Process Development For The Synthesis Of Tucatinib

Tucatinib is a tyrosinase inhibitor that can effectively bind and inhibit the phosphorylation of Erb B-2,preventing the activation of Erb B-2 signal transduction pathway,thereby inhibiting the growth of tumor cells.Compared with other targeted drugs,tucatinib has the characteristics of high selectivity and less off-target effects and has been recognized by the FDA as a rare disease drug for the treatment of brain metastatic breast cancer.There are few studies on the synthesis process of tucatinib,the existing process has long steps,the separation and purification of intermediate products are difficult,and the use of expensive reagents such as trifluoroacetic anhydride,1,1’-thiocarbonylbis（imidazole）and hydroxylamine-O-sulfonic acid,the production cost is high,and it is difficult to industrialize application.In this paper,through the analysis and exploration of the existing synthetic route of tucatinib,the synthetic route of using 2-methyl-4-nitrophenol and 2-amino-4-chloropyridine as raw materials was determined.The key steps such as nucleophilic substitution reaction,intramolecular dehydration ring closure and methylation reaction were explored in detail,and on this basis,other steps were studied,and the optimization of the entire synthesis process was completed.In the aromatic nucleophilic substitution reaction,by exploring the influence of different coupling methods and aryl chlorides on the reaction,it was determined that2-amino-4-chloropyridine can be used as the raw material to effectively realize the construction of diaryl ethers.The reaction conditions were further optimized,and the effects of reaction temperature,reaction time,solvent effect and other factors on the reaction were explored to determine the optimal process conditions,and the product yield reached 63.3%;By analyzing the mechanism of dehydration cyclization of N-hydroxy-N’-[4-（2-methyl-4-nitrophenoxy）-2-pyridinyl]methanimidamide,The effects of dehydration reagents,reaction temperature on the reaction were studied.Acetic anhydride was used as dehydration reagent.The process was simple and more economical than the methods reported in the literature;In the cyclization reaction of N’-（2-cyano-4-nitrophenyl）-N,N-dimethylmethanimidamide,the influence of the type and amount of acid,reaction temperature and other factors on the reaction yield was studied,the cyclization reaction yield was increased to 93.4%,which was 12.4%higher than that reported in the literature.In the process of synthesizing 4,4-dimethyl-2-oxazolidinethione,the influence of different synthesis methods on the reaction was explored,the process route of using2-amino-2-methyl-1-propanol and carbon disulfide as raw materials was determined,and the formation of side reactions was effectively avoided by adding hydrogen peroxide as an oxidant in the reaction system,and the product yield was increased to91.9%,which was 10.9% higher than that reported in the literature.In the methylation reaction of 4,4-dimethyl-2-oxazolidinethione,methylation reagents such as methyl iodide,dimethyl carbonate,and dimethyl sulfate were discussed.Determined the better process conditions,and the yield of the product with dimethyl sulfate as the methylating reagent reached 94.3%,which was more economical;By studying the effect of different catalysts on the hydrogenation reduction reaction,it was found that Raney nickel can achieve reductive hydrogenation under mild conditions.By further optimizing the catalyst dosage,hydrogen pressure and other conditions,the reaction yield was increased to 92.3%,and the synthesis process was further simplified.This article designed and optimized the synthesis process of Tucatinib,compared with the existing synthetic route,it has the characteristics of high atom economy,convenient separation and purification of intermediate products,low production cost,and has important application value and development prospect.