Triethylamine → 2-(Difluoromethyl)-5-[[(2-methyl-1-oxopropyl)amino]methyl]benzoic acid

HRID 241440Notes

Reaction equation

HRID 241440 reaction equation
[C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH:20]([F:22])[F:21])=[C:14]([CH:19]=1)[C:15]([O:17]C)=[O:16].C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[F:21][CH:20]([F:22])[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[CH:19][C:14]=1[C:15]([OH:17])=[O:16]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 62325Isobutyryl chlorideHCID 67970562HCID 67970562, compound

Product 1

HCID 679705062-(Difluoromethyl)-5-[[(2-methyl-1-oxopropyl)amino]methyl]benzoic acidYield 94.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Add isobutyryl chloride (0.571 mL, 5.42 mmol, 1.05 equiv) to a mixture of methyl 5-(aminomethyl)-2-(difluoromethyl)benzoate hydrochloride (1.30 g, 5.17 mmol, 1.0 equiv) and triethylamine (1.51 mL, 10.85 mmol, 2.1 equiv) in DCM (50 mL) at room temperature and stir the mixture for one hour. Dilute the mixture with DCM; wash with water; then with a saturated sodium chloride aqueous solution. Separate the organic layer; dry over sodium sulfate; filter; and concentrate the filtrate under reduced pressure. Dissolve the resulting crude material in 1,4-dioxane (10 mL), and add sodium hydroxide (5 N, 2 mL, 10 mmol, 1.93 equiv). Stir the resulting suspension at 40° C. overnight. Concentrate the mixture under reduced pressure, and treat the resulting residue with 1 N aqueous hydrochloric acid until the pH reaches 3. Extract the resulting suspension with EtOAc (2×30 mL). Wash the combined organic layers with a saturated sodium chloride aqueous solution (50 mL); dry over sodium sulfate; filter; and concentrate the filtrate under reduced pressure to give the title compound as a white solid (1.32 g, 94% yield). ES/MS (m/z) 272 (M+1).

Workup

  1. washwash with water
  2. customSeparate the organic layer
  3. dry with materialdry over sodium sulfate
  4. filtrationfilter
  5. concentrationand concentrate the filtrate under reduced pressure
  6. dissolutionDissolve the resulting crude material in 1,4-dioxane (10 mL)
  7. stirringStir the resulting suspension at 40° C. overnight
  8. concentrationConcentrate the mixture under reduced pressure
  9. additiontreat the resulting residue with 1 N aqueous hydrochloric acid until the pH
  10. extractionExtract the resulting suspension with EtOAc (2×30 mL)
  11. washWash the combined organic layers with a saturated sodium chloride aqueous solution (50 mL)
  12. dry with materialdry over sodium sulfate
  13. filtrationfilter
  14. concentrationand concentrate the filtrate under reduced pressure

Sources & evidence

ORD record
ord-26031bc8ecd74956892ec2428c3abe04
Source dataset
uspto-grants-2014_02
Patent number
US08648200B2

Reaction notes

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