Boron tribromide → 2-[(1S)-1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-3-chloro-4-fluorophenol

HRID 2095699Notes

Reaction equation

HRID 2095699 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19]C)=[CH:17][CH:16]=[C:15]([F:21])[C:14]=3[Cl:22])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:14]([Cl:22])=[C:15]([F:21])[CH:16]=[CH:17][C:18]=3[OH:19])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1

Participants

4

Reactant 2

HCID 25134Boron tribromideHCID 670045375-Bromo-3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine

Product 1

HCID 670041092-[(1S)-1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-3-chloro-4-fluorophenol

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 5-bromo-3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (1.015 g, 2.646 mmol) in CH2Cl2 (25 mL), cooled to −78° C., 1.0 M of boron tribromide in CH2Cl2 (8 mL, 8 mmol) was added in parts, over the course of 10 min. The solution was allowed to warm to ambient temperature for 18 h (acetone/dry ice bath removed at 1.5 h). The reaction mixture was cooled to 0° C., after which methanol was added to quench the reaction. After stirring at rt for 30 min, the reaction solution was concentrated in vacuo. The sample was resuspended in CH2Cl2 and a standard aqueous workup with saturated aqueous NaHCO3 solution was performed. The organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was dissolved in minimal CH2Cl2/MeOH, adsorbed onto a pre-packed silica solid load cartridge (RediSepRf 25 g size), and purified by the ISCO/Teledyne purification system [RediSepRf silica column, 12 g size], using a 0-50% EtOAc:CH2Cl2 solvent gradient. Fractions containing product were combined and concentrated in vacuo, giving the title material as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=9.50 (br s, 1H), 8.34 (s, 1H), 7.62 (s, 1H), 7.43 (s, 1H), 6.99 (dd, J=8.6, 8.6 Hz, 1H), 6.62 (dd, J=9.1, 4.5 Hz, 1H), 5.03 (dtd, J=7.3, 7.2, 1.3 Hz, 1H), 1.77 (d, J=7.1 Hz, 3H). MS (ES+): m/z 370.97/372.98 (100/43) [MH+]. HPLC: tR=1.56 min (TOF, polar—3 min).

Workup

  1. custom(acetone/dry ice bath removed at 1.5 h)
  2. temperatureThe reaction mixture was cooled to 0° C.
  3. additionafter which methanol was added
  4. customto quench
  5. customthe reaction
  6. concentrationthe reaction solution was concentrated in vacuo
  7. washThe organic layers were washed with brine
  8. dry with materialdried over anhydrous Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. dissolutionThe crude was dissolved in minimal CH2Cl2/MeOH
  12. custompurified by the ISCO/Teledyne purification system [RediSepRf silica column, 12 g size]
  13. additionFractions containing product
  14. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-072b171ba66146f58ece4a7cc572c2f9
Source dataset
uspto-grants-2013_05
Patent number
US08445510B2

Reaction notes

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