Triethylamine → 2-Cyclohexylbenzoxazole-4-carboxylic acid

HRID 1987976

Reaction equation

HRID 1987976 reaction equation
Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH:13]1([C:19](Cl)=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.O>[CH:13]1([C:19]2[O:12][C:11]3[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:2]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 75938Cyclohexanecarbonyl chlorideHCID 521998p-Toluenesulfonic acid monohydrateHCID 668807402-Amino-3-hydroxybenzoic acid hydrobromide

Product 1

HCID 690006542-Cyclohexylbenzoxazole-4-carboxylic acidYield 66.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (500 mg, 2.13 mmol) and cyclohexane carbonyl chloride (0.29 mL, 2.13 mmol) in dichloromethane (20 mL) was added triethylamine (0.90 mL, 6.41 mmol) dropwise, then the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with dichloromethane, and then washed with 2 N HCl. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in toluene (8 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (485 mg, 2.55 mmol). The reaction mixture was then heated to reflux for 5 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was separated, then washed with water (7×100 mL), brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by re-crystallization from ethyl acetate and hexanes to afford 2-cyclohexylbenzoxazole-4-carboxylic acid (346 mg, 66%) as a brown solid: 1H NMR (500 MHz, DMSO-d6) δ 13.01 (br s, 1H), 7.92 (dd, J=8.0, 0.9 Hz, 1H), 7.84 (dd, J=7.8, 0.9 Hz 1H), 7.44 (t, J=7.8 Hz, 1H), 3.08-3.02 (m, 1H), 2.14-2.05 (m, 2H), 1.82-1.75 (m, 2H), 1.72-1.60 (m, 3H), 1.47-1.38 (m, 2H), 1.35-1.25 (m, 1H); MS (ESI+) m/z 246 (M+H).

Workup

  1. washwashed with 2 N HCl
  2. extractionThe aqueous layer was extracted with dichloromethane
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. dissolutionThe crude product was dissolved in toluene (8 mL)
  8. temperatureThe reaction mixture was then heated
  9. temperatureto reflux for 5 h
  10. temperatureThe reaction was cooled to room temperature
  11. extractionextracted with ethyl acetate
  12. customThe organic layer was separated
  13. washwashed with water (7×100 mL), brine
  14. dry with materialdried (Na2SO4)
  15. filtrationfiltered
  16. concentrationconcentrated
  17. customThe crude product was purified by re-crystallization from ethyl acetate and hexanes

Sources & evidence

ORD record
ord-fefd0296accc4449abd785857bc25606
Source dataset
uspto-grants-2009_06
Patent number
US07553846B2

Linked notes

Loading…