Study On The Synthesis Of Indole Derivatives From Ethylene Glycol

As an important bioactive molecule,indole has been widely used in the fields of pesticide,perfume,fluorescent dye,etc.The study on its synthesis has important theoretical and practical significance.It is found that the one-step reaction of ethylene glycol and aniline to synthesize indole has many advantages:the supply of ethylene glycol is much more than the demand and the price is low;the by-products are hydrogen and water.At present,the previous studies involved in the reaction of indoles from ethylene glycol mostly suffered high temperature and high pressure（reaction temperature>300℃,reaction pressure>10 MPa）,or to use the precious metal catalyst,and the aniline derivatives of the substrate to expand range is narrow,based on this,this article mainly of ethylene glycol and aniline derivatives step reaction in the synthesis of indole derivatives,A series of drug active structural intermediates were synthesized in order to improve the practicability of ethylene glycol synthesis of indole compounds,and provide a new idea for the synthesis of some indole structurally active molecules.First of all,the broad-spectrum properties of Pt/Al₂O₃ supported catalysts prepared in laboratory were firstly explored.Using substituted aniline and ethylene glycol as raw materials,the substrate expansion for the synthesis of indole derivatives was investigated.The optimal condition is:the dosage of aniline compounds was 1 mmol,ethylene glycol 54 mmol,catalyst0.015 mmol,reaction time was 24 h,reaction temperature was 190℃.The results showed that aniline derivatives bearing strong electron-withdrawing groups were less efficient for this reaction（yields<20%）,most reactions started with other anilines underwent in about 40%yields.Notably,indole derivatives synthesized from 2-naphthylamine got a highest yield,reaching 95.1%.In order to increase the utilization rate of Pt/Al₂O₃ catalyst,taking the reaction of 2-naphthylamine as an example,the recovery,activation and reuse of catalyst were studied.The reaction yield decreased gradually with the increase of reaction times.Then the catalysts before and after the reaction were characterized by transmission electron microscopy.The results were as below:the Pt particles in the catalyst were uniformly dispersed at first,the particles were small;with the increase of reaction times,the distribution became chaotic and the particle size became uneven.These results indicated that the catalyst had some significant changes such as high temperature sintering and loss of active-sites,which reduced the catalytic activity.Finally,the reaction solution of 2-naphthylamine at different time was analyzed by GC-MS to capture some reaction intermediates.According to the structure of by-products and intermediates,the possible reaction mechanism of 2-naphthylamine and ethylene glycol catalyzed by Pt/Al₂O₃ was deduced.Then the synthesis of the drug intermediate N-methyl indole and the precursor of melatonin 5-methoxytryptamine were studied.Firstly,N-methylaniline was selected as substrate to investigate the synthesis reaction conditions of Oxitinib intermediate N-methylindole catalyzed by palladium.Finally,a three-component catalytic reaction system of Pd/Al₂O₃,Ts OH and Zn O was obtained,and the yield of N-methyl indole could up to 40.0%.Then,the catalytic conditions of melatonin intermediate 5-methoxy indole synthesis reaction were explored.The target product was obtained with 49.6%yield under the catalytic condition of Pt/Al₂O₃.Finally,the synthesis process of melatonin was further optimized.After a series of explorations,melatonin precursor 5-methoxytryptophan was synthesized by 4 steps with a total yield of 14.0%.