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

HRID 523242Notes

Reaction equation

HRID 523242 reaction equation
[Br:1][C:2]1[C:14]([F: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[F:15]

Participants

7

Reactant 4

HCID 3283Diethyl EtherHCID 25517Ammonium ChlorideHCID 117761209ethyl 5-bromo-8-carbamoyl-6-fluoro-9H-carbazole-2-carboxylateHCID 178418348HCID 178418348, compound2×

Product 1

HCID 1177610104-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamideYield 50%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

A solution of ethyl 5-bromo-8-carbamoyl-6-fluoro-9H-carbazole-2-carboxylate (0.500 g, 1.32 mmol) in THF (9.0 mL) at −78° C. was treated dropwise over 10 min with 1.6 M methyllithium in ether (2.47 mL, 3.96 mmol). The mixture was stirred at −78° C. for 30 min, then was treated with additional methyllithium solution (1.65 mL, 2.64 mmol) and the mixture was stirred at −78° C. for 45 min more. The mixture was 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 a pale yellow solid which was purified by reverse phase preparative HPLC. The appropriate fractions were neutralized with saturated aqueous NaHCO3 and concentrated. The residue was partitioned between EtOAc and water, and the organic layer was washed with brine. The aqueous layers were extracted with EtOAc, and the combined organic layers were dried and concentrated to provide 4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide as a pale yellow solid (0.240 g, 50% yield). Mass spectrum m/z 347, 349 (M+H—H2O)+. 1H NMR (500 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.50 (d, J=8.6 Hz, 1H), 8.22 (br. s., 1H), 7.96 (d, J=10.3 Hz, 1H), 7.94 (d, J=1.1 Hz, 1H), 7.65 (br. s., 1H), 7.39 (dd, J=8.5, 1.5 Hz, 1H), 5.09 (s, 1H), and 1.51 (s, 6H).

Workup

  1. stirringthe mixture was stirred at −78° C. for 45 min more
  2. temperatureto warm to room temperature
  3. washwashed sequentially with water and brine
  4. extractionThe aqueous layers were extracted with EtOAc
  5. customthe combined organic layers were dried
  6. concentrationconcentrated
  7. customto provide a pale yellow solid which
  8. customwas purified by reverse phase preparative HPLC
  9. concentrationconcentrated
  10. customThe residue was partitioned between EtOAc and water
  11. washthe organic layer was washed with brine
  12. extractionThe aqueous layers were extracted with EtOAc
  13. customthe combined organic layers were dried
  14. concentrationconcentrated

Sources & evidence

ORD record
ord-0e7b8c70cdd24389bfed555c76badc50
Source dataset
uspto-grants-2016_05
Patent number
US09334290B2

Reaction notes

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