Studies Of Buchwald-Hartwig C-N Coupling Reactions And Their Application In The Synthesis Of Pyrimidine Derivatives And Novel ALK Small Molecule Inhibitors

Pyrimidine and its derivatives are a very important class of organic compounds with good biological and pharmacological activities.The majority of the pyrimidine polycyclic compounds which contain nitrogen heterocycles in the new drug are synthesized by Buchwald-Hartwig C-N coupling reaction,but few systematic report about it.In this paper,a systematic study on the Buchwald-Hartwig C-N cross-coupling reaction of chloropyrimidine with nitrogen heterocyclic amine was carried out.On this basis,the C-N cross-coupling reaction was applied to the synthesis of novel pyrimidine ALK small molecule inhibitors.This paper is divided into two parts.First of all,take the coupling reaction of2-chloropyrimidine and 2-chloropyrazine as the research object,and the condition of the reaction is optimized,the yield of N-(pyrazin-2-yl)pyrimidin-2-amine up to 84.4%.Secondly,the effect of coupling reaction between 2-chloropyrimidine and different nitrogen heterocyclic amines was studied for investigating the amine substrates which suit this reaction system.The results showed that the different nucleophilic nitrogen heterocyclic amines resulted in different yields.The number of nitrogen atoms in the nitrogen heterocycle,the introduction of the benzene ring,and the position of the amino substituent are closely related to the nucleophilic ability of the nitrogen heterocyclic amine.The nitrogen heterocyclic amine compound having a single ring and a small number of nitrogen atoms,corresponding to a high yield.Finally,in order to further investigate the universality of this reaction system,5-chloropyrimidine,2,5-dichloropyrimidine and nitrogen heterocyclic amine were used for the reaction.The results showed that the 2,5-dichloropyrimidine has the highest electrophilic ability and 2-chloroactivity is higher than of 5-chloro’s.In the second part,firstly,the essential intermediate 2-chloro-5-isopropylpyrazine was synthesized by Minisci reaction and the final yield reached50% through process optimization.Then,the target compounds were obtained successively by Buchwald-Harting C-N cross-coupling,Boc protection and Buchwald-Harting C-N cross-coupling.The total yield of target compounds were24.4% and 20.3%,respectively.Finally,the in vitro antitumor activities ISPy-Pip-Py or ISPy-Pip-To-Py against non-small cell lung cancer NCI-H460 and NCI-H520 were investigated by MTT method.The results indicated that ISPy-Pip-Py or ISPy-Pip-To-Py showed good inhibition activities and they are expected to become novel ALK small molecule inhibitors.