Synthesis Of 3-substituted Piperidines

3-Substituted piperidine derivatives are natural producst having a characteristic framework structure resulting in unique biological and pharmacological activities,which is highly favored by pharmaceutical chemists.As a structural unit,it is widely present in the pharmaceutical composition.And the role of 3-substituted piperidines in the new drugs is more and more important.Research on short and high efficient synthesis process has important theoretical and practical significance for 3-substituted piperidines.Synthesis process of 3-aminopiperidine dihydrochloride salt,3-hydroxypiperidine and3-methylpiperidine was researched respectively.In the catalytic hydrogenation process of3-aminopyridine to 3-aminopiperidine dihydrochloride,3-aminopyridine was chosen as starting material.The process was studied respectively with different catalyst 5wt%Rh/C and 5wt%Pd/C.Through acetylation,3-acetylaminopyridine was synthesized from3-aminopyridine.And then,3-acetylaminopyridine was synthesized under such optimum conditions:with water as solvent,5wt%Pd/C as catalyst,at 80℃,the maximum system pressure 2.0MPa,p H=5.0～6.0,m_（water）:m_{（substrate）}:m_{（catalyst）}=200:20:1.The yield of this process was 97.6%.Finally 3-aminopiperidine dihydrochloride was got by salt formation.The optimum condition was following:water as solvent,5wt%Rh/C as catalyst,at 80℃,the maximum system pressure 2.0MPa,m_（water）:m_{（substrate）}:m_{（catalyst）}=200:20:1.3-Aminopiperidine was prepared from 3-aminopyridine.Through the salt formation,3-aminopiperidine dihydrochloride was got and final yield was 97.6%.With 3-hydroxypyridine as starting material,the catalytic hydrogenation process of3-hydroxypyridine to 3-hydroxypiperidine was researched.The results showed that the optimum condition was found following as:water as solvent,5wt%Pd/C as catalyst,at75℃,the maximum system pressure 2.0MPa,m_（water）:m_{（substrate）}:m_{（catalyst）}=250:12.5:1.And the yield could reach to 98.5%.3-Methylpiperidine was synthesized by catalytic hydrogenation from 3-methylpyridine as starting material,.The results showed that the optimum condition was found:water as solvent,5wt%Pd/C as catalyst,at 70℃,the maximum system pressure 3.0MPa,m_（water）:m_{（substrate）}:m_{（catalyst）}=200:20:1.The yield of the process was 96.3%.The above three products were characterized by mass spectra（MS）,infrared spectra（IR）,nucear magnetic resonance hydrogen spectra（¹H-NMR）,and the results were consistent with the standard spectra.Instead of the organic solvent,using water as solvent to synthesize 3-substituted piperidines by catalytic hydrogenation is an important innovation of this paper.Catalytic hydrogenation process using water as the solvent medium has the advantages of safety,environmental protection,easy operation and so on.In this paper,the synthesis processes for the three kinds of 3-substituted piperidines compounds have great value in the application fields owing to these procedures meeting green chemistry and atom economy requirements.