Study On The Synthetic Process Of FAK Inhibitor Defactinib

Focal Adhesion Kinase(FAK)is a kind of intracellular Non-Receptor Protein Tyrosine Kinase(PTK)belonging to the Protein Tyrosine Kinase Family.It is an important signaling molecule involved in a variety of receptor and Non-Receptor Tyrosine Kinases signal transduction pathways.FAK kinase plays an important role in the physiological and pathological processes cell adhesion,migration,proliferation and transformation,and is currently a high-profile anti-tumor therapeutic target.Defactinib is a novel ATP-competitive reversible second-generation small molecule inhibitor of FAK,which was developed by Pfizer and has been acquired by Verastem.It is currently in clinical phaseⅡtrials.The drug shows good safety and tolerability,and has broad application prospects and development potential.In this article we analyzed and compared the synthetic routes of Defactinib reported in the literature,and comprehensively considered the advantages and disadvantages of each synthetic route.Finally,we determined a synthetic route that is more suitable for large-scale industrial production.Using 3-chloro-pyrazine-2-carbon-itrile and N-methyl-methane-sulfonamide as raw materials,the substitution reaction of them to obtain N-(3-cyanopyrazin-2-yl)-N-methylmethanesulfonamide(1),Intermediate 1 was aminoprotected to obtain(3-(N-methylsulfonamido)pyrazin-2-yl)methyl)ammonia(2)by Sodium Borohydride Lewis Acid System Reduction One-Pot Method,and then the key intermediate N-(3-aminomethylpyrazine-2-yl)-N-methyl methanesulfonamide(3)was obtained by de Boc protection with trifluoroacetic acid.Then 2,4-dichloro-5-(trifluoro-methyl)pyrimidine and4-amino-N-methyl-benzamide were reacted in the mixed solution of tert-butylalcohol and dichloromethane to obtain 4-((4-chloro-5-(trifluoromethyl)-pyrimidin-2-yl)-amino)-N-methylbenzamide(4).Then,the substitution reaction between Intermediate 3 and intermediate 4 in alkaline environment was occurred and obtained the target product N-methyl-4-((4-(((3-(N-methylmethyl-sulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoro-methyl)-pyrimidin-2-yl)amino)benzamide(Defactinib),with a total yield of 48.68%.In this paper,we optimized the synthesis process of Defactinib and its intermediates.The optimized synthetic route did not use a pressurized reactor,which reduced the requirements for reaction equipment,and did not use palladium-carbon catalyst and other expensive reagents,which reduced heavy metal residue,reduced experimental cost,and the reaction operation was simple.It has laid a solid foundation for its derivatization and large-scale industrial production in the future.The structures of the target compounds and some intermediates have been confirmed by ~1H-NMR and LC/MS.