Hydrochloric Acid → 3-(6-Methylpyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylic acid

HRID 1948529Notes

Reaction equation

HRID 1948529 reaction equation
[OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1.Br/[C:13](=[CH:19]\[C:20]([F:23])([F:22])[F:21])/[C:14]([O:16]CC)=[O:15].IF.[Cl-].[In+3].[Cl-].[Cl-].C(=O)([O-])O.[K+].[Li+].[OH-].Cl>C(OCC)(=O)C.CCO>[CH3:10][C:6]1[N:5]=[C:4]([C:3]2[C:19]([C:20]([F:23])([F:22])[F:21])=[C:13]([C:14]([OH:16])=[O:15])[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=1

Participants

10

Reactant 7

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 139637Iodine fluoride (IF)HCID 159675indium(III)chlorideHCID 516893Potassium BicarbonateHCID 19884326ethyl (2Z)-2-bromo-4,4,4-trifluorobut-2-enoateHCID 136337383N-hydroxy-6-methylpicolinimidoyl chloride

Product 1

HCID 583741633-(6-Methylpyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylic acid

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

To a mixture of N-hydroxy-6-methylpicolinimidoyl chloride (2.5 g, 14.65 mmol) and (Z)-ethyl 2-bromo-4,4,4-trifluorobut-2-enoate, Int-I-F (3 g, 12.15 mmol) in ethyl acetate (40 mL) was added indium(III) chloride (0.559 g, 2.53 mmol). After 1 hour, potassium hydrogen carbonate (2.022 g, 20.20 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with H2O. The organic layer was dried with MgSO4, filtered, and concentrated. The resulting material was purified on a silica gel cartridge using an EtOAc/hexanes gradient. The fraction with desired mass was isolated and checked by NMR. The product was found to be contaminated with dimerization product of the starting bromoolefin. This material was hydrolyzed using 1N LiOH (2eq) in EtOH for 1 hour. The pH was adjusted to 6-7 with concentrated HCl. The resulting material was extract with EtOAc 4 times and then extracts were combined, dried, and concentrated to yield 360 mg of 3-(6-methylpyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylic acid. MS (m+1)=273. HPLC Peak RT=1.66 minutes (Analytical Method B).

Workup

  1. washwashed with H2O
  2. dry with materialThe organic layer was dried with MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe resulting material was purified on a silica gel cartridge
  6. customThe fraction with desired mass was isolated
  7. customfor 1 hour
  8. extractionThe resulting material was extract with EtOAc 4 times
  9. customdried
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-a6094928eaa249c7a2c3f007995a10d4
Source dataset
uspto-grants-2013_03
Patent number
US08399451B2

Reaction notes

Loading…