4-N-cyclohexyl were prepared from 1-phenylethyl-4-piperidinone through the Strecker reacti -on, hydrolysis, esterification reaction. The Atheron-Todd reaction has been used for studying the synthesis path of phosphorylation reaction about N- phenyl-4-methoxycarbonyl fentanyl. The models such as diethyl phenylphosphoramidate and diethyl methyl(phenyl) phosphora–midate were prepared successfully. Because of steric hindrance, we had difficulty in synthesi -zing the phosphorylation reaction target product of 4-methoxycarbonyl fentanyl. And then, we hoped that we could obtain the target product through synthesizing key intermediate. In the process of preparing the intermediate, we found that the intermediate has been synthesized possibly by LC-Ms analysis. Because of low yield, the experimental conditions is in the exploratory stage.
We also used the microwave catalytic synthesis method to improve on the technology of some reaction steps so that the yield increased, and the reaction time was shortened.
In addition, HOMO, LUMO, charges density pictures of 4-methoxycarbonyl fentanyl derivatives molecules were obtained through calculations. At the same time, the activity part of molecules were estimated.
一些4-位取代的芬太尼的衍生物中,4-甲氧羰基芬太尼类化合物是镇痛活性最强类型之一,因此对于芬太尼尤其是4-甲氧羰基芬太尼类化合物的合成研究,无论是对于临床医疗还是用于反恐都有着非常重要的价值。
磷不但是构成人体的重要元素之一,而且参与生命活动中非常重要的代谢过程,磷酰基的转移反应与生命过程息息相关,而4-甲氧羰基芬太尼4-N-酰基的存在对于产生强效镇痛活性有重要的作用,目前研究的都是4-N-丙酰基,还没有发现有4-N-磷酰基的情况,因此我们对4-甲氧羰基芬太尼的磷酰化反应的合成路径进行了探索研究。
我们在参考文献的基础上,设计了合成路线,以1-苯乙基-4-哌啶酮为原料,经过Strecker反应、两步水解、酯化反应,最终合成了4-N-苯基和4-N-环己基的4-甲氧羰基芬太尼类化合物的中间体,并且借助Atheron-Todd反应对N-苯基-4-甲氧羰基芬太尼磷酰化反应的合成路径进行了探索,以相似结构苯胺和N-甲基苯胺为模型,成功合成了其磷酰化产物,但是由于空间位阻的原因,4-甲氧羰基芬太尼的磷酰化反应很难通过Atheron-Todd反应直接实现。于是,我们又希望通过合成一关键中间体,达到目标产物的实现,在合成中间体的实验中,通过LC-Ms分析发现,这一中间体可能生成,但是由于产率太低,故实验条件处于摸索阶段中。
我们采用微波催化合成的方法,对部分实验进行了工艺条件的改进,结果表明提高了产率,缩短了反应时间。
另外,我们计算了4-甲氧羰基芬太尼类化合物的HOMO、LUMO以及电荷密度图,并对其活性部位进行了预测。
The force of terrorism has been outspread rapidly and rampant increasingly since 1990s, especially 9.11 events occurred. It indicated that the terrorism and the anti-terrorism were entering a recent stage of development. In 2002, the hostages were held by armed militants in the theater of Moscow axletree factory, this finally led to more than 100 hostages to be death. Russian government used the fentanyl derivatives to rescue hostages. It was reported that fentanyl is a kind of powerful effect analgesic medicine in the beginning of 1960s. Because of its high analgesia intensity and particular structure, many investigators have interest in it. This kind of medicine belongs to something that cures, and its derivatives have the relevant alexipharmic noloxone, this alexipharmic can protect the hostages from being injured.
Some 4-substituent fentanyl derivatives, for instance, 4-methoxycarbonyl fentanyl is one of strongest types of analgesia activities. Therefore, it is important to research fentanyl for both clinic study and anti-terrorism, especially 4-methoxycarbonyl fentanyl.
Phosphore is one of important elements of bodys, and it participates in crucial metabolis -m activity of lives. Phosphorylation transfer reaction and life process are closely bound up. 4-N-acyl is very important to produce strong narcotic analgesic activities in the molecular structure of 4-methoxycarbonyl fentanyl. So far, 4-N-posphoracyl has not been reported, only 4-N-propionyl is well-informed. So we explored the synthesis path of phosphorylation reactio -n about 4-methoxycarbonyl fentanyl.
