Hydrochloric Acid → Benzyl 3-amino-6-chloro-2-fluorobenzoate

Temperature

-78 °C

To 4-chloro-2-fluoro-phenylamine (15, 6.30 mL, 57.0 mmol) in 300 mL of tetrahydrofuran cooled with dry ice/acetone bath under an atmosphere of nitrogen, n-butyllithium (2.50 M in hexane, 24.4 mL) was added slowly. After 20 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (12.9 g, 60.0 mmol) dissolved in tetrahydrofuran (40.0 mL) was added slowly to the reaction. After 1 hour, n-butyllithium (2.50 M in hexane, 25.0 mL) was added slowly to the reaction. The reaction was stirred at −78° C. for 20 minutes and then allowed to warm to room temperature over 60 minutes. The reaction was cooled to −78° C., followed by addition of n-butyllithium (2.50 M in hexane, 26.0 mL) slowly. After 80 minutes, benzyl chloroformate (2, 10.0 mL, 70.0 mmol) was added to the reaction. The reaction mixture was stirred at −78° C. overnight followed by addition of 80 mL of water and 25 mL of concentrated 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 (16, 12.5 g, 78.3%). MS(ESI) [M+H+]+=280.0.

1. additionwas added slowly to the reaction
2. waitAfter 1 hour
3. temperatureto warm to room temperature over 60 minutes
4. temperatureThe reaction was cooled to −78° C.
5. waitAfter 80 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-d1ef9090a37748a1a97b85ac4ab78116

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08901301B2