Potassium Carbonate → 1,1-Dimethylethyl N-(5-((4-methylphenyl)sulfonyl)-5H-pyrrolo(2,3-b)pyrazin-2-yl)carbamate

HRID 1969744Notes

Reaction equation

HRID 1969744 reaction equation
Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[C:21](=[O:28])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH2:22].C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C)C>[S:11]([N:8]1[C:5]2=[N:6][CH:7]=[C:2]([NH:22][C:21](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:3]=[C:4]2[CH:10]=[CH:9]1)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 77922tert-Butyl carbamateHCID 529876432-Bromo-5-((4-methylphenyl)sulfonyl)-5H-pyrrolo(2,3-b)pyrazine

Product 1

HCID 580097831,1-Dimethylethyl N-(5-((4-methylphenyl)sulfonyl)-5H-pyrrolo(2,3-b)pyrazin-2-yl)carbamateYield 39%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 3776IsopropanolSolvent2×

Conditions

Temperature
95 °C

Procedure

2-Bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0 g, 85 mmol), tert-butyl carbamate (14.9 g, 128 mmol), 325 mesh potassium carbonate (35.3 g, 256 mmol), palladium acetate (0.19 g, 0.85 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos) (0.99 g, 1.70 mmol) were charged to a three-neck, 1 L cylindrical reactor equipped with an over head stirrer, thermocouple and a reflux condenser. The solids were purged with argon for not less than 120 min. 2-methyl-butanol (240 mL) and 1,4-dioxane (60 mL) were charged to a separate 500 mL round bottom flask and purged with argon for not less than 60 min. The solvent mixture was transferred to the 1 L flask using a cannula under a positive pressure of argon, the temperature was raised to about 95° C. and the reaction mixture was stirred for about 3 h under a positive pressure of argon. The reaction mixture was cooled to about 40° C., THF (100 mL) was added and filtered through a 2 inch pad of celite. The reaction mixture was split into 2 equal batches (about 200 mL) and each of the batches were purified separately. Each batch was diluted with THF (250 mL) and was transferred to a 1 L cylindrical flask equipped with a magnetic stir bar. A solution of L-cysteine (0.76 g), potassium bicarbonate (1.52 g) and sodium chloride (0.76 g) in water (250 mL) was added to the above flask and was allowed to stir for about 2-4 h. The aqueous layer was separated. Formation of a rag layer was observed that was kept with the organic layer. The organic layer was washed with saturated sodium chloride solution (100 mL) and the aqueous layer was separated. Charcoal (0.76 g) was added to the flask, stirred for about 2-4 h, filtered through a 2 inch pad of celite, rinsed with THF (30 mL) and concentrated in vacuo at about 60° C. to obtain an oil/solid slurry. A mixture of isopropanol (50 mL) and heptanes (15 mL) were added to the oil/solid slurry and concentrated in vacuo to obtain light yellow colored solid. Isopropanol (90 mL) was added to the solid, heated to about 60° C. and mixed for about 1 h. The mixture was allowed to cool to room temperature with stirring, solids were filtered off, rinsed with heptane (40 mL) and dried overnight in a vacuum oven at about 50° C. The 2 batches were combined to obtain tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (12.87 g), as a light yellow colored solid. 1H NMR (400 MHz, DMSO) δ 10.11 (s, 1H), 8.77 (s, 1H), 8.16 (d, J=4.1 Hz, 1H), 7.99-7.92 (m, 2H), 7.40 (d, J=8.4 Hz, 2H), 6.83 (d, J=4.1 Hz, 1H), 2.32 (s, 3H), 1.46 (s, 9H).

Workup

  1. customequipped with an over head stirrer
  2. customThe solids were purged with argon for not less than 120 min
  3. addition2-methyl-butanol (240 mL) and 1,4-dioxane (60 mL) were charged to a separate 500 mL round bottom flask
  4. custompurged with argon for not less than 60 min
  5. temperatureThe reaction mixture was cooled to about 40° C.
  6. additionTHF (100 mL) was added
  7. filtrationfiltered through a 2 inch pad of celite
  8. customThe reaction mixture was split into 2 equal batches (about 200 mL)
  9. customeach of the batches were purified separately
  10. additionEach batch was diluted with THF (250 mL)
  11. customwas transferred to a 1 L cylindrical flask
  12. customequipped with a magnetic stir bar
  13. additionA solution of L-cysteine (0.76 g), potassium bicarbonate (1.52 g) and sodium chloride (0.76 g) in water (250 mL) was added to the above flask
  14. stirringto stir for about 2-4 h
  15. customThe aqueous layer was separated
  16. washThe organic layer was washed with saturated sodium chloride solution (100 mL)
  17. customthe aqueous layer was separated
  18. additionCharcoal (0.76 g) was added to the flask
  19. stirringstirred for about 2-4 h
  20. filtrationfiltered through a 2 inch pad of celite
  21. washrinsed with THF (30 mL)
  22. concentrationconcentrated in vacuo at about 60° C.
  23. customto obtain an oil/solid slurry
  24. additionwere added to the oil/solid slurry
  25. concentrationconcentrated in vacuo
  26. customto obtain light yellow colored solid
  27. temperatureheated to about 60° C.
  28. additionmixed for about 1 h
  29. temperatureto cool to room temperature
  30. stirringwith stirring
  31. filtrationsolids were filtered off
  32. washrinsed with heptane (40 mL)
  33. customdried overnight in a vacuum oven at about 50° C

Sources & evidence

ORD record
ord-250e277279b44c94ba44a788a8d5dec2
Source dataset
uspto-grants-2013_04
Patent number
US08426411B2

Reaction notes

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