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

Temperature

-78 °C

To 4-chloro-2-fluoro-phenylamine (11, 6.30 mL, 57.0 mmol) in 300 mL of tetrahydrofuran, cooled with dry ice/acetone bath under an atmosphere of nitrogen, n-butyllithium (24.4 mL, 2.50 M in hexane) was added slowly. After 20 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (12.9 g, 60.0 mmol) dissolved in 40.0 mL of tetrahydrofuran was added slowly to the reaction. After 1 hour, n-butyllithium (25.0 mL, 2.50 M in hexane) 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 slowly adding n-butyllithium (26.0 mL, 2.50 M in hexane). After 80 minutes, benzyl chloroformate (20, 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 and 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 resulting material was purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a colorless oil (12, 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
14. customThe resulting material was purified by silica gel column chromatography
15. washeluting with 20% ethyl acetate in hexane
16. concentrationconcentrated under vacuum

ORD record

ord-9e93e686e83e4a5084443d4e910086ec

Source dataset

uspto-grants-2012_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08153641B2