Benzyl chloroformate → Benzyl 3-amino-6-chloro-2-fluorobenzoate

Temperature

-78 °C

A flame dried flask equipped with a stir bar and rubber septum was charged with 4-chloro-2-fluoroaniline (5.00 g, 34.35 mmol) and dry THF (170 mL). This solution was chilled to −78° C., and n-BuLi (14.7 mL, 1.07 eq. of 2.5M solution in hexanes) was then added over a 15 minute period. This mixture was stirred at −78° C. for 20 minutes, and then a THF solution (25 mL) of 1,2-bis(chlorodimethylsilyl)ethane (7.76 g, 1.05 eq.) was added slowly (over a 10 minute period) to the reaction mixture. This was stirred for 1 hour, and then 2.5M n-BuLi in hexanes (15.11 mL, 1.1 eq.) was added slowly. After allowing the mixture to warm to room temperature for one hour, the mixture was chilled back to −78° C. A third allotment of n-BuLi (15.66 mL, 1.14 eq.) was added slowly, and the mixture was stirred at −78° C. for 75 minutes. Benzyl chloroformate (7.40 g, 1.2 eq.) was then added slowly, and the mixture was stirred at −78° C. for one hour. The cooling bath was then removed. The mixture was allowed to warm for 30 minutes and then quenched with water (70 mL) and concentrated HCl (25 mL). The mixture was allowed to continue to warm to room temperature. The mixture was then extracted with EtOAc. The extracts were washed twice with a saturated Na2HCO3 solution, once with water, dried over sodium sulfate and concentrated. The resulting residue was flashed on a 65 Biotage (30% ethyl acetate/hexane) to produce benzyl 3-amino-6-chloro-2-fluorobenzoate (4.3 g, 45%) as an oil. 1H NMR (DMSO-d6, 400 MHz) δ 7.37-7.48 (m, 5H), 7.07 (dd, 1H, J=8, 2), 6.87 (t, 1H, J=8), 5.61 (br s, 2H), 5.40 (s, 2H).

1. customA flame dried flask
2. customequipped with a stir bar
3. stirringThis was stirred for 1 hour
4. temperatureto warm to room temperature for one hour
5. temperaturethe mixture was chilled back to −78° C
6. stirringthe mixture was stirred at −78° C. for 75 minutes
7. stirringthe mixture was stirred at −78° C. for one hour
8. customThe cooling bath was then removed
9. temperatureto warm for 30 minutes
10. customquenched with water (70 mL) and concentrated HCl (25 mL)
11. temperatureto warm to room temperature
12. extractionThe mixture was then extracted with EtOAc
13. washThe extracts were washed twice with a saturated Na2HCO3 solution, once with water
14. dry with materialdried over sodium sulfate
15. concentrationconcentrated

ORD record

ord-4d7f36601fe849b686a9b89fa4ca2d72

Source dataset

uspto-grants-2013_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08394795B2