Toluene → 5-Bromo-2-(6-chloropyridin-3-yloxy)benzoic acid

HRID 931537Notes

Reaction equation

HRID 931537 reaction equation
Br[C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[N:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>CCOC(C)=O>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([O:12][C:13]2[CH:18]=[N:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]

Participants

6

Reactant 4

HCID 1140TolueneHCID 10796Cesium carbonateHCID 118912,5-Dibromobenzoic acidHCID 8198212-Chloro-5-hydroxypyridine

Product 1

HCID 574756345-Bromo-2-(6-chloropyridin-3-yloxy)benzoic acidYield 87.7%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
105 °C

Procedure

A mixture of 2,5-dibromobenzoic acid (1244 g, 4.44 mol), 5-hydroxy-2-chloropyridine (663.3 g, 5.12 mol) and cesium carbonate (2893.3 g, 8.88 mol) was stirred for 20 minutes under a nitrogen atmosphere. To this slurry were added copper (I) trifluoromethanesulfonate toluene complex (59.7 g, 0.115 mol), toluene (9 L) and EtOAc (39 mL). The resulting suspension was heated to 105° C. and stirred for 2 h before being cooled to RT. The toluene was decanted, and water (8 L) and EtOAc (8 L) were added. The resulting mixture was stirred until the solid was completely dissolved. The EtOAc layer was separated and the pH of the aqueous layer was adjusted to pH 2˜3 with 6N HCl. The aqueous layer was extracted with EtOAc (3×5 L). The combined organic layers were dried over Na2SO4, filtered and concentrated to give 1.28 Kg of 5-bromo-2-(6-chloropyridin-3-yloxy)benzoic acid as brown solid. This material was used in next step without further purification.

Workup

  1. stirringstirred for 2 h
  2. temperaturebefore being cooled to RT
  3. customThe toluene was decanted
  4. additionwater (8 L) and EtOAc (8 L) were added
  5. stirringThe resulting mixture was stirred until the solid
  6. dissolutionwas completely dissolved
  7. customThe EtOAc layer was separated
  8. extractionThe aqueous layer was extracted with EtOAc (3×5 L)
  9. dry with materialThe combined organic layers were dried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-60af4efd1ecb4a9c970a400b83e8d80c
Source dataset
uspto-grants-2016_03
Patent number
US09296759B2

Reaction notes

Loading…