Chemical Structural Modification Of Tanshinone Compounds And Synthesis Of Halogenated Intermediate

Tanshinone compounds, the fat-soluble substances of Traditional ChineseMedicine dan shen, have been widely used in medical field. However, the poor water-solubility has greatly limited its application for a long time. In medicinal chemistry,chemical modification of natural products structure plays a crucial role in therapeuticimprovement and drug development. This study targets the cardiovascular compounds,tanshinons, tanshinoneⅡA, tanshinoneI and1,2-dehydro tanshinoneⅡA to transformand modify structures. The proposed products are expected to exhibit improved watersolubility and thus effectively function in halogenated reaction series.The traditional method to improve the water solubility is the introduction of polargroups in the drug structure. However, it is difficult to carry out such structuralmodification in tanshinones-like ring. Over the years, lots of work have been done totransform the tanshinone from fat-soluble to water-soluble. A critical key is to choosean appropriate structure change which can release the parent drug under physiologicalconditions and also improve the transport and metabolism of drugs (therefore,bioavailability) according to requirement of body tissues. Moreover, the polarityadjustment by introducing polar groups in the tanshinones and thebiological/pharmacological activity improvement of tanshinone derivatives are widelyaccepted and employed by the current research, such as the preparation of Chlorinatedtanshinone. The study investigated the mechanisms of tanshinones halogenatedreaction; chemical transformation; synthesis of a series of tanshinone halogenatedcompounds and its intermediate; and synthesis of tanshinone compounds. Through aseries of iodine of tanshinone compounds synthesized in the generation and bromide,the best conditions of tanshinones halogenated reaction were determined by IR, NMR;product intermediates and single crystal diffraction methods were tested and structureswere characterized.Tanshinone compounds iodination. The study used tanshinoneⅡA as raw material, halogenation reagent with potassium iodide and iodate formed by reaction in glacialacetic acid; research ratio on the reaction solvent, reaction time, reaction temperatureand tanshinoneⅡA and iodine quantity were discussed, and the optimum reactionconditions were determined as follows: glacial acetic acid was solvent, the ratio of rawmaterials n (tanshinoneⅡA):n (potassium iodide):n (potassium iodate)=10:10.5:7,reaction was performed at80℃for an hour, TLC test until the material pointdisappeared means the end point of the reaction, the reaction then can be terminated.Tanshinones bromination. Through the comparison of the two synthetizedmethods of1,16-dibromine tanshinoneⅡA, the optimum reaction conditions weredetermined as follows: dichloromethane was used as solvent, benzoyl peroxide (BPO)was initiator, reaction temperature was40℃, tanshinone brominated compoundswere as high as75%or above yield. Synthesis of1,16-dibromine tanshinone II A,the yield was75%;16-bromination of tanshinoneⅠ, the yield reached83%.Though it’s difficult to modify the anshinone structure, introducing activity ofhalogenated groups of intermediates and further implementation of polar groupssubstituted strategies are the purpose of the present study. All tanshinone iodo cantherefore stably synthesize with high yield. It has been realized as tanshinones polarwater soluble intermediates of molecular compound transformation.