Synthesis Of Pyrazolopyridine Tyrosine Kinase Inhibitors

Cancer,in all of its forms,carries a major disease burden in all over the world.In recent decades,we have made great progress in understanding the pathogenesis of cancer.It is now clear that cancer is produced by a multi-step mutagenesis process whereby the cancer cells acquire some common properties,such as angiogenesis.Currently,anti-angiogenic therapy has become an approved cancer treatment method.Vascular endothelial growth factor?VEGF-A?and its receptor VEGFR-2 are effective targets for fighting cancer because this system is a major player in tumor angiogenesis.Studies have shown that tyrosine kinase inhibitors that reduce angiogenesis,targetting VEGFR-2,also have anticancer activity.These inhibitors are generally small molecule compounds that act on the ATP competition mechanism by binding to the ATP pocket of the protein kinase domain.In this paper,we mainly discussed the synthesis and of the pyrazolopyridines that were designed by the method of computer aided drug design?CADD?.The main contents of this thesis are as follows:1.First,the substituted pyridine derivatives and hydroxylamine-O-sulfonic acid are reacted at 90°C to produce an intermediate N-aminopyridinium salt.And then,in the presence of K₂CO₃,N-aminopyridinium salt and ethyl propiolate are reacted through1,3-Dipolarcycloadditionreactiontoproducesubstituted Pyrazolo[1,5-a]pyridine-3-carboxylate derivatives,followed by hydrolysis under basic conditions to give substituted pyrazoles[1,5-a]Pyridin-3-carboxylic acid derivatives.2.Thesynthesisofbenzothiazolederivativeswasexplored.2-aminobenzothiazoleand2-hydroxymethylbenzothiazoleweresuccessfully synthesized.2-aminobenzothiazole was prepared from phenylthiourea,which were achieved by reaction of aniline and its derivatives with ammonium thiocyanate in the presence of bromine.3.Thesynthesisofbenzothiazolederivativeswasexplored.6-methyl-3-nitroquinolin-4-ol was successfully synthesized.In sodium hydroxide solution,nitromethane itself reacts to obtain nitroacetaldehyde oxime sodium salt,and the resulting sodium salt is acidified to obtain intermediate nitroacetaldehyde oxime.The obtained nitroacetaldehyde oxime is reacted with 5-methyl-2-aminobenzoic acid to form intermediate is reacted with 5-methyl-2-aminobenzoic acid to form intermediate 5-methyl-2-??2-nitrovinyl?amino?benzoic acid,which continue to produce6-methyl-3-nitroquinolin-4-ol under the action of potassium acetate and acetic anhydride.4.Pyrazolopyridine derivatives and 2-aminobenzothiazole were linked by amide bond under the action of three ethylamine,and a series of target compounds of pyrazolopyridine-benzothiazole,which are connected by the amide bond,are obtained.