Alkali Synthetic Anti-cancer Drug Imatinib (imatinib)

Imatinib, a kind of N-phenyl-2-pyrimidine-amine derivative, is the first specifically targeted small molecule tyrosine kinase inhibitor and as such is an effective therapy for chronic myelogenous leukemia (CML). We now report a convenient method for synthesis of Imainib base by a process consisting of ten steps from 3-acetyl pyridine and total yield is 45.4%.After studied the impact factor of solvents, tempreture and time, an efficient synthetic method of enaminones was developed that uses acetyl heteroarylcycles and N,N-dimethylformamide dimethylacetal as reactant. This convenient reaction can be performed at 120-130℃in good yield. Seven enaminones compounds were prepared in yields of 86%-92%. The structures of the compounds were confirmed by IR, MS and ¹HNMR.A highly efficient copper-catalyzec N-arylation of heterorylamines with aryl halides is achieved. And using this optimized method, 25mol% CuI, 25mol% N, N '-dimethylethylenediamine (DMEDA) and 2.0 equiv of K₂CO₃ in dioxane at 90-100℃, we successfully synthesed a number of C-N cuppling adducts in good yield.According to our experimental results, we proposed a possible mechanism. And all the phenomenon appearing in the experiment can be demonstrated.Another improvement of our Imatinib synthesis rout is employing hydrazine hydrate as reduction regent and FeCl₃ as catalyst in the reduction reaction of aromatic nitro compounds. Comparing with the former methods, using this reduction system make the reduction reaction easy to process and decrease cost.In conclusion, we have developed an efficient, mild, inexpensive and green strategy for the synthesis of the Imatinib and its analogues by employing copper-catalyzed N-arylation methods.