2,4-Difluorobenzylamine → HCID 66882984, compound

Alternatively, 8-chloro-3-(4-phenoxyphenyl)isochromen-1-one (48 mg, 0.14 mmol) and 2,4-difluorobenzylamine (24 μL, 0.20 mmol) were combined in toluene (2.0 mL) in a round-bottomed flask under nitrogen. To the resulting mixture was added a solution of methyl aluminoxane (0.11 mL, of a 1.5 M solution in toluene, 0.16 mmol). The resulting yellow solution was then heated to reflux. TLC of the reaction mixture after 1 hour at reflux showed no 8-chloro-3-(4-phenoxyphenyl)isochromen-1-one remaining. Heating was discontinued and the reaction was allowed to cool to ambient temperature. The reaction was then quenched by the addition of 1N HCl (aq.) (5 mL), and diluted with EtOAc (25 mL). The layers were separated and the acidic aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with H2O (10 mL), saturated aqueous NaHCO3 (10 mL), then brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a white solid. The crude solid was purified by silica gel column chromatography by adsorbing the material onto silica gel from a CH2Cl2 solution, loading the resulting solid onto the column and eluting with a gradient from 0% to 20% EtOAc/hexane. The main peak that eluted was collected to afford a compound of formula (W), 2-chloro-N-(2,4-difluorobenzyl)-6-[2-oxo-2-(4-phenoxyphenyl)ethyl]benzamide, (54 mg, 79% yield) as a white solid; 1H-NMR (400 MHz, CDCl3): δ 7.87-7.82 (2H, m), 7.46-7.41 (2H, m), 7.35-7.21 (4H, m), 7.14-7.10 (2H, m), 7.05-7.02 (1H, m), 7.01-6.96 (2H, m), 6.66-6.60 (1H, m), 6.53-6.47 (1H, m), 6.43 (1H, t, J=6.1 Hz), 4.49 (2H, d, J=6.1 Hz), 4.25 (2H, s); which could be used in the next step to produce a corresponding compound of formula (Id).

1. temperatureThe resulting yellow solution was then heated to reflux
2. temperatureTLC of the reaction mixture after 1 hour at reflux
3. temperatureHeating
4. customThe reaction was then quenched by the addition of 1N HCl (aq.) (5 mL)
5. additiondiluted with EtOAc (25 mL)
6. customThe layers were separated
7. extractionthe acidic aqueous layer was extracted with EtOAc (3×10 mL)
8. washThe combined organic layers were washed with H2O (10 mL), saturated aqueous NaHCO3 (10 mL)
9. dry with materialThe organic layer was dried over Na2SO4
10. filtrationfiltered
11. concentrationconcentrated under reduced pressure
12. customto afford a white solid
13. customThe crude solid was purified by silica gel column chromatography
14. washeluting with a gradient from 0% to 20% EtOAc/hexane
15. washThe main peak that eluted
16. customwas collected

ORD record

ord-5f8c00f47ddd4e929adc9c634cc5bd3e

Source dataset

uspto-grants-2007_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07265131B2