Hydrochloric Acid → N-[4-chloro-2-(4-fluoro-benzoyl)-phenyl]-4-fluoro-benzamide

Temperature

180 °C

To p-fluorobenzoyl chloride (49.7 g, 314 mmol), heated to 120° C., was added p-chloroaniline (17.8 g, 139 mmol) over 10 min. The mixture was then heated to 180° C. and ZnCl2 (23.8 g, 174 mmol) was added over 10 min. The resulting mixture was heated at 205° C. for 2 h. After cooling to 120° C., 3N HCl (125 mL) was added cautiously and the mixture was maintained at 120° C. for 1 h. The hot aqueous portion was then decanted and the remaining residue was washed with hot 3N HCl (2×125 mL). The residue was poured onto ice and extracted with CH2Cl2 (3×100 mL). The combined organic portions were washed with 3N HCl (2×50 mL), 5N NaOH (2×50 mL) and H2O (3×50 mL) and were then dried over MgSO4, filtered and concentrated in vacuo to provide 15 g (29%) of the N-[4-chloro-2-(4-fluoro-benzoyl)-phenyl]-4-fluoro-benzamide as a dark yellow powder. To a flask containing the acylated amino-benzophenone (6.7 g, 18 mmol) was added 1:1 conc. HCl:AcOH (700 mL) and the resulting mixture was heated to 105° C. and stirred for 16 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was poured onto ice and extracted with CH2Cl2 (3×100 mL). The combined organic portions were washed with 5N NaOH (2×50 mL) and H2O (3×50 mL) and then dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel, 5 to 25% EtOAc/hexanes) and recrystallized from hexanes to provide 1t (3.4 g, 76%) MS m/z=250 (M+H).

1. temperatureThe resulting mixture was heated at 205° C. for 2 h
2. temperatureAfter cooling to 120° C.
3. temperaturethe mixture was maintained at 120° C. for 1 h
4. customThe hot aqueous portion was then decanted
5. washthe remaining residue was washed with hot 3N HCl (2×125 mL)
6. additionThe residue was poured onto ice
7. extractionextracted with CH2Cl2 (3×100 mL)
8. washThe combined organic portions were washed with 3N HCl (2×50 mL), 5N NaOH (2×50 mL) and H2O (3×50 mL)
9. dry with materialwere then dried over MgSO4
10. filtrationfiltered
11. concentrationconcentrated in vacuo

ORD record

ord-a2e647ab411647d98e9187d511241f4a

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09102678B2