Synthetic Study Of Maleimide Derivatives And Belinostat

In molecular biology, the function and mechanism research of protein, fat and other biological macromolecules have important significance. The high complexity of macromolecular structure and metabolic characteristic make related researches with great challenge. Bioorthogonal reactions, which can make the small molecule probes selectively label the biological macromolecules by the covalent bonds, is very helpful to study the function and mechanism of the biological macromolecules. Bioorthogonal reactions have special requirement. Till now, bioorthogonal reactions which were found are mainly divided into two types:the dipole reactions and the cycloaddition reactions.This paper attempts to develop maleimide derivatives as the bioorthogonal reaction reagent. We designed three kinds of maleimide derivatives with electron withdrawing substituents (bromo, nitro, sulfonic acid group) on C-3. N-benzyl-3-bromomaleimide was successfully synthesized. The condition of cycloaddition reaction between N-benzyl-3-bromo maleimide and azide was explored. Through the study, we found the cycloaddition reaction can occur in toluene or ethyl acetate under reflux condition and generate maleimide-[1,2,3]thiazole structure compound. The reaction solvent and temperature make maleimide derivatives with bromo group on C-3 not suitable for bioorthogonal reaction. We also tried to introduce nitro or sulfonic acid group into maleimide derivatives. When N-(t-butyl) maleimide was heated to 50? in nitric acid/acetic anhydride system, N-(t-butyl)-4-diazo-2,3,5-pyrrolidinetrione was generated. While N-(t-butyl) maleimide reacted in nitric acid/ acetic anhydride system, catalyzed by concentrated sulfuric acid under 30?, the product of N-(t-butyl)-3'-nitro-3,4-dihydromaleimideisoxazole was formed.In addition, this paper did a study on the synthesis of Belinostat, which is a drug for the treatment of peripheral T cell lymphoma in adults, approved by FDA in 2014. At present, the synthetic method of Belinostat has some disadvantages:the starting material 3-carboxybenzenesulfonic acid sodium salt is not easy to be prepared; Oxidant is PCC in the oxidation of primary alcohols to aldehyde, which is unfavorable for the quality of the drug and environment because of metal chromium ions; improved oxidizing agent 2-iodoxybenzoic acid (IBX) is expensive and results in high cost of production.This study mainly focuses on the improvement and optimization of Belinostat's synthetic process route. The inexpensive benzoic acid was used as raw material.Via chlorosulfonation, condensation with aniline, reduction, Parikh-Doering oxidation, Witting-Horner condensation and hydrolysis of the ester, chlorine replacement and hydroxylamine condensation six step reactions, Belinostat was prepared. Among them,3-carboxybenzenesulfonyl chloride (compound II), a key intermediate of Belinostat, was synthesized through chlorosulfonation. The reaction steps were reduced. In view of the shortcomings of the existing process, the oxidant of the primary alcohol (compound IV) oxidation reaction was screened. With dimethyl sulfoxide (DMSO) as oxidant, aldehyde (compound V) was synthesized successfully using phosphorus pentoxide or pyridine sulfur trioxide as auxiliary oxidant in the yields of 52% and 76% after purification. Preferably, pyridine sulfur trioxide as auxiliary oxidant was selected. Compared with IBX, the method greatly cut down the cost of production. We purified aldehyde (compound V) through salifying with sodium bisulfite and then made it free by adding alkali. Through a large number of experiments, we optimized the reaction conditions and the feed ratio of reactants, which layed a foundation for the large-scale production.