Synthetic Method Optimization Of Protein Kinases Inhibitors CO-1686 And PF-4708671

The drug discovery of protein kinase inhibitors has been a very hot field. CO-1686 and PF-4708671 are two novel protein kinase inhibitors reported recently. CO-1686 is an irreversible mutant selective epidermal growth factor receptor tyrosine kinase inhibitor, and PF-4708671 is a specific inhibitor of p70S6K1. In order to obtain the two kinase inhibtors in tens of grams scale in an easier, cheaper and efficient way for drug development, their synthetic routes were carefully optimized.The synthetic route of CO-1686 was mainly optimized by changing the orders of 2-and 4-substitution in the pyrimidine ring which results in a greatly improved selectivity of the reaction in step 1. Meanwhile, by using protection group free reagent m-phenylenediamine instead of N-Boc-m-phenylenediamine, the new route was successfully shorted by 2 steps without any compromise. Beyond that, excellent reaction conditions and workup protocols were obtained from exploration and optimization, which prevented the use of column chromatography for the whole route and make it for industrial scale production.The synthetic route of PF-4708671 was mainly optimized by changing the starting material, in order to solve the problems of the original one, which is scarce, expensive, and difficult to synthesize, and to solve the problems of step 1 which has a slow rate and a low yield. Moreover, the new route adopts the strategy to build an imidazole ring in the last step, avoiding the use of a low yield intermediate in the original route. In addiction, reaction conditions and workup protocols were optimized for the whole route to achieve a fairly good yield in each step without using of column chromatography for all product purifications.