Study on Optimization of Synthetic Process of Candidate Drugs of Procyclitinib Hydrochloride(CY03529B)
Chronic myeloid leukemia(CML)is a myeloproliferative disease caused by genetic mutations acquired from hematopoietic stem cells.As Tyrosine kinase inhibitors imatinib were approved by the Food and Drug Administration as clinical treatment of the disease,the problem of acquired drug resistance became more and more obvious,and the mutation of gene T315I was the most difficult to overcome.The second generation of Bcr-Abl tyrosine kinase inhibitors did not respond to the mutant,and the third generation inhibitors had good therapeutic effect but had great side effects.Therefore,by reviewing literatures and analyzing the eutectic structure of Type Ⅱtyrosine kinase inhibitors and Bcr-Abl kinase proteins,this research group designed and synthesized procyclitinib with tetrahydronaphthalene as its parent nucleus.Studies on cell activity and in vivo activity showed that it had better inhibitory effect on K562/G01 resistant cells and was superior to imatinib.In this process,6-methoxy-1-naphthomanone was used as the starting material to obtain procyclitinib hydrochloride through nucleophilic substitution,reduction,amide exchange and salt formation.On the basis of controlling the reaction material,the process parameters of each step were further investigated and optimized to achieve the synthesis process of procyclitinib hydrochloride,which was beneficial to scale-up production.The structure of the obtained product was confirmed by mass specturm(MS)and nuclear magnetic resonance hydrogen(1 H-NMR),and the results showed that the structure was correct.The whole process is short in time,simple in operation,low in cost,and the total yield is more than 26%.
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