Des-(dibutylpropylamine) Methanesulfonyl Dronedarone synthesis

Yield:1448297-16-2 9.18 g

Reaction Conditions:

with pyridine in dichloromethane at 30 - 35; for 1.5 h;

Steps:

28 4-({2-butyl-5-[(methylsulfonyl)amino]-1-benzofuran-3-yl}carbonyl)phenyl-methanesulfonate (2i)

12.4 g of 4-[(2-butyl-5-amino-1-benzofuran-3-yl)carbonyl]phenyl-methanesulfonate (6i) was dissolved in 124 ml of dichloromethane.
The mixture was warmed to 30 to 35°C and 2.8 g pyridine was added at this temperature in 5 minutes. 4.0 g of methanesulfonyl chloride was added at this temperature in 30 minutes and the mixture was stirred at 30 to 35°C for 1 hour.
After cooling to 20°C the mixture was washed with 60 ml of hydrochloric acid solution of 5%, with 60 ml of water, 60 ml of sodium bicarbonate of 5% and with 60 ml of water.
The phases were evaporated.
Mass of product: 11.52 g (77.1 %).
The product was crystallized in 80 ml of hot methanol.
Mass of pure product: 9.18 g.
Purity (HPLC): 100%. M.p.: 168.9-170.7 °C.
1H NMR(DMSO): 9.62(s,1H); 7.89(d, J=8.7Hz, 2H); 7.64(d, J=8.8,1H); 7.53(d, J=8.6, 2H); 7.29(d, J=2.1,1H); 7.21(dd, J=8.8, 2.2 1H); 3.47(2,3H); 2.88(s, 3H); 2.79 (t, J=7.5,Hz, 2H); 1.65(5', J=7.5Hz, 2H); 1.24(6', J=7.4Hz, 2H); 0.81(t, J=7.3Hz, 3H):

References:

EP2617718,2013,A1 Location in patent:Paragraph 0137 - 0142