Study On The Synthesis Of Novel Benzimidazole Derivatives

Benzimidazoles is a class of aromatic heterocyclic compounds containing nitrogen,comprised by benzene ring and imidazole ring.Benzimidazole and its derivatives with biological activity and good reaction activity,antibacterial,anti-cancer,anti diabetic,anti ulcer,anti hypertension is widely used,synthesis study on benzimidazoles is profoundly significant.Recent studies show that benzimidazole and its derivatives have good anticoagulant activity,and dabigatran as a novel thrombin inhibitor has anticoagulant effect can be predicted,oral administration,without clinical detection,few drug interactions,broadly application prospect.However,the oral bioavailability of dabigatran was only 7.2%,and there were some adverse reactions such as bleeding,constipation,fever,nausea and so on.Therefore,it is of great value to study the synthesis methods and structures of dabigatran.In this paper,we used convenient source of 4-dimethylamino-3-nitrobenzoic acid as raw material,we used cheap and convenient source of 4-dimethylamino-3-nitrobenzoic acid as raw material,improved the synthesis process of dabigatran,and prepared three kinds of benzimidazole derivatives,discussed the reaction mechanism and the success of each synthetic route,the structure of products and intermediates were characterized by UV,IR and NMR characterization.The main work is as follows: 1.Using an inexpensive and convenient source of 4-dimethylamino-3-nitrobenzoic Acid1.Using an inexpensive and convenient source of 4-dimethylamino-3-nitrobenzoic Acid as raw material,through esterification,reduction,amidation,cyclization,reaction of amidine,the synthesis process of dabigatran was improved,the yield increased to 57.1% from 12.5%,and the synthesis process has the characteristics of mild condition and easy operation.2.Using aminobenzonitrile and 4-dimethylamino-3-nitrobenzoic Acid as raw material,the synthesis of benzimidazole derivatives 2-cyclization reaction through esterification,reduction,(((4-cyano phenyl)amino)methyl)-1-methyl-1H-benzimidazole-5-ethyl formate(I).3.Using dabigatran key intermediate 3-[(3-amino-4-methylamine benzoyl(-2-)pyridine base)amino] ethyl propionate(G)for the synthesis of benzimidazole derivatives 3-[[[2-(Hexyloxy)carbonyl] amino] methyl]-1-methyl-1H-benzimidazole-5-] carbonyl](-2-pyridine base)amino] ethyl propionate(II),using the traditional high temperature acid reflux conditions did not succeed,try the microwave catalytic cyclization conditions also failed.The reaction mechanism was discussed.4.Using dabigatran and resveratrol to preparation of benzimidazole derivatives as raw materials(III,IV),by screening the linking group(Succinic anhydride,Succinic acid and Terephthalic acid)model reaction,and ultimately determine Succinic anhydride as the linking group of coupling reaction.