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

Temperature

-78 °C

To 2,4-difluoro-phenylamine (1, 5.11 mL, 50.7 mmol) in tetrahydrofuran (250 mL), cooled with dry ice/acetone bath under an atmosphere of nitrogen, was added n-butyllithium (1.60 M in hexane, 34.0 mL, 54.4 mmol) slowly. After 30 minutes, 1,2-Bis-(chloro-dimethyl-silanyl)-ethane (11.5 g, 53.4 mmol) dissolved in tetrahydrofuran (40.0 mL) was added to the reaction slowly. After 1 hour, n-butyllithium (1.60 M in hexane, 31.9 mL, 51.0 mmol) was added slowly to the reaction. 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., followed by addition of n-butyllithium (1.60 M in hexane, 35.1 mL, 56.2 mmol) slowly. After 70 minutes, benzyl chloroformate (7.97 mL, 55.8 mmol) was added to the reaction. The reaction mixture was stirred at −78° C. overnight followed by addition of 2 N HCl (120 mL). 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, filtrated and concentrated. The desired compound was isolated by silica gel column chromatography (ethyl acetate/hexane 20%) to give a colorless oil (50, 10.6 g, 79.7%). MS (ESI) [M+H+]+=264.1.

1. additionwas added to the reaction 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. filtrationfiltrated
13. concentrationconcentrated

ORD record

ord-c424c57324264b79809a3f97d9fe9abd

Source dataset

uspto-grants-2012_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08198273B2