Potassium Hydroxide → 6-(Cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid

HRID 624996Notes

Reaction equation

HRID 624996 reaction equation
[OH-].[K+].Cl[C:4]1[N:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:13]1([F:17])[CH2:16][CH2:15][CH2:14]1.[CH:18]1([CH2:21][OH:22])[CH2:20][CH2:19]1>CS(C)=O>[CH:18]1([CH2:21][O:22][C:4]2[N:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:5]=2[C:13]2([F:17])[CH2:16][CH2:15][CH2:14]2)[CH2:20][CH2:19]1

Participants

5

Reactant 3

HCID 14797Potassium HydroxideHCID 75644Cyclopropanemethanol2×HCID 902026236-Chloro-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid

Product 1

HCID 902026076-(Cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acidYield 31%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

Powdered potassium hydroxide (240 mg, 4.28 mmol) was added to a solution of 6-chloro-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid (Example 130 e, 393 mg, 1.71 mmol) in DMSO (7.86 mL). The mixture was stirred at ambient temperature for 15 minutes. Cyclopropylmethanol (136 mg, 153 μL, 1.88 mmol) was added and stirring was continued for 5 h at 60° C. Additional cyclopropylmethanol (68 mg, 76 μL, 94 mmol) was added, the mixture was stirred for 14 h at ambient temperature, poured onto ice/brine (100 mL) and extracted with TBME (2×100 mL). The aqueous layer was acidified with 1 N HCl and extracted with EtOAc (2×150 mL). The combined organic layers were washed with ice/brine (50 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash-chromatography (20 g SiO2, dichloromethane/MeOH 0-3% in 75 min) to give the title compound (65 mg, 31%) as colorless oil, MS (ESI) m/e=264.5 [M−H−].

Workup

  1. stirringstirring
  2. waitwas continued for 5 h at 60° C
  3. stirringthe mixture was stirred for 14 h at ambient temperature
  4. additionpoured onto ice/brine (100 mL)
  5. extractionextracted with TBME (2×100 mL)
  6. extractionextracted with EtOAc (2×150 mL)
  7. washThe combined organic layers were washed with ice/brine (50 mL)
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. customThe solvent was removed under reduced pressure
  11. customthe residue was purified by flash-chromatography (20 g SiO2, dichloromethane/MeOH 0-3% in 75 min)

Sources & evidence

ORD record
ord-849d1ba198ab4e878f1796c935b74993
Source dataset
uspto-grants-2016_04
Patent number
US09303012B2

Reaction notes

Loading…