Dichloromethane → N-(4-methoxybenzyl)-4,5-difluoro-2-hydroxybenzamide

HRID 1271050Notes

Reaction equation

HRID 1271050 reaction equation
[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([OH:12])[CH:3]=1.C(OC(=O)C)(=O)C.ClCCl.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>N1C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([F:11])[C:2]([F:1])=[CH:3][C:4]=2[OH:12])=[CH:27][CH:26]=1

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 7918Acetic AnhydrideHCID 754524-MethoxybenzylamineHCID 120408324,5-Difluoro-2-hydroxybenzoic acid

Product 1

HCID 18452522N-(4-methoxybenzyl)-4,5-difluoro-2-hydroxybenzamideYield 85.2%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

To a solution 4,5-difluoro-2-hydroxybenzoic acid (1 g, 6 mmol, US0061666246) in pyridine (2 mL) was added acetic anhydride (0.8 mL, 7 mol) and the mixture was stirred at room temperature for 2 hr. To this added 10% HCl (10 mL) and extracted the acetate intermediate with ethyl acetate. The ethyl acetate was evaporated and the residue taken up in dichloromethane (10 mL). To this solution added oxalyl chloride (1 mL) and few drops of dimethylformamide and stirred for 1 hr. The solvent was removed and the acid chloride was re-dissolved in dichloromethane (10 mL) and added slowly to dichloromethane solution (10 mL) of p-methoxybenzylamine (0.855 mL, 6.5 mmol). The reaction mixture after 2 hr showed new peak by HPLC and complete disappearance of the starting material. The dichloromethane was removed and the residue dissolved in methanol and to it added 10% aqueous NaOH solution (3 mL) and mixture stirred for 1 hr. The methanol was removed and the residue acidified and extracted with ethyl acetate. The ethyl acetate layer was dried, filtered and evaporated to yield 1.5 g (85%) of N-(4-methoxybenzyl)-4,5-difluoro-2-hydroxybenzamide as a white solid. RP-HPLC: 2.70 min; ES-MS (M+H)+=294; 1H-NMR (CD3OD) δ (ppm) 7.8 (dd, 1), 7.4 (d, 2), 6.8 (d, 2), 6.6 (dd, 1), 4.6 (s, 2), 3.8 (s, 3).

Workup

  1. extractionTo this added 10% HCl (10 mL) and extracted the acetate intermediate with ethyl acetate
  2. customThe ethyl acetate was evaporated
  3. additionTo this solution added oxalyl chloride (1 mL) and few drops of dimethylformamide
  4. stirringstirred for 1 hr
  5. customThe solvent was removed
  6. dissolutionthe acid chloride was re-dissolved in dichloromethane (10 mL)
  7. waitThe reaction mixture after 2 hr showed new
  8. customThe dichloromethane was removed
  9. dissolutionthe residue dissolved in methanol and to it
  10. additionadded 10% aqueous NaOH solution (3 mL) and mixture
  11. stirringstirred for 1 hr
  12. customThe methanol was removed
  13. extractionextracted with ethyl acetate
  14. dry with materialThe ethyl acetate layer was dried
  15. filtrationfiltered
  16. customevaporated

Sources & evidence

ORD record
ord-c3604ad70992421d8a0007a95905604b
Source dataset
uspto-grants-2007_04
Patent number
US07205296B2

Reaction notes

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