Synthetic Process Study Of Lenvatinib Mesylate

Lenvatinib Mesylate is an oral multi-target tyrosine kinase inhibitor(TKI)developed and produced by Eisai Japan which targets VEGFR1-3,FGFR1-4,PDGFR-α,c-kit receptor,RET protein,etc.Currently there are three approved indications:treatment of aggressive,locally advanced or metastatic differentiated thyroid cancer(DTC);combined with everolimus(everolimus)for advanced renal cell carcinoma(RCC);first-line treatment of unresectable Hepatocytes Cancer(HCC).In September2018,Lenvatinib Mesylate was approved by the CFDA for import to treat unresectable Hepatocellular Carcinoma(HCC).This thesis will start with the process development and process impurities and conduct research on the process control of Lenvatinib,and study impurites spectrum,laying the foundation for future product quality control and research.This article analyzes the existing routes and determines the synthetic route of lenvatinib mesylate after four steps of reactions.The starting materials 4-chloro-7-methoxyquinoline-6-carboxamide(1)and 3-chloro-4-aminophenol(3)were reacted by phenolic hydroxyl alkylation,then 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide(7)was obtained.When prepare Lenvatinib from 7,the "one pot method" in the literature is replaced by a two-step method:The key intermediate{4-[(6-aminocarbony-l-7-methoxy-quinolin4-yl)oxy]-2-chlorophenyl}carbamic acid phenyl ester(12)is obtained after 7 and 4 undergo nucleophilic substitution amidation reaction;Then 12 reacted with cyclopropylamine to generate lenvatinib by nucleophilic substitution amination.In methanol,lenvatinib and methanesulfonic acid form lenvatinib mesylate.The total yield of the four steps is 67.5%(calculated as compound 1),the purity of the final product is 99.89%,and the specific impurities are less than 0.1%.The structure is confirmed by mass spectrometry and 1H-NMR.The process reaches the laboratory scale of one hundred grams,which is stable and controllable and has good repeatability.In this paper,the following optimizations have been made for each step of the synthesis process:1)Using 3-chloro-4-aminophenol(3)to replace its hydrochloride,the reaction time was shortened from 20 h to 2h;By adjusting the feed ratio,the reaction cost were reduced;2)The intermediates 7 and 4 were reacted without water and the reaction time is reduced from 3h to 0.5h;Combined with the conditions of process impurities at different temperatures,the reaction temperature(-20℃)was verified;3)Using DIPEA as base,the reaction time is shortened from 15 h to 0.5 h;4)The marketed crystal form A of lenvatinib mesylate was prepared,which was confirmed by XPRD.Based on the synthesis route,by the reasonable estimation,synthesis,verification and quality control of the process impurities in each step of the reaction,reasonable impurity limit standard was established.A total of thirteen organic impurities were speculated,including eleven potential process impurities and two potential degradation impurities,and they were tracked and removed;a suitable analysis method was established.The finished product and impurities were well separated,and the impurity spectrum in the finished product was detected and analyzed.