Synthesis Of1-pyridyl-4-methylaminopiperidine Derivatives

In the thesis,4-(N-Boc-N-methylamino)piperidine and a series of3-chloro-pyridine derivatives were synthesized. Then the Buchwald-Hartwig amination reaction of3-chloropyridine derivatives with4-(N-Boc-N-methylamino)piperidine was investigated.1. The preparation of the4-(N-Boc-N-methylamino)piperidine and3-chloropyridine derivativesFirstly, the4-(N-Boc-N-methylamino)piperidine was synthesized from N-benzyl-4-piperidinone by using reductive amination reaction, acylation reaction and catalytic hydrogenolytic cleavage reaction (Scheme1). Scheme1The synthesis of the4-(N-Boc-N-methylamino)piperidineSecondly,3-chloropyridine derivatives were produced from2,3-dichloro-pyridine,3-bromine-5-chlorinepyridine and2,5-dichloropyridine by means of nucleophilic substitution reactions, Suzuki coupling reaction and Buchwald-Hartwig amination reaction (Scheme2). The desired products were characterized by1H NMR and GC-MS. Scheme2The synthesis of3-chloropyridine derivatives 2. The coupling reaction of4-(N-Boc-N-methylamino)piperidine with3-chloropyridine derivativesThe coupling reaction of4-(N-Boc-N-methylamino)piperidine and3-chloropyridine was chosen as the model reaction. After studied the influence of Pd sources, ligands, bases, solvents, temperature and reaction time to the coupling reaction, we found that the coupling reaction of4-(N-Boc-N-methylamino)piperidine with3-chloropyridine can be carried out under the optimization conditions with Pd(OAc)2and DavePhos as catalysts,t-BuONa as a base, and toluene as solvent. Under the optimum reaction condition, the Buchwald-Hartwig amination reaction scope was extended to a variety of3-chloropyridine derivatives (heteroaryl chlorides) and4-(N-Boc-N-methylamino)piperidine (3-(methylamino)pyrrolidine-l-carboxylate) to give the corresponding products in moderate to good yields (Scheme3). Scheme3The amination reaction of heteroaryl halides3. DeprotectionThe selected products were reacted with HCl/Dioxane and concentrated to afford the corresponding amine hydrochloride (Scheme4).