Acetyl chloride → tert-Butyl 6a-isothiazol-5-yl-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate

Temperature

45 °C

Isopropyl alcohol (5.66 L) is cooled to 5° C. and acetyl chloride (941.23 mL, 13.23 mol) is added drop wise (exothermic). The mixture is heated to 45° C., and tert-butyl 6a-isothiazol-5-yl-1-[(4-methoxyphenyl)methyl]-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (460.17 g, 1.10 mol) is added to the reactor in portions. The resulting white suspension is stirred at 45° C. for 1 hour. Most of the solvent is evaporated to give a wet, off-white solid, which is dissolved in trifluoroacetic acid (2.76 L, 36.52 mol). The resulting dark solution is heated to 70° C. and stirred at this temperature for 1 hour. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is azeotroped with toluene (2×2.5 L) to give a light brown solid. The residue is dissolved in 2 M aq. HCl solution (4.6 L) and DCM (4.6 L) and stirred vigorously at 40° C. for 30 minutes until full dissolution. The mixture is cooled to room temperature and separated. The aqueous layer is washed with DCM (2×500 mL). The acidic aqueous layer is cooled to 5° C. and the pH is adjusted to 10.5 by the addition of 50% wt/wt aq. NaOH solution. The mixture is cooled to 10° C. and a solution of BOC2O (252.57 g, 1.16 mol) in tetrahydrofuran (2.30 L) is added slowly. The mixture is stirred for 5 minutes and warmed to 25° C. and then stirred 1 hour longer. MTBE (2 L) is added and the resulting phases are separated. The aqueous layer is extracted with MTBE (2×1 L) and the combined organic layers are washed with brine solution (2 L), dried over MgSO4, filtered, and evaporated under reduced pressure to give the crude product as an off-white solid (347.2 g). The crude solid is dissolved in boiling 7:3 v/v isohexane/ethyl acetate (2.8 L) and the resulting clear solution is allowed to slowly cool to room temperature and then cooled in an ice-bath. The resulting white suspension is filtered and washed with cold 7:3 isohexane:ethyl acetate. The white solid is dried under vacuum and nitrogen for 2 days to give the title compound as a white solid (291.30 g, 88.9%). ES/MS (m/e): 298 (M+H).

1. customMost of the solvent is evaporated
2. customto give a wet, off-white solid, which
3. temperatureThe resulting dark solution is heated to 70° C.
4. stirringstirred at this temperature for 1 hour
5. temperatureThe reaction mixture is cooled to room temperature
6. concentrationconcentrated under reduced pressure
7. customThe residue is azeotroped with toluene (2×2.5 L)
8. customto give a light brown solid
9. temperatureThe mixture is cooled to room temperature
10. customseparated
11. washThe aqueous layer is washed with DCM (2×500 mL)
12. temperatureThe acidic aqueous layer is cooled to 5° C.
13. additionthe pH is adjusted to 10.5 by the addition of 50% wt/wt aq. NaOH solution
14. temperatureThe mixture is cooled to 10° C.
15. stirringThe mixture is stirred for 5 minutes
16. temperaturewarmed to 25° C.
17. stirringstirred 1 hour longer
18. customthe resulting phases are separated
19. extractionThe aqueous layer is extracted with MTBE (2×1 L)
20. washthe combined organic layers are washed with brine solution (2 L)
21. dry with materialdried over MgSO4
22. filtrationfiltered
23. customevaporated under reduced pressure
24. customto give the crude product as an off-white solid (347.2 g)
25. dissolutionThe crude solid is dissolved
26. temperatureto slowly cool to room temperature
27. temperaturecooled in an ice-bath
28. filtrationThe resulting white suspension is filtered
29. washwashed with cold 7:3 isohexane
30. customThe white solid is dried under vacuum and nitrogen for 2 days

ORD record

ord-a15dd8db7f664c2fac134a36bc73ee73

Source dataset

uspto-grants-2014_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08889856B2