Dimethylformamide → N-(2-Fluoro-4-hydroxy-benzyl)-2-(4-fluoro-phenoxy)-nicotinamide

HRID 1297590Notes

Reaction equation

HRID 1297590 reaction equation
[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.Cl.[F:30][C:31]1[CH:38]=[C:37]([OH:39])[CH:36]=[CH:35][C:32]=1[CH2:33][NH2:34]>ClCCl.C(N(CC)CC)C>[F:30][C:31]1[CH:38]=[C:37]([OH:39])[CH:36]=[CH:35][C:32]=1[CH2:33][NH:34][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[N:15][C:7]=1[O:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=1

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 65578Oxalyl chlorideHCID 6051232-(4-Fluorophenoxy)nicotinic acidHCID 220584394-(Aminomethyl)-3-fluorophenol hydrochloride

Product 1

HCID 17832836N-(2-Fluoro-4-hydroxy-benzyl)-2-(4-fluoro-phenoxy)-nicotinamide

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8471TriethylamineSolvent

Procedure

To 2-(4-fluoro-phenoxy)-nicotinic acid (20.47 g) were added anhydrous dichloromethane (200 mL), dimethylformamide (2 mL), and oxalyl chloride (2.0 M in dichloromethane, 46.10 mL) were then added. The solution was cooled in a dry ice/acetone bath. Triethylamine (24.5 mL) and 2-fluoro-4-hydroxy-benzylamine hydrochloride (7.81 g) were then added. The solution was allowed to warm to ambient temperature and stir overnight. The reaction was then diluted with 200 mL dichloromethane and washed with 100 mL water. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was then taken up in a solution of tetrahydrofuran (50 mL) and methanol (25 mL). Lithium hydroxide (5.26 g) in water (25 mL) were then added to the mixture, and the reaction was allowed to stir overnight at ambient temperature. The solution was then concentrated in vacuo. The resulting residue was taken up in 100 mL water, and acidified with conc. aq. HCl to pH 4. The aqueous layer was then extracted with ethyl acetate (3×300 mL). The combined organics were dried over magnesium sulfate and concentrated in vacuo. Recrystallization from methanol yielded pure title compound (9.75 g)

Workup

  1. additionwere then added
  2. temperatureThe solution was cooled in a dry ice/acetone bath
  3. washwashed with 100 mL water
  4. dry with materialThe organic phase was dried over magnesium sulfate
  5. concentrationconcentrated in vacuo
  6. additionLithium hydroxide (5.26 g) in water (25 mL) were then added to the mixture
  7. stirringto stir overnight at ambient temperature
  8. concentrationThe solution was then concentrated in vacuo
  9. extractionThe aqueous layer was then extracted with ethyl acetate (3×300 mL)
  10. dry with materialThe combined organics were dried over magnesium sulfate
  11. concentrationconcentrated in vacuo
  12. customRecrystallization from methanol yielded pure title compound (9.75 g)

Sources & evidence

ORD record
ord-7a03d51ebb064843b829c0517ae002d4
Source dataset
uspto-grants-2007_07
Patent number
US07250518B2

Reaction notes

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