Bilastine intermediate preparation method

Abstract

The present invention relates to a Bilasiting intermediate 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-2H-oxazol-2-yl)-1-methyl-ethyl]-phenyl}-ethyl)-piperidin-4-yl]-1H-benzimidazole preparation method, the compound 2-{1-[4-(2-hydroxyethyl) phenyl]-1-methylethyl}-4,5-2H-4,4-dimethyl-oxazole is dissolved in an organic solvent, trifluoromethanesulfonyl chloride is dissolved, and added dropwise to the system, after the completion of the addition, triethylamine is added for heating and refluxing for 1h to obtain structure II compound 2-[4-(1-(4,4-dimethyl-2H-oxazol-2-yl)-1-methylethyl) phenyl] ethyl triflate, and the resulting compound 2-[4-(1-(4,4-dimethyl-2H-oxazol-2-yl)-1-methylethyl) phenyl] ethyl triflate is dissolved in an organic solvent, under nitrogen protection, sodium methoxide is added for reaction for 2 h, 2-(4-piperidine)-1 H-benzimidazole is added for heating and refluxing for 2h to obtain 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-2H-oxazol-2-yl)-1-methyl-ethyl]-phenyl}-ethyl)-piperidin-4-yl]-1H-benzimidazole.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to bilastine intermediate 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-2H-oxazol-2 base)- Preparation of 1-methyl-ethyl]-phenyl}-ethyl)-piperidin-4-yl]-1-(2-ethoxy-ethyl)-1H-benzimidazole. Background technique [0002] Bilastine is the second generation of histamine H developed by Spanish FAES pharmaceutical company 1 Receptor antagonist, approved by the European Union in 2010 for the treatment of allergic rhinitis and chronic idiopathic urticaria. This product is safe, without the sedative effect and cardiotoxicity of commonly used antihistamines. [0003] [0004] The literature mentions that in the preparation of intermediate 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-2H-oxazol-2yl)-1-methyl-ethyl ]-phenyl}-ethyl)-piperidin-4-yl]-1H-benzimidazole adopts p-toluenesulfonyl chloride as an acylating reagent, because when utilizing p-toluenesulfonyl chloride to prepare, the reaction yield is low, only ...

AI Technical Summary

Problems solved by technology

[0004] The literature mentions that in the preparation of intermediate 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-2H-oxazol-2yl)-1-methyl-ethyl ]-phenyl}-ethyl)-piperidin-4-yl]-1H-benzimidazole adopts p-toluenesulfonyl chloride as an acylating reagent, because when utilizing p-toluenesulfonyl chloride to prepare, the reaction yield is low, only 65%, and the post-reaction treatment is difficult, and it is difficult to realize industrialization

In the subsequent nucleophilic substitution reaction of H on the benzimidazole ring, the sodium hydride used is a flammable and explosive reagent, which is relatively dangerous and requires high reaction equipment, which is a major hidden danger in industrial production.

Images