Study On Synthesis And Technology Of Ambroxol

Ambroxol is an expectorant used for in therapy of respiratory diseases, which was effectively synthesized in a total yield of69.3%with o-toluidine as starting material via electrophilic bromination, acetylation, radical bromination, N-alkylation, and hydrolyzation processes.2-Amino-3,5-dibromotoluene was prepared from electrophilic bromination of o-toluidine in a high yield and conversion of substrate by using molecular bromine under methylene chloride/water media. The addition of aqueous hydrogen peroxide could effectively improve the utilization of bromine.Two acylation reagents involving acetic acid and acetic anhydride systems were chosen to prepare2-diacetamino-3,5-dibromotoluene. It was found that94.5%yield was achieved by the use of acetic anhydride in a catalytic amount of sulfuric acid.Various technological parameters such as bromination reagent, solvent, catalysts and reaction temperature, were discussed in detail in the preparation of2-diacetylamino-3,5-dibromobenzyl bromide. A89.6%yield was obtained at75℃by using N-bromosuccinimide in the presence of azodiisobutyronitrile catalyst under1,2-dichloroethane medium.N-alkylation of2-diacetylamino-3,5-dibromobenzyl bromide with trans-4-aminocyclohexanol was conducted to form the title compound. The reaction could be promoted by stronger base in an aprotic solvent. And87.2%yield of ambroxol was achieved by using the optimal molar ratio of2-diacetylamino-3,5-dibromobenzyl bromide to trans-4-aminocyclohexanol of1:3via a following hydrolysis.