Synthesis Of3,8-diazabicyclo[3.2.1] Octane Derivatives

3,8-diazabicyclo[3.2.1]octane compound is a very important pharmaceuticalintermediates, its derivatives received great interest for their biological acativities suchas anti-tumor activity, antiarrhythmic activity, antinociceptive activity, analgeticactivity, causing the attention pfarmacologists and chemists. The synthesis of3,8-diazabicyclo[3.2.1]octane derivatives so for has not a complete report, this paperstudies the reaction of diethyl2,5-dibromoadipate with benzylamine, reduction,repacing the producting group, mesylation and cyclation reaction, preparation of thenucleus of3,8-diazabicyclo[3.2.1]octane and optimize the process of the key step inthe route. Got a quick and easy route preparation of such compounds, and laid thefoundation for the synthesis and activity of its derivatives.This paper specifically accomplish the fllowing tasks:Systematic study of the condition of the reaction of diethyl2,5-dibromoadipatewith benzylamine, isopropylamine, methylamine, p-methoxybenzylamine and theproduct was found to give the highest yield of cis reaction with benzylamine. Byexploring the reaction conditions such as the reaction solvent, feeding mode, the ratioof raw materials, the reaction emperature and reaction time, to obtain a preparation ofcis1-benzyl-pyrrolidine-2,5-dicarboxylic acid diethyl preferred process conditions:n(benzylamine): n(diethyl2,5-dibromoadipate)=2:1, cyclohexane as solvent, thebenzylamine was added dropwise at reflux temperature, the yield of the cis productwas75.0%under the this reaction conditions.Systematic study of the reaction of1-Boc-2,5-Bis-methanesulfonyloxymethyl–pyrrolidine with representative aliphatic amines and aromatic amines. By analysisingthe reaction results, we found fatty amine cyclization easier than aromatic amines, forfatty amine, cyclization reaction can occur smoothly and yield is ok. For aromaticamines, the aromatic ring with the electron withdrawing group is an aromatic amine cyclization yield is far greater than on the aromatic ring with an aromatic amine for theelectronic group. And optimizie the process of the cyclization reaction withbenzylamine, by examing the reaction solvent, reaction time, reaction temperature andthe ratio of maaterials on experimental obtained optimum conditions: n(benzylamine):n(-pyrrole alkyl)=3:1, acetonitrile as solvent at reflux temperature for4days, thecyclization yield was56.6%under the reaction conditions.In summary,3-benzyl-8-Boc-3,8-diazabicyclo[3.2.1]octane was synthesized fromdiethyl2,5-dibromoadipate and benzylamine as the raw materials by five steps in25.90%total yield. The process route is simle, convenient and practical, suitable forlarge-scable preparation.