Synthesis And Preliminary Activity Evaluation Of Dasatinib Analogues And Preparation Of Gastric Floating Tablets

Based on the previous work, dasatinib gastric floating agents were designed andprepared for low oral bioavailability using commercial dasatinib tablets. We also studiedthe synthesis of dasatinib for the realization of its high yield, low-cost, low consumption inindustrial production. With combination principle, we designed and synthesized oneseries of dasatinib analogues. The cytotoxic activity of these target compounds wasevaluated in vitro by MTT assay against K562, dasatinib used as a positive control.In the synthesis of dasatinib, we focused on the synthetic process of intermediateβ-ethoxy acryloyl chloride(3),4,6-dihydroxy-2-methylpyrimidine(7) and4,6-di-chloro-2-methylpyrimidine(8).①During the synthesis of β-ethoxy acryloylchloride(3) with vinyl ether and oxalyl chloride, the temperature of the de-HClreaction was strictly controlled at room temperature22℃.②The optimalconditions of synthesis of4,6-dihydroxy-2-methylpyrimidine were investigated byorthogonal test. They were: n(acetamidine hydrochloride)/n(sodium methoxide)=1:3.4, in methanol at20℃for4h, the yield of4,6-dihydroxy-2-methylpyrimidine was85.76%.③The intermediate4,6-dichloro-2-methylpyrimidine(8) was chloridizedwith phosphorus oxychloride and triphosgene. The optimal conditions of chlorinationwith phosphorus oxychloride were investigated by orthogonal test. They were: n(N,N-diethyl-Benzenamine)/n(4,6-dihydroxy-2-methylpyrimidine)=2:1, in phosphorusoxychloride at105℃for4h, the yield of4,6-dichloro-2-methylpyrimidine was69.55%.The optimized conditions of chlorination with triphosgene were: n(triphosgene)/n(4,6-dihydroxy-2-methylpyrimidine)=3.5, in1,2-dichloroethane use appropriateorganic base N, N-diethyl aniline at reflux temperature, the yield of4,6-dichloro-2-methylpyrimidine was92.30%.Based on the study of the synthetic chemistry of dasatinib, ten dasatinibanalogues were designed,synthesized and confirmed by1H NMR and LC-MS. Thesynthetic route was simple, the raw materials was easy to get, and the yield washigh. These compounds was tested of the inhibitory activity on human chronicmyelogenous leukemia cells (K562) by the method of MTT. Most of them have theinhibitory activity, and target compounds A-2, A-5and A-8exhibited potent anticancer activity against the K562cell lines with IC50values of1.6,1.5and1.6nmol·L-1,respectively. Based on the results, we also discussed the structure-activityrelationship of these compounds. This study provided some theory basis forsearching for better activity of compounds in the latter.In this paper, we prepared gastric floating tablets using hydroxypropyl methylcellulose, ethyl cellulose, pregelatinized starch and stearyl alcohol as the pharmaceuticalexcipients. UV had been used for the determination of dasatinib in vitro. The optimizedprescription of preparation of gastric floating tablets was m(dasatinib):m(HPMC):m(EC):m(pregelatinized starch):m(stearyl alcohol)=1:5.85:1.05:1.05:1.05.In vitro, the release propertie of gastric floating tablet complied with pharmacopoeiarequirements.