Synthesis And Characterization Of Tacrine Analongues

Tacrine(THA) was the first cholinesterase inhibitor approved in USA for symptomatic treatment of AD. It is a centrally acting reversible cholinesterase inhibitor. However, it exhibits hepatotoxicity by markedly elevating serum alanine aminotransferase levels, and thus has a limited clinical application.Considerable amount of THA derivatives and its analogues were synthesized in this paper in order to find compounds with reduced side effects. The intermediate product 3-amino-1-aryl-1H-benzo[f]chromene-2-carbonitrile and 2-amino-4-aryl-4H- benzo[h]chromene-3-carbonitrile were prepared by the reaction of malononitrile and naphthol with corresponding aromatic aldehydes in ethanol. Then, 5-substituted-1,3- cyclohexanedione reacted with the intermediate product respectively by condensation reaction and dieckman to afford a series of novel Tacrine derivatives.We have utilized two methods for the synthesis of target compounds, in the first traditional the method that benzo[f/h]chromenes reacted with 5-substituted-1, 3-cyclohexanedione using pTSA (P-Toluene sulphonic acid) as catalyst in toluene, and then the title compounds were obtained in THF using K2CO3/Cu2Cl2 as catalysts. the method suffered from certain drawbacks such as long reaction time, unsatisfactory yields, using of hazardous solvents, complex process, low selectivity, co-occurrence of several side reactions and needing of chromatography for purification of adducts. In the second method, we improved the method, we used methanol instead of toluene using dilute hydrochloric acid as catalyst. Compared to other methods, the new methods offered many advantages such as simple operation, short reaction time and low toxic.Twenty-eight new heterocyclic compounds were synthesized in this paper, including 11 tacrine analogues, the structures of all the synthesized compounds were characterized by IR,1H NMR,MS spectrum and elemental analysis. We also trained two single crystals to characterize the space configuration by using X-Ray diffraction. In addition, we discussed the Plausible Formation Mechanism and the optimum condition for reaction.