Optimization On The Synthesis Of Anticancer New Drug LY989-03

According to incomplete statistics,more than 14 million new cancer patients were occurred each year and eight million deaths were caused by cancer which about one-sixth of the total deaths.Antineoplastic drugs may be divided into two categories:cytotoxic and non-cytotoxic agents.However,anticancer drugs induce high toxicities and side effects in patients because the antineoplastic drugs commonly affect not only the cancer cells,but other cells that commonly reproduce quickly.Non-cytotxic agents include tyrosine kinase inhibitors that can block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression.To develop the small molecular targeted drugs based on tyrosine kinase signaling pathway provides a new way for the treatment of related malignant tumors.LY989-03 is an oral effective selective inhibitors of tyrosine kinase developed by AB Bioscience Company.According to bioisosterism principle and Imatimib,replaced pyrimidine with thiazole to get LY989-03.It has good oral bioavailability and not interaction with Abl that can reduces the toxicity of the heart.Some clinical researches indicated that LY989-03 has potential therapeutic effects on gastrointestinal tumors,hypertrophic cells,acute leukemia,melanoma and other tumors.With the deepening of clinical research,it is expected to expand its therapeutic range of cancers.However,this drug has neither been listed in our country,nor imported and the cost is expensive.The technology research of LY989-03 has great practical value.In the study of synthetic process referred to the references,we optimized the synthetic methods of LY989-03.At first,LY989-03 was synthesized from 2-methyl-5-nitroaniline by condensation,thiazole cyclization and hydrogenation to give 6-methyl-N-?4-?pyridin-3-yl?thiazol-2-yl?benzene-1,3-diamine,then followed by Schotten-Baumann reaction.The structure of LY989-03 and intermediates were confirmed by ¹H-NMR,¹³C-NMR and high resolution Mass Spectrum.Secondly,based on the original preparation process,we optimized the bromination,condensation,cyclization,hydrogenation and some post-processing methods.The experiments proved that these changes were advantageous to improve the yield and purity of the product.The overall yield of the optimized route was 33.1%[based on 4-?chloromethyl?benzoic acid,28%in the literature],which increased 5%than the reported route.To sum up,these optimized methods can improve environment,reduce costs and simplified the production processes,which was more suitable for the industrial process.