Methanesulfonic Acid → 4-[4-(N-(3-chloro-(2R)-2-hydroxy-1-propyl)amino)phenyl]morpholin-3-one

Participants

Reaction Steps

Under an atmosphere of nitrogen to a solution of 28.12 g of (S)-3-chloro-1,2-propanediol (MW=110.54; 1 eq.) in 600 mL of methylenechloride were added dropwise 30.26 g of thionylchloride (MW=118.97; 1 eq.). After stirring for 1 h at room temperature, the reaction mixture was concentrated in vacuo to a mass of 255 g. To the concentrate of (R)-4-chloromethyl-[1,3,2]dioxathiolane 2,2-dioxide (MW=156.59; 1 eq.) were added 200 mL of water and 45 mg of RuCl3.3 H2O (MW=261.47; 0.0007 eq.) The mixture was cooled to 0° C. At this temperature, 215 mL of a cold solution of sodium hypochlorite (1.7 M; 1.4 eq.) were added in 60 min. After addition of sodium hypochlorite was finished, the reaction mixture was stirred for 15 min at 0° C. Then the layers were separated. The aqueous layer was extracted twice with 160 mL of methylenechloride. To the combined methylenechloride layers were added 4 mL of isopropanol and 120 mL of water. After stirring for 5 min the layers were separated. To the organic layer, 1.6 g charcoal were added. After 5 min of stirring, the suspension was filtered. To the filtrate were added 32.09 g of 4-(4-aminophenyl)-morpholin-3-one (APMO) (MW=192.22; 0.66 eq.) and 23.28 g (MW=101.12; 0.9 eq.) of triethylamine. The reaction mixture was stirred for 24 h at room temperature. Then the resulting suspension was concentrated in vacuo and the concentrate was dissolved in 1000 mL of acetonitrile. 96 g of methane sulfonic acid (MW=96.11; 3.9 eq.) and 20 g of water (MW=18; 4.4 eq.) were added and the solution was stirred at ambient temperature. After stirring for 5 h, the reaction mixture was neutralized by addition of 127 g of sodium hydrogencarbonate (MW=84.01; 5.9 eq.). The resulting suspension was filtered and the cake washed with 500 mL of acetonitrile. The combined acetonitrile layers were concentrated in vacuo. To the concentrate were added 660 mL of 2-propanol and the mixture was stirred for 1 h at ambient temperature. The resulting slurry was cooled to 0° C. After stirring for at least 2 h at this temperature, the product was isolated by filtration and the filter cake was washed with 125 mL of 2-propanol. After drying in vacuo at 30° C., 29.73 g of the crystalline title compound were isolated. Yield=41.0%.

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