Synthesis Of ALK Small Molecule Inhibitors Based On Triazolopyrazine Pharmaceutical Intermediates

Lung cancer is the most common malignancy in the world,and anaplastic lymphoma kinase(ALK)fusion gene is one of the key genes driving non-small cell lung cancer.In recent years,new highly active drugs are urgently needed to be developed with the emergence of drug resistance of listed ALK inhibitor.This paper studied the synthesis of new ALK small molecule inhibitors based on [1,2,4]triazolo[4,3-a]pyrazin-3-amines pharmaceutical intermediates。Firstly,this paper applied a novel,mild and convenient synthetic method to synthesize [1,2,4]triazole[4,3-a]pyrazin-3-amine compounds.Secondly,this paper explored the synthesis of ALK small molecule inhibitors(N3-(5-chloro-4-((2-(isopropyl sulfonyl)phenyl)amino)pyrimidin-2-yl)-N6-(isoquinolin-8-yl)-[1,2,4]triazolo[4,3-a]pyrazine-3,6-diamine 12).This paper studied the synthesis of pharmaceutical intermediates [1,2,4]triazolo[4,3-a]pyrazin-3-amines,used two step method and studied the factors of the reaction.The first step is to explore the reaction range of halogenated pyrazine.When the pyrazine ring contains electron withdrawing group,chlorine atom,bromine atom,4-methoxy phenyl group,halogenated pyrazine can take the nucleophilic substitution reaction with guanidine carbonate to get the target products.The synthesis process of 1-(pyrazin-2-yl)guanidines was optimized in terms of reactant ratio,temperature,solvent,alkali selection and dosage and so on.When pyrazine ring contains electron-donating group,amino,formamide,8-aminoisoquinoline,halogenated pyrazine can not undergo nucleophilic substitution reaction to obtain the target products.When the pyridine ring contains tert-butyl carbamate,the group can not be stable in the nucleophilic substitution reaction with guanidine carbonate.The second step is to explore the reaction range of 1-(pyrazin-2-yl)guanidine compounds in the cyclization reaction.When 5-or 6-position on pyrazine ring contains chlorine atom,bromine atom,4-methoxy phenyl group,1-(pyrazin-2-yl)guanidine compounds can undergo cyclization reaction to obtain the target compounds.The synthesis process of [1,2,4]triazole[4,3-a]pyrazin-3-amines was optimized in terms of temperature,solvent,alkali selection and dosage and so on.When 3-position on pyrazine ring contain chlorine atoms,1-(3-chloropyrazin-2-yl)guanidine can not undergo cyclization reaction to obtain target compound.This paper also explored the synthesis of ALK small molecule inhibitors(compound 12).The results show that the 6-position bromine atom in compounds 9 and ⅠI1 and the 3-amino in and compounds IV3 can not undergo Buchwald-Hartwig coupling reaction due to their low activity.When the temperature is raised to increase the activities of the groups,the compounds can not exist stably.The stability of compound 9 at different pH and temperature was further studied.The results show that the acid-base properties of the solution directly affect the stability of the compound and the temperature also has a certain influence on the stability of the compound,which may lead to the open ring hydrolysis of the compound.The stability of the compound is lower with the higher temperature and the stronger alkalinity of the solution.