Acetone → 3-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide

HRID 2410877Notes

Reaction equation

HRID 2410877 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=C(C(OCC)=O)[CH:7]=[CH:6][C:5]2=1.[CH3:23][Mg]Br.[CH3:26][C:27]([CH3:29])=[O:28]>C1COCC1>[Br:1][C:2]1[CH:14]=[C:13]([C:15]([NH2:16])=[O:17])[C:12]2[NH:11][C:10]3[C:5]([C:4]=2[CH:3]=1)=[CH:6][CH:7]=[C:26]([C:27]([OH:28])([CH3:23])[CH3:29])[CH:9]=3

Participants

5

Reactant 3

HCID 180AcetoneHCID 66604694ethyl 6-bromo-8-carbamoyl-9H-carbazole-2-carboxylateHCID 178418573HCID 178418573, compound

Product 1

HCID 666052403-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamideYield 46.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

Ethyl 6-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (1.05 g, 2.471 mmol, Example 58C) was dissolved in THF (100 mL) in a 250-ml round bottom flask and cooled to 0° C. Methylmagnesium bromide (1.4 M solution in 25%THF+75%toluene) (26 mL, 36 4 mmol) was added and the mixture stirred at 0° C. for 1 hour, than the reaction was allowed to warm to room temperature during 1 hour. The reaction mixture was cooled to −78° C. and excess Grignard reagent quenched by the addition of acetone (5 mL, 68.1 mmol). The mixture was stirred for 30 minutes at -78° C., then quenched with sat. aq. NH4Cl solution (at −78° C.). The flask was transferred into a water/ice bath and stirred for 10 minutes. The reaction mixture was poured into a separating funnel loaded with water and ethyl acetate. The layers were separated, the aqueous extracted once more with EtOAc (pH of aqueous ˜9) The organic layer was washed once with water, once with brine, then dried over Na2SO4, filtered and concentrated in vacuum. (bath temp <30° C.). The crude product was purified by flash column chromatography on silica (25 g BIOTAGE® cartridge, eluent gradient from 5% EtOAc in DCM to 75% EtOAc in DCM during 96 fractions a 21 ml). Product eluted in fractions 57-80. Product containing fractions were combined and evaporated to give 395.5 mg 3-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide. 1H NMR (DMSO-d6) δ ppm 11.38 (s, 1H), 8.48 (d, 1H, J=1.8), 8.22 (b, 1H), 8.09-8.09 (m, 2H), 7.88 (d, 1H, J=1.0), 7.54 (b, 1H), 7.33 (dd, 1H, J=8.3, 1.5), 5.05 (s, 1H), 1.52 (s, 6H). MS (ESI) m/e+=347/349 (1 Br isotope pattern) consistent with [M+H]+ and m/e+=330/332 (1 Br isotope pattern) consistent with [M+H−NH3]+. HPLC retention time 9.89 min. (Sunfire C18 3.5 μm, 3.0×150 mm column, 15 min gradient, 10-100% B, 0.5 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA).

Workup

  1. temperatureto warm to room temperature during 1 hour
  2. temperatureThe reaction mixture was cooled to −78° C.
  3. stirringThe mixture was stirred for 30 minutes at -78° C.
  4. customquenched with sat. aq. NH4Cl solution (at −78° C.)
  5. customThe flask was transferred into a water/ice bath
  6. stirringstirred for 10 minutes
  7. additionThe reaction mixture was poured into a separating funnel
  8. customThe layers were separated
  9. extractionthe aqueous extracted once more with EtOAc (pH of aqueous ˜9) The organic layer
  10. washwas washed once with water, once with brine
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated in vacuum
  14. custom(bath temp <30° C.)
  15. customThe crude product was purified by flash column chromatography on silica (25 g BIOTAGE® cartridge, eluent gradient from 5% EtOAc in DCM to 75% EtOAc in DCM during 96 fractions a 21 ml)
  16. washProduct eluted in fractions 57-80
  17. additionProduct containing fractions
  18. customevaporated

Sources & evidence

ORD record
ord-e6d1c46d73b045f2b8d085e93ca6904e
Source dataset
uspto-grants-2014_08
Patent number
US08815840B2

Reaction notes

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