Synthetic Study Of Epinastine Intermediates

Epinastine hydrochloride, a non-sedating and cardiac toxicity allergy, is successfully developed by Boehringer Ingelheim, which chemical name is 3-amino-9,13-dihydro-1H-dibenzo[c,f]-imidazo[1,5-a]azepine hydrochloride. At present, it is used for the treatment of urticaria, atopic dermatitis, allergic rhinitis, allergic bronchitis and asthma.In this paper, we designed and tried two novel synthetic route for the synthesis of epinastine. The first synthetic route includes the use of a-chloroacetophenone as a starting compound and react with hexamethylenetetramine, followed by hydrolysis, amino group protection, Schiff s base formation. This route was not successful for we did not get the imine. The second synthetic route, namely benzene glycine methyl ester hydrochloride was chosen as a starting material to synthesize epinastine as well as its intermediate through amidation, transition metal-catalyzed C-N coupling reaction with o-iodobenzoate, ester hydrolysis, intramolecular Fridel-Crafts acylation to form the seven-membered ring, and then the key imidazoline unit was formed by cyclization through reduction and nucleophilic addition. This whole process was expected to achieve green synthesis of epinastine by avoiding the use of cyanide. It also related to the synthesis of an important intermediate of epinastine, whose chemical name is,6-amino-11-dihydro-5H-dibenzo [b, e] azepine. After repeated experiments, the compound methyl 2-((2-oxo-l-phenyl-2-ureidoethyl)amino) benzoate (12) was obtained, which was an important synthetic precursor for the synthesis of epinastine. Although we have not obtained the target molecule, it has laid a good foundation for the ultimate synthesis of epinastine. Up to now, we have obtained seven new compounds which have not been recorded. That is, compound 12,13,19,20,21,22 and 23; and their structures have been confirmed by 1H NMR,13C NMR and HRMS.