Aza, Oxa, The Thia Tetrahydroacridine Derivatives Synthesis

Recent advances in the synthesis and pharmacological effects of tacrine derivatives and their analogues is summarized.Tetrahydroacridine molecule was manipulated by introduction of nitrogen atom, oxygen atom, sulfur atom in aliphatic ring and methoxy in aryl ring, based on isosterism principle and used tacrine as lead compound, tetrahydroacridine as matrix. Ten new tetrahydroacridine derivatives compounds were designed and synthesized in two different methods by Friedlander procedure and one-pot reaction.The nitro-veratrylaldehyde (2a) and 3,6-dimethoxy-2-nitrobenzaldehyde (2b) have been prepared from veratraldehyde (la) and 2,5-dimethoxy-benzaldehyde (lb) in the presence of acetic anhydride with nitric acid at the room temperature,. Reduction of (2a²b) with iron powder afford the corresponding amino aldehyde (3a-3b). Condensation of the aminoaldehydes (3a³b) with cyclic ketones (4a⁴e) respectively in ethanol with catalytic amount of sodium ethoxide yielded the expected target compounds (5a⁵j) in high yields.In addition, dimethoxy substituted o-nitrobenzaldehydes(2a²b) reacting with N-substituted-4-piperidone(4a⁴c) by one-pot reaction in ZnCl₂/SnCl₂and absolute alcohol, in which the intermediate o-aminobenzaldehyde was not isolated, but immediately converted into new tetrahydroacridine derivatives (5a⁵c, 5f⁵h) by Friedlander condense reaction. The construction of compounds (5a⁵j) were confirmed by IR, MS, ¹H NMR and Elemental Analysis.The reaction conditions of Friedlander condensation and one-pot reaction, such as solvent, catalyst, reaction temperature and time were discussed. The synthesis is useful to produce and extend new medicine production in the industry. It offers the basis of studying and producing new medicine.