Lithium Hydroxide → 2-Fluoro-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid

HRID 923622Notes

Reaction equation

HRID 923622 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[C:20]([F:28])[CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Li+].[OH-]>CN(C=O)C.CC(=O)OCC.C1COCC1.CO>[F:28][C:20]1[CH:19]=[C:18]([NH:17][C:10](=[O:12])[CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:13]([F:16])([F:15])[F:14])[CH:27]=[CH:26][C:21]=1[C:22]([OH:24])=[O:23]

Participants

9

Reactant 4

HCID 3939Lithium HydroxideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 21957875Methyl 4-amino-2-fluorobenzoateHCID 467375752-(4-Methoxy-2-(trifluoromethyl)phenyl)acetic acid

Product 1

HCID 710768612-Fluoro-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acidYield 25%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

Prepared using General Procedures 6 and 9. To a stirring solution of 2-(4-methoxy-2-(trifluoromethyl)phenyl)acetic acid (500 mg, 2.13 mmol) and methyl 4-amino-2-fluorobenzoate (361 mg, 2.13 mmol) in DMF (5 mL) were added HATU (852 mg, 2.24 mmol) and TEA (744 μl, 5.34 mmol). After stirring at room temperature for 18 h the reaction mixture was diluted with EA (20 mL) and washed with NaHCO3 (2×20 mL) and 1 M HCl (2×20 mL). The organic phase was concentrated in vacuo to afford an orange solid which was dissolved in THF (5 mL) and MeOH (2 mL) and 1 M LiOH (4.3 μL, 4.27 mmol) was added. After stirring at room temperature for 2 h the reaction mixture was concentrated in vacuo, the residue dissolved in water (10 mL) and acidified to pH 1 using 1 M HCl. A white precipitate was formed and the mixture was filtered under vacuum. The captured solid was washed with MeOH (5 mL) to afford a pale brown solid. The solid was triturated with MeOH (5 mL) to afford 198 mg (25%) of 2-fluoro-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-78 as a white solid. LCMS-ESI (m/z) calculated for C17H13F4NO4: 371; found 372 [M+H]+, tR=1.94 min (Method 10).

Workup

  1. customPrepared
  2. washwashed with NaHCO3 (2×20 mL) and 1 M HCl (2×20 mL)
  3. concentrationThe organic phase was concentrated in vacuo
  4. customto afford an orange solid which
  5. stirringAfter stirring at room temperature for 2 h the reaction mixture
  6. concentrationwas concentrated in vacuo
  7. dissolutionthe residue dissolved in water (10 mL)
  8. customA white precipitate was formed
  9. filtrationthe mixture was filtered under vacuum
  10. washThe captured solid was washed with MeOH (5 mL)
  11. customto afford a pale brown solid
  12. customThe solid was triturated with MeOH (5 mL)

Sources & evidence

ORD record
ord-969b05721bee4daeae19740bbf3fb5f5
Source dataset
uspto-grants-2016_03
Patent number
US09278910B2

Reaction notes

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