Research On Optimization Of KX2-391 Synthesis Process

As the first killer of human beings in the new century.Malignant tumor is one of the hot topics of global public health.In recent years,with the increasing demand for anti-cancer drugs in the global pharmaceutical market.The development of targeted drugs has become a research trend of anti-tumor drugs.Protein kinase inhibitors account for the most in the mechanism of action of antitumor drugs.Src kinase is a protein with the activity of protein tyrosine kinase.It plays an important role in cell processes such as cell proliferation,differentiation,movement and localization.It regulates the behavior of cells and is closely related to the occurrence of various tumors.It is a promising anti-cancer molecular target.KX2-391 is the first clinical Src inhibitor(peptidomimetic)and a highly selective Src kinase inhibitor that can treat or prevent cell proliferative disease.In preclinical studies,KX2-391 has demonstrated potent antitumor activity in a wide range of tumor cell lines,which lays the foundation for further research in Phase II clinical trials.Digging into the literature,there are some shortcomings in the synthetic routes of KX2-391 which can not enlarge production perfectly.and there is a great market demand for KX2-391 and its intermediate.Therefore,this subject is entrusted by the partner.Entrusted.Develop laboratory technology and do the corresponding standards so that lay the foundation for the Pilot scale and the study of derivatives in the test next step.This paper selects and designed the synthetic route of KX2-391 and its key intermediates,and it is determined that the line one is more suitable for pilot scale production through the process optimization.4-hydroxyphenylboronic acid and 5-bromo-2-iodopyridine were used as raw materials to form two intermediates by transesterification,williamson ether reaction and substitution,hydrolysis and amidation reaction,and then the target product KX2-391 was carried out by Suzuki coupling reaction.Compared to the literature precedence,this route is low-cost,easy purification and convenient.The key intermediates can be subjected to Suzuki coupling reaction with different aryl borate esters to form derivatives,and the synthetic route of a derivative is determined through experiments.After optimization,the total yield of the route was 23.1%(the yield of vast majority of intermediates were more than 80%).The purity of the final product is greater than 99.94%.The intermediates and target product structures synthesized herein were characterized by 1H NMR and MS.