The Ohmefentanyl Intermediate Synthesis

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.