Hydrochloric Acid → 6-Cyclobutoxy-5-furan-2-yl-nicotinic acid

HRID 240749Notes

Reaction equation

HRID 240749 reaction equation
Br[C:2]1[C:3]([O:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[B-](F)(F)(F)[C:23]1[O:27][CH:26]=[CH:25][CH:24]=1.[K+].C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH:12]1([O:11][C:3]2[C:2]([C:26]3[O:27][CH:23]=[CH:24][CH:25]=3)=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=2)[CH2:15][CH2:14][CH2:13]1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 10796Cesium carbonateHCID 11371790Bis(adamantan-1-yl)(butyl)phosphaneHCID 23669286Potassium 2-furantrifluoroborateHCID 66678843HCID 66678843, compound

Product 1

HCID 712944156-Cyclobutoxy-5-furan-2-yl-nicotinic acidYield 74.7%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
120 °C

Procedure

In a 50 mL 4-necked flask, 5-bromo-6-cyclobutoxynicotinic acid (1 g, 3.68 mmol, Eq: 1.00, preparation see Example 47) and cesium carbonate (3.59 g, 11.0 mmol, Eq: 3) were combined with toluene (25 mL) and water (2.8 mL) to give a colorless solution. The reaction mixture was 3× degassed and purged with argon before successively potassium 2-furantrifluoroborate (959 mg, 5.51 mmol, Eq: 1.5), palladium(II) acetate (41.3 mg, 184 μmol, Eq: 0.05) and butyldi-1-adamantylphosphine (198 mg, 551 μmol, Eq: 0.15) were added. The evacuating-purging cycle was repeated after each addition. The reaction mixture was then heated to 120° C. for 5 hours when TLC showed that the starting material had disappeared. Work up: The reaction mixture was cooled to RT, poured into 30 mL 1N HCl and extracted with AcOEt/THF 2:1 (4×50 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was then purified by triturating it with methanol to afford 713 mg of the title compound as yellow solid; MS (EI) 258.4 (M−H)−.

Workup

  1. customto give a colorless solution
  2. customdegassed
  3. additionwere added
  4. additionafter each addition
  5. temperatureThe reaction mixture was cooled to RT
  6. extractionextracted with AcOEt/THF 2:1 (4×50 mL)
  7. washwashed with brine
  8. dry with materialdried over Na2SO4
  9. concentrationconcentrated in vacuo
  10. customThe crude material was then purified
  11. customby triturating it with methanol

Sources & evidence

ORD record
ord-1d5f839a9ded4492b35591db297a5d0f
Source dataset
uspto-grants-2014_02
Patent number
US08648099B2

Reaction notes

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