In this paper, the intermediates of 4-methoxycarbonyl fentanyl about 4-N-phenyl and 4-N-cyclohexyl were prepared from 1-phenylethyl-4-piperidinone through the Strecker reacti -on, hydrolysis, esterification reaction. The Atheron-Todd reaction has been used for studying the synthesis path of phosphorylation reaction about N- phenyl-4-methoxycarbonyl fentanyl. The models such as diethyl phenylphosphoramidate and diethyl methyl(phenyl) phosphora–midate were prepared successfully. Because of steric hindrance, we had difficulty in synthesi -zing the phosphorylation reaction target product of 4-methoxycarbonyl fentanyl. And then, we hoped that we could obtain the target product through synthesizing key intermediate. In the process of preparing the intermediate, we found that the intermediate has been synthesized possibly by LC-Ms analysis. Because of low yield, the experimental conditions is in the exploratory stage.
We also used the microwave catalytic synthesis method to improve on the technology of some reaction steps so that the yield increased, and the reaction time was shortened.
In addition, HOMO, LUMO, charges density pictures of 4-methoxycarbonyl fentanyl derivatives molecules were obtained through calculations. At the same time, the activity part of molecules were estimated.
引文
[1]何因.莫斯科人质危机中的神秘“气体”.现代军事, 2002: 9-11
[2]金昔陆.μ阿片受体激动剂羟甲芬太尼麻醉作用的研究.上海:中国科学院上海药物研究所, 1997
[3] Eisleb O, Schaumann O. Dolantin, a new antispasmodic and analgesic. Dtsch Medical Wochenschr, 1939, 65: 967-968
[4] Gates M, Tschudi G. The synthesis of morpine. Journal of the American Chemical Society, 1952, 74: 1109-1110
[5] Beckett A H, Casy A F. Synthetic analgesics: stereochemical considerations. Journal of Pharmacy and Pharmacology, 1954, 6(12): 986-1001
[6]高峰丽,张丽华.吗啡类强效镇痛药物的研究进展.包头医学院学报, 2001, 17(3): 255-257
[7] Janssen P A J. A review of the chemical features associated with strong morphine like activity. British Journal of Aneasthesia, 1962(34): 260
[8] Riley T N, et al. 4-Anilinopiperidine analgesics I. synthesis and analgesic activity ofcertainring methylated 1-substituted 4-propananilidoplperidines. Journal of Pharmaceutic -cal Science, 1973, 62: 983
[9] Van Bever W F M, et al. Synthetic analgesics: synthesis and pharmacology of the diastereoisomers of N-[3-methyl-1-(2-phenylethyl)-4-phenylpropanamide] and N-[3-met -hyl-1-(1-methyl-2-phenyl-ethyl)-4-piperidyl]-N-phenylpropanamide. Journal of Medical Chemistry, 1974(17): 1047
[10]温素姐,杨玉龙,邵华宙等. 3-甲基-4-甲氧羰基芬太尼类似物的合成与镇痛活性.中国药科大学学报, 1992, 23(4): 196-202
