Synthesis Of TRK Inhibitor Larotrectinib And Synthesis Of Benzoxazole And Benzothiazole Derivatives Catalyzed By Imidazole Hydrochloride

This paper consists of the synthesis of TRK inhibitor Larotrectinib and the synthesis of benzoxazole and benzothiazole derivatives catalyzed by imidazole hydrochloride.Part 1: Synthesis of TRK inhibitor Larotrectinib.Larotrectinib is the first TRK targeting inhibitor for the treatment of unresectable or metastatic solid tumors containing NTRK fusion protein in adult and pediatric patients.Researches on mechanism suggest that Larotrectinib can inhibits both the catalytic activity and autophosphory-lation of TRK receptor by competitively binding to the ATP site of intracellular TRK receptor,which consequently blocks the conduction of downstream signaling pathways and exerts anti-tumor effect.The U.S.Food and Drug Administration authorized Larotrectinib for the treatment of TRK fusion-positive cancer in Nov.2018.In the following year,Larotrectinib was accepted for clinical application in China in Jan.2019,accompanied with its marketing approved by European Medicines Agency in Jul.At present,the synthesis of Larotrectinib mainly includes the following: Haas J proposed to use pyrrolidine-1-carboxylic acid tert-butyl ester and 2,5-difluorobromobenzene as starting materials,which undergoes successively palladium-catalyzed coupling reaction,DIEA-catalyzed con-densation,nitration,zinc powder reduction and other reactions to obtain Larotrectinib.This method has low yield and high synthesis cost;Arrigo A proposed that Larotrectinib was obtained from 2,5-difluorobromobenzene,2-oxopyrrolidine-1-carboxylic acid tertiary Butyl ester through Grignard reaction,hydrogenation reduction,nitration,chlorination and so on.Reynolds M put 2,5-difluorobenzalde-hyde,(R)-tert-butylsulfinamide,phenyl chloroformate as raw materials to obtain Larotrectinib with a total yield of 46%.This method reduces the synthesis cost and improves the total yield.On the basis of literature,our team have designed a new synthetic route of Larotrectinib: the key intermediates which were synthesized through hydrobration-oxidation,hydroxyl activation and intramolecular ring closure with the raw materials of 2,5-difluoroben-zaldehyde,tert-butylsulfinamide and allyl magnesium bromide were used to obtain Larotrectinib.However,during the experiment,it was found that there are some difficulties on intramolecular ring closure.At the same time,due to the difficulty in synthetizing the key intermediates,we proposed to use 5-chloro-3-nitropyrazolo [1,5-a] pyrimidine,butyrolactam,methyl 2,5-difluorobenzoate as raw materials and undergo CN coupling,aldol condensation,intramolecular decarboxylation to form rings and then condense with(S)-3-hydroxypyrrolidine to obtain Larotrectinib.This method avoids the synthesis of intermediates that are hard to synthesize,reduces the reaction steps,and improves the utilization of raw materials.Part 2: Imidazole hydrochloride catalyzes the synthesis of benzoxa-zole and benzothiazole derivatives.The benzoxazole and benzothiazole are an important part of various natural compounds,luminescent materials and drugs,which also play an important role in many fields such as biology,chemistry,and physics.In this paper,imidazole hydrochloride was used as a catalyst to synthetize benzoxazole and benzothiazole derivatives.This method is simple in operation,low in cost,high in yield,and with broad scopes of substrate.