Diethyl Ether → 4-bromo-7-(2-hydroxypropan-2-yl)-3-methyl-9H-carbazole-1-carboxamide

HRID 523251Notes

Reaction equation

HRID 523251 reaction equation
[Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([C:16](=[O:18])[NH2:17])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7](C(OCC)=O)=[CH:8][C:9]=1[NH:10]2.[CH3:24][Li].CC[O:28][CH2:29][CH3:30].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:29]([OH:28])([CH3:30])[CH3:24])=[CH:6][CH:5]=3)[NH:10][C:11]=2[C:12]([C:16]([NH2:17])=[O:18])=[CH:13][C:14]=1[CH3:15]

Participants

7

Reactant 4

HCID 3283Diethyl EtherHCID 25517Ammonium ChlorideHCID 117761166ethyl 5-bromo-8-carbamoyl-6-methyl-9H-carbazole-2-carboxylateHCID 178418348HCID 178418348, compound3×

Product 1

HCID 1177610854-bromo-7-(2-hydroxypropan-2-yl)-3-methyl-9H-carbazole-1-carboxamideYield 85%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

A solution of ethyl 5-bromo-8-carbamoyl-6-methyl-9H-carbazole-2-carboxylate (0.500 g, 1.33 mmol) in THF (12 mL) at −78° C. was treated dropwise over 10 min with 1.6 M methyllithium in ether (2.50 mL, 4.00 mmol). The mixture was stirred at −78° C. for 30 min, then was treated with additional methyllithium solution (1.67 mL, 2.67 mmol). After 30 min more, additional methyllithium solution (1.67 mL, 2.67 mmol) was added and stirring was continued for 45 min. The mixture was then treated with saturated aqueous NH4Cl and allowed to warm to room temperature. The mixture was diluted with EtOAc and washed sequentially with water and brine. The aqueous layers were extracted with EtOAc, and the combined organic layers were dried and concentrated to provide an off-white solid. The solid was triturated and sonicated with MeOH and collected by filtration. The filtrate was purified by reverse-phase preparative HPLC. The appropriate fractions were treated with saturated aqueous NaHCO3 and concentrated. The residue was partitioned between EtOAc and water. The organic phase was washed with brine, and the aqueous layers were extracted with EtOAc. The combined organic layers were dried and concentrated, and the residue was combined with the first solid to give 4-bromo-7-(2-hydroxypropan-2-yl)-3-methyl-9H-carbazole-1-carboxamide as a tan solid (0.409 g, 85% yield). Mass spectrum m/z 343, 345 (M+H—H2O)+. 1H NMR (500 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.56 (d, J=8.6 Hz, 1H), 8.12 (br. s., 1H), 7.91-7.89 (m, 2H), 7.48 (br. s., 1H), 7.36 (dd, J=8.3, 1.7 Hz, 1H), 5.06 (s, 1H), 2.53 (s, 3H), and 1.51 (s, 6H).

Workup

  1. waitAfter 30 min more
  2. stirringstirring
  3. waitwas continued for 45 min
  4. temperatureto warm to room temperature
  5. washwashed sequentially with water and brine
  6. extractionThe aqueous layers were extracted with EtOAc
  7. customthe combined organic layers were dried
  8. concentrationconcentrated
  9. customto provide an off-white solid
  10. customThe solid was triturated
  11. customsonicated with MeOH
  12. filtrationcollected by filtration
  13. customThe filtrate was purified by reverse-phase preparative HPLC
  14. additionThe appropriate fractions were treated with saturated aqueous NaHCO3
  15. concentrationconcentrated
  16. customThe residue was partitioned between EtOAc and water
  17. washThe organic phase was washed with brine
  18. extractionthe aqueous layers were extracted with EtOAc
  19. customThe combined organic layers were dried
  20. concentrationconcentrated

Sources & evidence

ORD record
ord-c22e8c56b0f347e8a0d5be9caae523d4
Source dataset
uspto-grants-2016_05
Patent number
US09334290B2

Reaction notes

Loading…