Study On The Synthesis Of Punabulin

Plinabulin is a new type of targeted anticancer drug,which targeted on the neoplasms and primary blood vessels,and induced tumor apoptosis through RAS-JNK channels.It can selectively act on the tubulin binding site inside the Endothelial tubulin,inhibit tubulin polymerization,disrupt the assembly of microtubules.So that it can damage the endothelial cell skeleton,inhibits tumor blood flow,but does not harm the normal vascular system Plinabulin block spindle formation and mitotic microtubule polymerization through the mechanism of tubulin chelating,eventually leading to tumor cell proliferation blocked.In addition,to target the tumor vascular system,this product can induce of tumor cell apoptosis directly.Combined Plinabulin and docetaxel have significant anti-tumor activity and safety.Plinabulin and X-ray radiotherapy have synergistic effects on tumor cells.In this paper,we through the study of the synthetic route of Plinabulin,glycine ethyl ester hydrochloride and methyl formate were selected as the starting materials.The reaction products were substituted,dehydrated,reduced and oxidized to get fragment ?.Glycine and acetic anhydride as the starting materials,the product is fragment ?.And then fragment? and ? interacts with the fragment? of benzaldehyde to get the target product Plinabulin.In this paper,we focus on some unit reactions:(1)A new route of synthetic intermediate 4-(1,1-dimethylethyl)-1H-imidazole-5-carbaldehyde was investigated,using 2,2-dimethyl-3-pentanone as a original material.After four steps of the bromination,hydrolysis,cyclization,oxidation to get the target product;(2)We improved the purification process of intermediates,greatly reduced the consumption of manpower and material resources caused by the original process,reduced the cost,and through control of single factor variables experiments,to explore the experimental conditions of the better reaction conditions.(3)The reduction effect of the different reducing agents on the ester groups of the intermediate 5-tert-butyl-1H-imidazole-4-carboxylate(3)was discussed.When the reducing agent was lithium aluminum hydride,the reaction yield was the highest.(4)The effects of different modes of activated manganese dioxide on the oxidation of(5-tert-butyl-1H-imidazol-4-yl)methanol were discussed.(5)In this paper,we use glycine ethyl ester hydrochloride,ethyl formate as raw materials,synthesized the intermediates of ethyl isocyanurate through amidation,elimination reaction and other steps.