Lithium Hydroxide → 6-(2-(4-Methoxy-2-(trifluoromethyl)phenyl)acetamido)nicotinic acid

HRID 923625Notes

Reaction equation

HRID 923625 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])=[CH:20][N: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.C(Cl)Cl.C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=2)=[O:12])=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1

Participants

10

Reactant 4

HCID 3939Lithium HydroxideHCID 737487Methyl 6-aminonicotinateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 467375752-(4-Methoxy-2-(trifluoromethyl)phenyl)acetic acid

Product 1

HCID 710767096-(2-(4-Methoxy-2-(trifluoromethyl)phenyl)acetamido)nicotinic acidYield 13%

Reagents, catalysts & solvents 5

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

Prepared using General Procedures 6 and 9. To a stirred solution of 2-(4-methoxy-2-(trifluoromethyl)phenyl)acetic acid (500 mg, 2.13 mmol) and methyl 6-aminonicotinate (325 mg, 2.13 mmol) in DMF (5 mL) were added HATU (852 mg, 2.24 mmol) and TEA (744 μL, 5.34 mmol). The reaction mixture was stirred at room temperature. After 1 h the reaction mixture was diluted with EA (30 mL) and washed with brine (2×30 mL). The organics were dried over MgSO4 and concentrated in vacuo to afford an orange oil which was dissolved in DCM (5 mL) and washed with 1 M HCl (5 mL). The mixture was passed through a phase separation cartridge and the organics concentrated in vacuo to afford an orange oil which was dissolved in THF (5 mL) and MeOH (3 mL). To the reaction mixture was added 1 M LiOH (4.27 mL, 4.27 mmol) and the reaction was stirred at room temperature for 1 h then concentrated in vacuo. The residue was suspended in water (15 mL), acidified to pH 1 using 1 M HCl and the mixture was filtered under vacuum. The crude product was triturated with MeOH (5 mL) and dried in vacuo to afford 97 mg (13%) of 6-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)nicotinic acid INT-80 as a white solid. LCMS-ESI (m/z) calculated for C16H13F3N2O4: 354; found 355 [M+H]+, tR=1.84 min (Method 10).

Workup

  1. customPrepared
  2. washwashed with brine (2×30 mL)
  3. dry with materialThe organics were dried over MgSO4
  4. concentrationconcentrated in vacuo
  5. customto afford an orange oil which
  6. washwashed with 1 M HCl (5 mL)
  7. customThe mixture was passed through a phase separation cartridge
  8. concentrationthe organics concentrated in vacuo
  9. customto afford an orange oil which
  10. stirringthe reaction was stirred at room temperature for 1 h
  11. concentrationthen concentrated in vacuo
  12. filtrationthe mixture was filtered under vacuum
  13. customThe crude product was triturated with MeOH (5 mL)
  14. customdried in vacuo

Sources & evidence

ORD record
ord-8f91c1efb1784c889518b66ef78c325e
Source dataset
uspto-grants-2016_03
Patent number
US09278910B2

Reaction notes

Loading…