[11] Van Daele P G H, De Bruyn M F L, Boey J M, et al. Synthetic analgesics: N-(1-[2-arylethyl]-4-substitued-4-piperidinyl)-N-arylalkanamides. Arzneim Forsch, 1976, 26(8): 1521-1526
[12] Van Daele P G H, Niemegeers C J E, Schellelens K H L, et al. N-4-substituted 1-(2-arylethyl)-4-piperidinyl-N-phenylpropanamides, a novel series of extremely potent analgesics with unusually high safety margin. Arzneim Forsch(Drug Research),1976, 26(8): 1548-1551
[13]杨玉龙,朱新文,朱国政等. 4-甲氧羰基-4-N-丙酰苯胺基哌啶1位衍生物的合成.药学学报, 1990, 25(4): 253-259
[14]杨玉龙,卢志英,杨志杰等. 4-甲氧甲基芬太尼类似物的合成及其镇痛作用.药学学报, 1991, 26(7): 493-498
[15] Jerome R B, Sheela A T, Frieda G R, et al. New 1-(heterocyclyalkyl)-4-(propionanilido)-4 -piperidinyl methyl eater and methylene methyl ether analgesics. Journal of Medical Chemistry, 1991, 34(2): 827-841
[16]卢志英,赵淑媛,袁小妹等. 4-甲氧羰基芬太尼的4-N-丙酰基结构类似物的合成与镇痛活性.药学学报, 1990, 25(5): 336-339
[17]杨玉龙,兰奋,陈常英等.芬太尼类化合物4-N-环己基类似物的合成与镇痛活性及构效关系研究.中国药科大学学报, 1993, 24(3): 139-144
[18]陈常英,徐振华,王秀珍等.芬太尼及其哌啶季胺离子的电子结构研究.化学学报, 1984, 42(3): 205-213
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[24]温素姐,李玉林,杨松林等. 4-甲氧羰基芬太尼(R31833)4-N-苯基结构类似物的合成和构效关系的研究.防化研究, 1986(1): 10-17
[25] Douglass F T, Mohammad R. Amide to eater conversion: a practical route to the carfentanil class of analgetics. Journal of Organic Chemistry, 1992, 57(14) : 4037-4038
[26]温素姐,杨玉龙,邵华宙等. 4-甲氧羰基芬太尼非芳基类似物的合成及其镇痛作用.药学学报, 1993, 28(3): 181-187
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[1]温素姐,杨玉龙,邵华宙等. 4-甲氧羰基芬太尼非芳基类似物的合成及其镇痛作用.药学学报, 1993, 28(3): 181-187
[2]杨玉龙,兰奋,陈常英.芬太尼类化合物4-N-环己基类似物的合成与镇痛活性及构效关系研究.中国药科大学学报, 1993, 24(3): 139-144
[3]卢志英,赵淑媛,袁小妹等. 4-甲氧羰基芬太尼的4-N-丙酰基结构类似物的合成与镇痛活性.药学学报, 1990, 25(5): 336-339
[4]温素姐,李玉林,杨松林等. 4-甲氧羰基芬太尼(R31833)4-N-苯基结构类似物的合成和构效关系的研究.防化研究, 1986(1): 10-17
[5] Van Daele P G H, De Bruyn M F L, Boey J M, et al. Synthetic analgesics: N-(1-[2-arylethyl]-4-substitued-4-piperidinyl)-N-arylalkanamides. Arzneim Forsch, 1976,26(8): 1521-1526
[6]温素姐,杨玉龙,邵华宙等. 3-甲基-4-甲氧羰基芬太尼类似物的合成与镇痛活性.中国药科大学学报, 1992, 23(4): 196-202
[1]雷英杰,杨易成,史小凤.抗癌活性天然化合物金雀异黄酮的量子化学研究.天津理工大学学报, 2006, 22(3): 52-54
[2]陈常英,李玉林,陈冀胜. 4-甲氧羰基芬太尼类化合物的电子结构及构效关系研究. 防化研究, 1986(4): 47-54
[3]陈常英,黎乐民.镇痛药3-甲基芬太尼及其类似物的结构活性关系和镇痛机理研究. 国际量子化学杂志, 1983, 23(4): 1597-1608
[2]金昔陆.μ阿片受体激动剂羟甲芬太尼麻醉作用的研究.上海:中国科学院上海药物研究所, 1997
[3] Eisleb O, Schaumann O. Dolantin, a new antispasmodic and analgesic. Dtsch Medical Wochenschr, 1939, 65: 967-968
[4] Gates M, Tschudi G. The synthesis of morpine. Journal of the American Chemical Society, 1952, 74: 1109-1110
