Studies On Synthesis Of Anticancer Drug Cabozantinib And Its Intermediates

Cabozantinib(XL184)is a small molecule inhibitor of the tyrosine kinases c-Met,VEGFR2 and Ret.It was developed by Exelixis Inc.and was approved by the U.S.FDA in2012 for medullary thyroid cancer and advanced renal cell carcinoma in people who have received prior anti-angiogenic therapy.Tivozanib(KRN-951)is a potent and selective VEGFR inhibitor,which has shown antitumor effects in human breast,colon and renal cell carcinoma(RCC)xenograft models.It was developed by AVEO Pharmaceuticals and Astellas.In 2016 AVEO Oncology published data in conjunction with the ASCO meeting showing a geographical location effect on Overall Survival in the Pivotal Phase III trial.They all belong to the anticancer drugs,and all contain 4-hydroxy quinoline compounds.In recent years,anticancer drugs appearing on the market of this kind are mostly complex derivatives of quinoline.With regard to preparing of these drugs and the key intermediates,it often involves multi-step reaction units,which are very harsh on the reaction condition,serious environmental pollution,not fit to the expansion of production,including high temperature conditions(260°C)of cyclization reaction.The solvent Ph OPh has a larger stimulus and difficult to recovery and the product contains black insoluble impurity and difficult to purification.The raw materials are expensive in some steps,so that the cost of this kind of drug is high.This paper reports the new synthesis of quinoline anticancer drugs containing of various kinds of structure.4-Hydroxy quinoline structure is designed,the synthetic conditions are optimized,the costs and the"three wastes"are reduced,in order to meets the requirements of green chemistry.The main work of this paper includes the following three aspects:First,the synthesis process of 4-hydroxyl-6,7-dimethoxy quinoline is optimized.Commercially available 1-(3,4-dimethoxyphenyl)ethan-1-one is used as the starting material,through nitration,condensation,reductive cyclization to give the6,7-dimethoxyquinolin-4-ol.This route contains mild reaction conditions after optimization.The reaction temperature is controlled under 110°C.The reaction yield are>75%of every step.The reaction process are calculated through the VASP system,the parameters of dynamics and thermal reaction in the process of calculation,verified the synthesis method is feasible and effective,energy consumption lower than the reported method has lots of advantages.Second,the synthetic process of cabozantinib is given.New and improved synthetic route of cabozantinib is described on a hectogram scale.Commercial available materials,simple reaction and operation are used,including nitration,condensation,hydrogenation,chlorination and so on,to give the final product in 31%yield over seven steps and>99%purity(HPLC),which has the potential of industrial production and practical value.Last,the reductive cyclization method is adopted in other fields.1.The synthesis of tivozanib is based on reductive cyclization method,to give the final product in 28.7%yield over six steps and>99%purity(HPLC).2.The synthesis of 3-cyano-4-hydroxyquinoline is adopted the method of reductive cyclization,which is the key intermediate of bosutinib.The reaction steps are less,and the operation is convenient.All of the compounds have been characterized by ~1HNMR,LC-MS spectra,and the final compound purity detection have been characterized by HPLC.