Study On The Synthesis Process Of LGK974

Tumors are produced due to the abnormal tissue proliferation of the local tissue cells in the body under the attraction of oncogenic factors.Tumors are classified into benign and malignant tumors.Benign tumors are highly curable while malignant tu-mors have extremely high mortality in the current medical environment.In recent years,malignant tumors have become a high-incidence diseases worldwide,seriously endangering human health.The researchs of anti-tumor drugs have shifted from the initial cytotoxic drugs to target therapeutic drugs,cell signaling inhibitors,and cellu-lar immunotherapy drugs.It was found that Wnt signaling pathway exists in the pro-cess of abnormal expression,proliferation and differentiation of tumor cells through the study of tumor cells.In the Wnt signaling pathway,Wnt protein needs to be modi-fied by palmitoylation of Porcupine to secrete extracellular.Therefore,the study of Porcupine inhibitor has become a hot spot in anti-tumor drug research.LGK974 is a small molecule inhibitor targeting Porcupine,which was developed by Novartis.It is currently in Phase II clinical research.In the field of Porcupine small molecule inhibitor research,LGK974 became the first clinical research drug,which shows that LGK974 is of great significance in anti-tumor research.It is found that LGK974 has some synthetic routes reported after a review of relevant literatures.But somereagents such as organotin and organozinc are involved in the existing synthetic routes,and some intermediates are not conducive to industrial production.Therefore,this study designed and optimized a new synthetic route to overcome the shortcom-ings of the existing methods,which lays the foundation for pilot experiment,scale-up production and related derivatives research of LGK974.This project studiedthe process route for the intermediates and final products of LGK974 commissioned by partner company.The designed routes are compared and screened to determine a more appropriate production route.The target compound is obtained by substitution reaction,Suzuki reaction,amidation reaction and so on using2-amino-5-bromopyridine,2-chloro-3-methylpyridine,2-iodopyrazine and 2-methyl-6-chloropyridine as raw materials.Compared with the reported routes,the route is simple,cost-effective and environment-friendly.The total route yield is 11.5%,and the final product purity is greater than 99%.The structures of the compounds were confirmed by ¹H NMR,¹³C NMR and MS.