Study On The Synthesis Of Pharmaceutical Building Blocks Containing Indole Structure

In modern organic catalysis,the C-H activation of the poorly nucleophilic benzene ring site on the indole ring has attracted great attention.Early related research was based on stoichiometry and directed metallization reaction to realize the functionalization of benzene ring.Recent studies have shown that the less active sites(C4-C7)on the benzene ring can be constructed by the strategy of C-H bond functionalization.C-H functionalization strategies based on transition metals,enzymes,and other non-metal catalysis provide new indole C-H activation methods,which will further promote the development of this field.In view of this,this article provides two examples of rhodium catalytic systems to achieve C-H activation of indole.The main research contents are as follows:Part 1Transition metal-catalyzed C-H activation of indole mostly uses guiding groups with strong coordination,but ester groups with weak coordination have not been reported.We introduced methyl indole formate at the C3 site of indole as the guiding group,and under the catalysis of rhodium,the indole C4-H activation reaction was realized.In the reaction,common acrylates are used as reagents to directly obtain indole C4 alkenylation products.Such as monosubstituted styrene,vinyl phenyl sulfone,etc.can be better adapted to the system.In addition,the corresponding products can also be obtained from the substrates of the methyl,methoxy,halogen and benzene ring substituents on the indole ring.Part 2Based on the relevant experience of rhodium-catalyzed C4-H catalytic activation of indole,we developed a diphenylacetylene reagent with greater steric hindrance to realize the C4 functionalization of indole.In this method,a weaker ester group is also used as the guiding group,and a rhodium reagent containing hexafluoroantimonic acid is specifically synthesized.Under the activation of the rhodium catalyst,the indole C-4 alkenylation product is obtained in a moderate yield..The diversified di-substituted alkynes in this system can make the reaction proceed smoothly.Part 3In recent years,cyanine dyes containing indole rings have been widely used in many aspects,but their synthesis methods have many shortcomings in yield and technology.And this part takes pentamethylene cyanine dyes as an example to provide an optimization method for its synthesis process route.We use 1,1,2-trimethyl-lH-benzo[e]indole as the starting material to synthesize carboxylated and sulfonated products with 6-bromohexanoic acid and 1,4-butane sultone,respectively.The sulfonated product and the hydrochloride salt are used to obtain the semi-cyanine intermediate,and then the pentamethine cyanine is obtained by the one-pot method with the carboxylated product,and finally the pentamethine cyanine esterified product is obtained with the bis(2,5-dioxopyrrolidin-1-yl)carbonate.By optimizing the reaction conditions and purification methods of each step,we have initially obtained a process route suitable for industrial production.