Study On The Synthesis Of Candidate Drugs For Small Molecule Inhibitors Targeting ALK

The most common type of lung cancer is non small cell lung cancer(NSCLC),the proportion of non small cell lung cancer is as high as 85%.With the advantage of high specificity and less side reaction,molecular targeted therapy has become the first choice for the treatment of tumor.This targeted therapy represents the direction for the treatment of NSCLC.The targeted drugs for ALK fusion gene can effectively inhibit tumor cell proliferation and induce apoptosis of tumor cells,thus achieving efficient and selective treatment of NSCLC.Therefore,researchers pay great interaction on targeting small molecule inhibitors of ALK.In view of the vital role ALK plays in a variety of tumor occurrence,two novel small molecule inhibitors N-(4-(1-(5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)piperidin-4-yl)-2-isopropoxy-5-methylphenyl)isoquinolin-8-amine(compound 1)and N-(1-(5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)piperidin-4-yl)isoquinolin-8-amine(compound 2)were designed,which takes ALK as the target for NSCLC.Firstly,2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine(compound 5)was synthesized through reduction and nucleophilic substitution reaction of 1-(isopropylsulfonyl)-2-nitrobenzene.The total yield was68.5%.Secondly,4-(4-(isoquinolin-8-ylamino)-5-isopropoxy-2-methylphenyl)piperidine(compound 13)was synthesized through nitration,nucleophilic substitution reaction,Suzuki coupling reaction,catalytic reduction reaction,amino protective reaction,nucleophilic substitution reaction,deprotection of 2-chloro-4-fluorine toluene.Compound 1 was synthesized through nucleophilic substitution reaction of compound 13 with compound 5.The total yield was 17.3% and the purity determined by high performance liquid chromatographic(HPLC)is 94.95%.Finally,4-(isoquinolin-8-ylamino)piperidine(compound 16)was synthesized through nucleophilic substitution reaction,deprotection of 4-Amino-1-Boc-piperidine.Compound 2 was synthesized through nucleophilic substitution reaction of compound16 with compound 5.The total yield was 58.9% and the purity determined by HPLC is 97.84%.