Synthesis And Antifungal Activity Of 2-methyl-6-alkyl-2,3,4,5-tetrahvdropyridines

Alkaloid has the basic framework of tetrahydropyridine,and it is an important component of proteins and nucleotides in organisms.It is involved in biological cycling and metabolism and has significant pharmacological activities(such as analgesic,anti-cancer,antibacterial,insecticidal,etc.).It has a very wide range of applications in medicine,agriculture and forestry.These alkaloids can be extracted from nature,but the content in animal and plant body is very small.The extraction process is cumbersome and the production cost is high.Therefore,it is impossible to extract the alkaloids from nature to meet the clinical and scientific research needs.At the same time,in the synthesis field,tetrahydropyridine is an important intermediate for the synthesis of piperidine,dihydropiperidine,pyridine and its derivatives and complex alkaloids.So how to use the chemical synthesis method to construct the tetrahydropyridine skeleton attracts the close attention of the researchers and many pharmaceutical companies.2-methyl-6_alkyl-2,3,4,5-tetrahydropyridine,which belongs to the pyridine alkaloid,is derived from the venom of red fire ants and has significant pharmacological activity.2-methyl-6-pentadecyl-2,3,4,5-tetrahydropyridine was used as a template to synthesize a series of 2-methyl-6-alkyl-2,3,4,5-tetrahydropyridine compounds by changing the chain length of 6-substituents.Their antibacterial activity were explored.Based on the literatures of synthetic 2,3,4,5-tetrahydropyridine ring,a reasonable synthetic route was proposed.In this paper,2-methy 1-6-alky 1-2,3,4,5-tetrahydropyridine were synthesized by a five-step reaction,in which glutaric acid and urea were starting materials.The first step,glutarimide was formed by ring-forming reaction of the raw material under high temperature melting conditons.In the second step,glutarimide reacted with methylmagnesium bromide(CH3MgBr)to introduce a methyl group on carbonyl carbon,followed by reduction of NaBH3CN to produce 2-methyl-6-piperidone.In the third step,the hydrogen on the nitrogen was protected by(Boc)2O,and N-Boc-2-methyl-6-piperidone was obtained.In the fourth step,a series of N-Boc-aminoketones were obtained by ring-opening reaction with Grignard reagent with different R alkyl.In the final step,under the reaction with HCl,the Boc protection was removed,the primary amine was exposed and proceeded by condensation reaction with the ketone carbonyl to form a series of 2-methyl-6-alkyl-2,3,4,5-tetrahydropyridine.Intermediates and products were characterized by nuclear magnetic resonance(1H-NMR and 13C-NMR)and high resolution mass spectrometry.The antimicrobial activity of 2-methyl-6-alky 1-2,3,4,5-tetrahydropyridine was tested for the first time,and it was found that it could inhibit the growth of various strains,had broad spectrum antimicrobial activity.In addition,it had a better inhibitory effect on VRE,which was particular.