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

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%.

1. concentrationthe reaction mixture was concentrated in vacuo to a mass of 255 g
2. stirringthe reaction mixture was stirred for 15 min at 0° C
3. customThen the layers were separated
4. extractionThe aqueous layer was extracted twice with 160 mL of methylenechloride
5. additionTo the combined methylenechloride layers were added 4 mL of isopropanol and 120 mL of water
6. stirringAfter stirring for 5 min the layers
7. customwere separated
8. additionTo the organic layer, 1.6 g charcoal were added
9. stirringAfter 5 min of stirring
10. filtrationthe suspension was filtered
11. stirringThe reaction mixture was stirred for 24 h at room temperature
12. concentrationThen the resulting suspension was concentrated in vacuo
13. dissolutionthe concentrate was dissolved in 1000 mL of acetonitrile
14. stirringthe solution was stirred at ambient temperature
15. stirringAfter stirring for 5 h
16. filtrationThe resulting suspension was filtered
17. washthe cake washed with 500 mL of acetonitrile
18. concentrationThe combined acetonitrile layers were concentrated in vacuo
19. additionTo the concentrate were added 660 mL of 2-propanol
20. stirringthe mixture was stirred for 1 h at ambient temperature
21. temperatureThe resulting slurry was cooled to 0° C
22. stirringAfter stirring for at least 2 h at this temperature
23. customthe product was isolated by filtration
24. washthe filter cake was washed with 125 mL of 2-propanol
25. customAfter drying in vacuo at 30° C.

ORDレコード

ord-dc5b05c94c2540bf85de31ba425f6598

出典データセット

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09221771B2