Optimization and improvement of the synthesis method of terbutaline sulfate

Abstract

In order to obtain high yield and product quality of terbutaline sulfate, the synthetic method of terbutaline sulfate is studied. Terbutaline sulfate is synthesized from 3,5-dibenzyloxyacetophenone by bromination, alkylation reaction, carbonyl reduction and catalytic hydrodebenzylation. The reaction conditions and parameters are optimized and improved. Bromination is optimized,with tetrahydrofuran and methanol as solvents,tetrabutylammonium tribromide is used instead of liquid bromide and copper bromide as bromination reagent, n(3,5-dibenzyloxyacetophenone)∶n(tetrabutyl ammonium bromide)=1∶1.3,the reaction time could be reduced to 6 hours, and the yield is up to 99.1%.In condensation reaction, with benzyl tert-butylamine instead of tert-butylamine,n(3, 5-dibenzyloxy-alpha-Bromoacetophenone)∶n(benzyl tert-butylamine)=1∶3, the yield is 69.9%. In catalytic hydrodebenzylation, the amount of Raney Ni is 15% in solvent methanol, the pressure is 1.0 MPa,temperatuer is 40 ℃,and the yield is up to 90.2%. Under the optimized conditions,the total yield is 62.4%,and the purity is 99.90%(by HPLC), the impurities are less than 0.1%. The structures of the target compound are confirmed by 1H-NMR and 13C-NMR. The improved synthesis process with mild reaction conditions, simple operation, and high yield is more suitable for industrial production.

Keywords

• pharmaceutical engineering
• β2 adrenoceptoragonist
• terbutaline
• electrophilic substitution
• carbonyl reduction
• catalytic hydrogenation