Study On Synthesis Of Antiarrhythmic Drug Sotalol Hydrochloride

Sotalol hydrochloride is an antiarrhythmic drug with Class II (P-receptor antagonist) and Class ? (cardiac action potential duration prolongation) properties, which was developed by BMS (Bristol-Myers Squibb), and was lunched in UK in 1974 in the beginning, and approved by FDA in 1993. Sotalol was prescribed for treatment of sinus without structural heart disease and atrial fibrillation in first class. As for excellent bioavailability, long half-time, excellent safety and tolerability, Sotalol hydrochloride was widely used in the clinical.Based on the detailed study and systematic investigation in literatures, we found a new route to get Sotalol hydrochloride (1),which was prepared from aniline by methylsulfonylation, Friedel-Crafts acylation, isopropylamination and hydrogen reduction. The reaction time, temperature and ratio of starting materials were studied and optimized. The optimal reaction condition for each step was showed as below:The best reaction condition for synthesis of N-phenylmethanesulfonamide (1-2) is n(sodium bicarbonate):n(aniline)=1.1:1 in water at ambient temperature for 5 h with the yield of 97%.The optimal reaction condition for synthesis of intermediate 3-1 is n (1-2):n (anhydrous aluminum trichloride):n (Chloroacetyl chloride)=1:2.1:1.2 in DCM at 0? for 7 h with the yield of 95%.The best reaction condition for synthesis of intermediate 1-4 is n(3-1):n(isopropylamine)=1:10 in methanol at room temperature for 5 h with the yield of 89%.The optimal reaction condition for synthesis of Sotalol hydrochloride (1) is 5%(w/w) 7%Pd/C in methanol under 0.2Mpa at ambient temperature for 4 h with the yield of 92.5%, The optimal reuse number of 7%Pd/C was 3 times.The total yield of the new route was up to 75.9% (based on aniline), and the purity was 99.8%. The structure of the product was confirmed by IR,1HNMR, ESI-MS and elemental analysis. The quality of product was in line with the US/EU pharmacopoeia requirements. This method is simple, green, economical and suitable for industrial production.