The Enzymatic Markovnikov Addition Of Imidazole Derivatives In Microreactors

Under the globle advocacy idea of“green pharmacy”,Enzymatic synthesis methods have attracted great attention in the synthesis of drugs and its'derivatives because of its high selectivity,mild reaction conditions and with good prospects.On the other hand,imidazoles as an important class of five-membered heterocyclic compounds,are the building blocks of many active natural products and synthetic products.Moreover,the easily combination of imidazole with biological systems capable of enzymes and receptors by intermolecular forces,imidazole derivatives show a wide range of biological activity.Such as the founction of anti-tumor,anti-microbial,anti-inflammatory,anti-viral,anti-histamine,anti-central nervous disease and lower blood pressure.Therefore,imidazole derivatives have become one of the hotspots of chemical research in recent years.In addition,the reaction in microfluidic chip is popular in the micro-analysis.With further research in this area and researchers found that the microreactor also has characters of fast mass and heat transfer,high conversion rate,the safety of operational,easy to enlarge.All these can allow to abtain enzymatic reaction rapidly and efficiently.Due to excellent characters of microreactor,it occupied a majoyrity position in the field of biocatalysis.Based on these,in this paper,we utilize the enzymatic synthesis of a series of imidazole derivatives in the microreactor for the first time.In this thesis,we report the Markovnikov addition of imidazole derivative catalysed by lipase/K₂CO₃ in the microreator.Five kinds of imidazole derivatives?4-nitroimidazole,2-methyl-4-nitroimidazole,imidazole,4-methylimidaole,6-nitrobenzimidaole?and four types of vinyl esters?vinyl acetate,vinyl laurate,vinyl palmitate,divinyl adipate?are employed as the substrate for the Markovnikov addtion.Finally,twenty products were synthsis and all these products were analyzed and proved by HPLC,¹H-NMR,¹³C-NMR,ESI-MS.The influence of Markovnikov addtion factors such as the amount of K₂CO₃,solvent,temperature,reaction time,the molar ratio of the substrate and the different substrates of addition were systematically examined in the microreactors in this paper.The results showed the optimal conditions of Markovnikov addition were that best ratio of the substrates is 1?6 in DMSO at 50?catalysed by lipase/K₂CO₃ in the microreactor.The chain lengths of vinyl esters and the different substituents in the imidazole ring were also investigated in this paper.The results showed that as the chain of the vinyl esters increase,enzymatic reactivity decreases,moreover,the reactivity of divinyl esters performed better than vinyl esters.Both electron-donating group of the substituents and the steric effects can reduce the reactivity of the heterocyclic ring.