3-Hydroxypyridine → 3-[3-Bromo-5-(4-methoxy-benzyloxy)-phenoxy]-pyridine

HRID 1784814Notes

Reaction equation

HRID 1784814 reaction equation
Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[OH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.[H-].[Na+].[OH-].[NH4+]>N1C(C)=CC(C)=CC=1C.[Cu]=O.C(OCC)(=O)C>[Br:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:5]=1)[O:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1

Participants

8

Reactant 4

HCID 79713-HydroxypyridineHCID 14923Ammonium HydroxideHCID 24758Sodium hydrideHCID 252583101,3-Dibromo-5-[(4-methoxyphenyl)methoxy]benzene

Product 1

HCID 509938663-[3-Bromo-5-(4-methoxy-benzyloxy)-phenoxy]-pyridineYield 25%

Reagents, catalysts & solvents 3

HCID 14829Copper oxideCatalystHCID 79532,4,6-TrimethylpyridineSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
210 °C

Procedure

A mixture of the 3,5-dibromo-1-p-methoxy-benzyloxybenzene (250 mg, 0.672 mmol) and 3-hydroxypyridine (128 mg, 1.34 mmol) and 96 mg (0.67 mmol) copper oxide in 3 mL of collidine was treated with sodium hydride (27 mg, 0.67 mmol) in a stirred tube. After 10 minutes to allow off-gassing, the tube was sealed and the reaction mixture was heated to 210° C. bath temperature overnight. It was then cooled and treated with ethyl acetate and aqueous ammonium hydroxide, and filtered through Celite®. The phases were separated, and the aqueous phase was extracted with additional ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated. The product was chromatographed (33% ethyl acetate/hexane) to give 66 mg of product 3-[3-bromo-5-(4-methoxy-benzyloxy)-phenoxy]-pyridine (25% yield). This material was converted to 3-(1H-indol-4-yl)-5-(pyridin-3-yloxy)-phenol as described in Example 35. 1H NMR (400 MHz, CD3OD): δ 11.22 (s, 1H), 9.77 (s, 1H), 8.43 (d, J=2.5 Hz, 1H), 8.36 (d, J=3.5 Hz, 1H), 7.53 (ddd, J=8.4, 2.7,1.3 Hz, 1H), 7.42 (dd, J=8.4, 4.7Hz, 1H), 7.36 (dd, J=5.4, 2.4Hz, 2H), 7.11 (t, J=7.7 Hz, 1H), 7.00 (d, J=7.0 Hz, 1H), 6.86 (s, 1H), 6.65 (s, 1H), 6.45 (s, 1H), 6.40 (t, J=2.0 Hz, 1H).

Workup

  1. customthe tube was sealed
  2. temperatureIt was then cooled
  3. filtrationfiltered through Celite®
  4. customThe phases were separated
  5. extractionthe aqueous phase was extracted with additional ethyl acetate
  6. washThe combined organics were washed with brine
  7. dry with materialdried over sodium sulfate
  8. concentrationconcentrated
  9. customThe product was chromatographed (33% ethyl acetate/hexane)

Sources & evidence

ORD record
ord-da44352d4d494044ba354295353557ff
Source dataset
uspto-grants-2009_03
Patent number
US07504401B2

Reaction notes

Loading…