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

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 dichloromethane (50 mL) at room temperature, add isobutyryl chloride (0.571 mL, 5.42 mmol, 1.05 equiv) and stir for one hour. Dilute the mixture with dichloromethane and wash with water then saturated aqueous NaCl. Separate the organic layer and dry over sodium sulfate, filter, and concentrate under reduced pressure. Dissolve the resulting crude material in 1,4-dioxane (10 mL), and add sodium hydroxide (5 N aqueous, 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 saturated aqueous NaCl (50 mL), dry over sodium sulfate, filter, and concentrate under reduced pressure to give the title compound as a white solid (1.32 g, 94%). MS (m/z) 272 (M+1).

1. washwash with water
2. customSeparate the organic layer
3. dry with materialdry over sodium sulfate
4. filtrationfilter
5. concentrationconcentrate 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 saturated aqueous NaCl (50 mL)
12. dry with materialdry over sodium sulfate
13. filtrationfilter
14. concentrationconcentrate under reduced pressure

ORD record

ord-0b6fa1aa20e54f0e82c9a1ba7ecd1f53

Source dataset

uspto-grants-2012_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08252831B2