Hydrochloric Acid → 4-(Benzylamino)-3,5-difluoro-2,6-dimethoxybenzoic acid

Temperature

10 °C

Methyl 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoate (24.0 g) was dissolved in ethanol (75 mL) and the solution stirred and cooled to 10° C. under a nitrogen atmosphere. Sodium hydroxide, 50% aqueous solution (12.5 g, 156 mmol) was added dropwise over 10 minutes at 10° C.–15° C. followed by ethanol (10 mL). The solution was stirred at 15° C.–25° C. A thick precipitate formed. Stirring was continued for a total of 2 hours at 15° C.–25° C. The mixture was heated to 50° C.–55° C. where it was held for 1.5 hours. The mixture was allowed to cool to room temperature and held overnight. Water (100 mL) was added and the resulting solution cooled in an ice bath and acidified with 37% HCl (13.5 mL) to pH 2. The mixture was extracted with toluene (100 mL) and methyl tert-butyl ether (100 mL) and the organic extract washed with water (10 mL) and concentrated to an oil. This was triturated with toluene (20 mL) to give crystals which were collected and vacuum dried at 45° C. to give 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoic acid (19.4 g, 60 mmol): mp: 85° C.–86° C. (decomposition with gas evolution).

1. stirringThe solution was stirred at 15° C.–25° C
2. customA thick precipitate formed
3. stirringStirring
4. customwas continued for a total of 2 hours at 15° C.–25° C
5. temperatureThe mixture was heated to 50° C.–55° C. where it
6. temperatureto cool to room temperature
7. waitheld overnight
8. temperaturethe resulting solution cooled in an ice bath
9. extractionThe mixture was extracted with toluene (100 mL) and methyl tert-butyl ether (100 mL)
10. extractionthe organic extract
11. washwashed with water (10 mL)
12. concentrationconcentrated to an oil
13. customThis was triturated with toluene (20 mL)
14. customto give crystals which
15. customwere collected
16. customvacuum dried at 45° C.

ORD record

ord-2ab1a3039a894610aa7d7a14d8c6fe55

Source dataset

uspto-grants-2007_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07196090B2