Synthesis Of Anti-cancer Drug Lenvatinib And Preparation Of Its Solid Dispersion

Lenvatinib,an oral inhibitor of multiple receptor tyrosine kinase(RTK),was developed by Japan Eisai company.It mainly against for locally recurrent or metastatic,progressive,radioactive iodine-refractory differentiated thyroid carcinoma(RRDTC).Lenvatinib is almost insoluble in water.In this dissertation,lenvatinib was prepared into solid dispersion(SD)to improve the solubility of drugs in water and improve the oral absorption rate.The research contents of this paper was as follows:(1)Synthesis of Lenvatinib:In this thesis,4-chloro-7-methoxyquinoline-6-carboxa-mide and 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea were synthesized as drug intermediates.Subsequently,the two intermediates were subjected to nucleophilic substitution under the catalysis of potassium t-butoxide and sodium carbonate to prepare the target compound lenvatinib.The product trait was white powder with a single step yield of85.2%.In the route,phenyl chloroformate was replaced by non-toxic phenyl p-nitrochloroformate to participate in the acylation reaction.The optimum feed ratio and reaction temperature of the raw materials in the acylation reaction and the two bases in the nucleophilic substitution reaction were investigated.The optimum feed ratio of the reagents.By optimizing the conditions,the reaction cost was reduced,the reaction yield was improved,and a non-toxic synthetic route was designed,which is in line with green chemical production.In addition,the lenvatinib structure was determined by Fourier Transform infrared spectroscopy(FT-IR),Electrospray Ionization Mass Spectrometry(ESI-MS)and Proton nuclear magnetic resonance(~1H-NMR);and the maximum absorbance of lenvatinib was determined by Ultraviolet and visible spectrophotometry(UV-Vis).(2)Pre-prescription study of lenvatinib solid dispersion:According to the physical-chemical properties of lenvatinib and the preparation process of SD,the dissolution of lenvatinib in different solvents was investigated.And the changing rules of lenvatinib under high temperature or strong light irradiation conditions were studied.The method for the determination of lenvatinib,the content of lenvatinib SD and dissolution were established by UV-Vis.(3)Preparation of lenvatinib solid dispersion:In this thesis,hydrophilic materials such as PEG4000,PVPk30,Co PVP and PEG6000 were used as SD carriers.And lenvatinib SD was prepared by melting method,solvent method and solvent-melting method,respectively.Based on the dissolution of lenvatinib SD in the dissolution medium,the carrier type,the ratio of the drug to the carrier,the preparation method,the reaction time,the reaction temperature,and the solvent dosage on the dissolution of the lenvatinib SD were investigated.The optimum preparation process of lenvatinib SD was discussed as follows:The solvent method was used as the preparation method,and methanol was used as the reaction solvent.Co PVP was used as carrier,and the mass ratio of the drug to the carrier was 1:7.The reaction time was 30 min,and the reaction temperature was 55?.The results show that the lenvatinib hardly dissolved within 60 min,while the dissolution of the lenvatinib SD reached 90.39%.(4)Quality evaluation of lenvatinib solid dispersion:In this thesis,X-Ray Diffraction(XRD),Differential Scanning Calorimetry(DSC),FT-IR and Scanning Electron Microscopy(SEM)were used to identify lenvatinib,Co PVP carrier material,lenvatinib SD and physical mixture(PM).The results showed that lenvatinib existed as needle-like crystals in PM,but amorphous state in SD,and no needle-like crystals.In addition,the content,properties and dissolution of lenvatinib SD were investigated by high temperature test,high humidity test,intense light irradiation test,accelerated test and long-term test.The results showed that the lenvatinib SD should be sealed and stored in low temperature and dry environment.