Hydrochloric Acid → Benzyl 3-amino-2,6-difluorobenzoate

Temperature

-78 °C

To 2,4-difluoro-phenylamine (1, 5.11 mL, 50.7 mmol) in 250 mL of tetrahydrofuran, cooled with dry ice/acetone bath under an atmosphere of nitrogen, n-butyllithium (1.60 M in hexane, 34.0 mL, 54.4 mmol) was added slowly. After 30 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (11.5 g, 53.4 mmol) dissolved in 40.0 mL of tetrahydrofuran was added slowly. After 1 hour, n-butyllithium (1.60 M in hexane, 31.9 mL, 51.1 mmol) was added slowly. The reaction was stirred at −78° C. for 30 minutes and then allowed to warm to room temperature over 40 minutes. The reaction was cooled to −78° C. and n-butyllithium (1.60 M in hexane, 35.1 mL, 56.1 mmol) was added slowly. After 70 minutes, benzyl chloroformate (2, 7.97 mL, 55.8 mmol) was added to the reaction. The reaction mixture was stirred at −78° C. overnight followed by addition of 120 mL of 2 N aqueous hydrochloric acid. The reaction was allowed to warm to room temperature for 2 hours. The organic layer was separated. The aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The desired compound was isolated by silica gel column chromatography (ethyl acetate/hexane 20%) to give a colorless oil (3, 10.6 g, 79.7%). MS(ESI) [M+H+]+=264.1.

1. additionwas added slowly
2. waitAfter 1 hour
3. temperatureto warm to room temperature over 40 minutes
4. temperatureThe reaction was cooled to −78° C.
5. waitAfter 70 minutes
6. stirringThe reaction mixture was stirred at −78° C. overnight
7. temperatureto warm to room temperature for 2 hours
8. customThe organic layer was separated
9. extractionextracted with ethyl acetate
10. washwashed with brine
11. dry with materialdried over anhydrous sodium sulfate
12. filtrationfiltered
13. concentrationthe filtrate concentrated under vacuum

ORD record

ord-c9901387aa234ebea0c8b1f57a1c6631

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08901301B2