Research On The Synthesis Of 2-trifluoromethylpyridine-3-carboxaldehyde

Due to its special biological activity,azaindole can be used for not only pharmaceuticals of anticancer,antibacterial and lowering blood pressure,but also intermediates such as pesticides,dyes,spices and other fine chemical products.With the growth of its market demand,the synthesis process has been attracting considerable attention.In this paper,the synthesis of azaindole is reviewed.The process route of pyridine-3-formaldehyde and ethyl azide acetate as raw material is one of the reaction paths for the industrial production of azaindole.However,there is little concern about the synthesis of raw materials,and the availability of raw materials is a key issue in whether or not it could be industrialized.Therefore,2-(trifluoromethyl)pyridine-3-carbaldehyde as the research object,this paper intends to develop a synthetic route which is economical,environmentally friendly,efficient,suitable for industrialization.Inspired by the synthesis of Hantzsch pyridine,3-amino-trifluorobuturate was synthesized.The specific process conditions are as follows:The ammoniation of ethyl trifluoroacetoacetate was developed.When the reaction conditions were polar methanol as the reaction solvent,the molar ratio of ethyl trifluoroacetoacetate and ammonia was 1:4;the reaction time was 2h at 100 ?,the yield is up to 90.5%.Eventually the excess ammonia was absorbed by the cold methanol and methanol was recovered by distillation.The synthesis of 3-trifluoromethylnicotinic acid ethyl ester was studied.The optimum condition was found:the molar ratio of acrolein and ethyl 3-aminotrifluorobutanoate was 1.6:1,piperidine(2 wt%)was used as catalyst,ethanol solvent was ethanol,the reaction temperature was 50?.After that,adding sulfur as oxidant,the reaction was heated to reflux for 12 h to complete the aromatization of dihydropyridine compound.Ethyl 3-trifluoromethylnicotinate was obtained in 70%yield.The "one pot" was used to avoid the separation of intermediates,which simplifying the reaction process.Using ethanol as solvent and sulfur as oxidant,this avoids the concentrated sulfuric acid,concentrated nitric acid or potassium permanganate oxidation system that the literature reported.Finally,a low-cost and green process of 3-trifluoromethyl nicotinate preparation was developed.The process for the preparation of 2-(trifluoromethyl)pyridine-3-methanol by reduction and oxidation of ethyl 3-trifluoromethylnicotinate was improved.NaBH4 was selected as a reducing agent.The 95.7%yield of reduction was achieved in methanol solvent.The reaction amount of MnO2 was 5 equivalents to 2-(trifluoromethyl)pyridine-3-methanol at 40 ? in the presence of dichloromethane as the solvent,and the yield was 81%.The process has the advantages of low cost,low toxicity,easy operation and so on,in which MnO2 oxidation was used instead of dimethyl sulfoxide(DMSO)oxidation and high iodide oxidation.