Divinyl sulfone → Thiomorpholine, 4-(2,6-difluorophenyl)-, 1,1-dioxide

Aluminum chloride (310 g, 2.3 mol) is added to chlorobenzene (2.5 L) to give a cloudy green suspension. Vinyl sulfone (230 mL, 2.3 mol) is added via funnel, followed by 2,6-difluoroaniline (250 mL, 2.3 mol). The light brown solution is heated to 110° C. Upon completion of the reaction, the heat is removed and the black solution is self-cooled to 70° C. The reaction mixture is then quenched in methylene chloride (4 L) and ice water (5 L), the aqueous phase is extracted with methylene chloride (3 L, 2 L, 2 L, 2 L) and the combined organic layers are concentrated, rediluted with branched octane (3 L), and then cooled to 0° C. for 30 minutes. The solids are filtered and washed with branched octane (2×500 mL) and are then dissolved in methylene chloride (3 L) and loaded onto a silica gel plug (1.8 kg). The column is eluted with dichloromethane (16 L) until clear. The methylene chloride solution is concentrated, and the solids are dissolved in hot ethyl acetate (3 L) followed by the addition of hexanes (900 mL). The black solution is self-cooled to room temperature overnight, and the resulting light amber crystal needles are filtered and washed with hexanes (4×250 mL). The solids are dried under reduced pressure at 50° C. overnight to give the title compound, 1H NMR (CDCl3) δ 7.08 (m, 1H), 6.91 (m, 2H), 3.67 (m, 4H), 3.18 (m, 4H).

1. customto give a cloudy green suspension
2. customUpon completion of the reaction
3. customthe heat is removed
4. temperaturethe black solution is self-cooled to 70° C
5. customThe reaction mixture is then quenched in methylene chloride (4 L)
6. extractionice water (5 L), the aqueous phase is extracted with methylene chloride (3 L, 2 L, 2 L, 2 L)
7. concentrationthe combined organic layers are concentrated
8. additionrediluted with branched octane (3 L)
9. temperaturecooled to 0° C. for 30 minutes
10. filtrationThe solids are filtered
11. washwashed with branched octane (2×500 mL)
12. dissolutionare then dissolved in methylene chloride (3 L)
13. washThe column is eluted with dichloromethane (16 L) until clear
14. concentrationThe methylene chloride solution is concentrated
15. dissolutionthe solids are dissolved in hot ethyl acetate (3 L)
16. additionfollowed by the addition of hexanes (900 mL)
17. temperatureThe black solution is self-cooled to room temperature overnight
18. filtrationthe resulting light amber crystal needles are filtered
19. washwashed with hexanes (4×250 mL)
20. customThe solids are dried under reduced pressure at 50° C. overnight

ORD-Eintrag

ord-d4550cb7550c44689f7de61a24633010

Quelldatensatz

uspto-grants-2006_11

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07141588B2