[5] Beckett A H, Casy A F. Synthetic analgesics: stereochemical considerations. Journal of Pharmacy and Pharmacology, 1954, 6(12): 986-1001
[6]高峰丽,张丽华.吗啡类强效镇痛药物的研究进展.包头医学院学报, 2001, 17(3): 255-257
[7] Janssen P A J. A review of the chemical features associated with strong morphine like activity. British Journal of Aneasthesia, 1962(34): 260
[8] Riley T N, et al. 4-Anilinopiperidine analgesics I. synthesis and analgesic activity ofcertainring methylated 1-substituted 4-propananilidoplperidines. Journal of Pharmaceutic -cal Science, 1973, 62: 983
[9] Van Bever W F M, et al. Synthetic analgesics: synthesis and pharmacology of the diastereoisomers of N-[3-methyl-1-(2-phenylethyl)-4-phenylpropanamide] and N-[3-met -hyl-1-(1-methyl-2-phenyl-ethyl)-4-piperidyl]-N-phenylpropanamide. Journal of Medical Chemistry, 1974(17): 1047
[10]温素姐,杨玉龙,邵华宙等. 3-甲基-4-甲氧羰基芬太尼类似物的合成与镇痛活性.中国药科大学学报, 1992, 23(4): 196-202
[11] Van Daele P G H, De Bruyn M F L, Boey J M, et al. Synthetic analgesics: N-(1-[2-arylethyl]-4-substitued-4-piperidinyl)-N-arylalkanamides. Arzneim Forsch, 1976, 26(8): 1521-1526
[12] Van Daele P G H, Niemegeers C J E, Schellelens K H L, et al. N-4-substituted 1-(2-arylethyl)-4-piperidinyl-N-phenylpropanamides, a novel series of extremely potent analgesics with unusually high safety margin. Arzneim Forsch(Drug Research),1976, 26(8): 1548-1551
[13]杨玉龙,朱新文,朱国政等. 4-甲氧羰基-4-N-丙酰苯胺基哌啶1位衍生物的合成.药学学报, 1990, 25(4): 253-259
[14]杨玉龙,卢志英,杨志杰等. 4-甲氧甲基芬太尼类似物的合成及其镇痛作用.药学学报, 1991, 26(7): 493-498
[15] Jerome R B, Sheela A T, Frieda G R, et al. New 1-(heterocyclyalkyl)-4-(propionanilido)-4 -piperidinyl methyl eater and methylene methyl ether analgesics. Journal of Medical Chemistry, 1991, 34(2): 827-841
[16]卢志英,赵淑媛,袁小妹等. 4-甲氧羰基芬太尼的4-N-丙酰基结构类似物的合成与镇痛活性.药学学报, 1990, 25(5): 336-339
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[1]温素姐,杨玉龙,邵华宙等. 4-甲氧羰基芬太尼非芳基类似物的合成及其镇痛作用.药学学报, 1993, 28(3): 181-187
[2]杨玉龙,兰奋,陈常英.芬太尼类化合物4-N-环己基类似物的合成与镇痛活性及构效关系研究.中国药科大学学报, 1993, 24(3): 139-144
[3]卢志英,赵淑媛,袁小妹等. 4-甲氧羰基芬太尼的4-N-丙酰基结构类似物的合成与镇痛活性.药学学报, 1990, 25(5): 336-339
[4]温素姐,李玉林,杨松林等. 4-甲氧羰基芬太尼(R31833)4-N-苯基结构类似物的合成和构效关系的研究.防化研究, 1986(1): 10-17
[5] Van Daele P G H, De Bruyn M F L, Boey J M, et al. Synthetic analgesics: N-(1-[2-arylethyl]-4-substitued-4-piperidinyl)-N-arylalkanamides. Arzneim Forsch, 1976,26(8): 1521-1526
[6]温素姐,杨玉龙,邵华宙等. 3-甲基-4-甲氧羰基芬太尼类似物的合成与镇痛活性.中国药科大学学报, 1992, 23(4): 196-202
[1]雷英杰,杨易成,史小凤.抗癌活性天然化合物金雀异黄酮的量子化学研究.天津理工大学学报, 2006, 22(3): 52-54
[2]陈常英,李玉林,陈冀胜. 4-甲氧羰基芬太尼类化合物的电子结构及构效关系研究. 防化研究, 1986(4): 47-54
[3]陈常英,黎乐民.镇痛药3-甲基芬太尼及其类似物的结构活性关系和镇痛机理研究. 国际量子化学杂志, 1983, 23(4): 1597-1608