Acetic Acid → 3-Chloro-6,7-difluorobenzo[d]isoxazole-5-carbaldehyde

Temperature

0 °C

A solution of n-butyllithium (2.5 M in hexanes) (16.7 ml, 42 mmol) was added slowly to a solution of 2,2,6,6-tetramethylpiperidine (7.6 ml, 45 mmol) in THF (50 ml) cooled in a dry ice-acetone bath. The solution was warmed to 0° C. and re-cooled in a dry-ice acetone bath before transferring via syringe to a solution of 3-chloro-6,7-difluorobenzo[d]isoxazole (Intermediate 529, 5.64 g, 30 mmol) in THF (50 ml). After 1 hour stirring, DMF (1.0 ml, 13.2 mmol) was added all at once and the mixture was stirred with cooling in a dry-ice acetone bath for 45 min. The mixture transferred via cannula to a solution of acetic acid (6.8 ml, 119 mmol) in 100 ml Et2O and the mixture was warmed to room temperature. The mixture was diluted with EtOAc and washed with brine. The combined aqueous layers were extracted again with EtOAc, which was washed with brine. Drying (MgSO4) of the combined extracts and removal of solvent gave a brown oil that was chromatographed on silica gel (10% CH2Cl2 in hexanes followed by gradient elution to 100% CH2Cl2) to give 3.32 g of product as a white solid.

1. temperaturecooled in a dry ice-acetone bath
2. temperaturere-cooled in a dry-ice acetone bath
3. stirringwas stirred
4. temperaturewith cooling in a dry-ice acetone bath for 45 min
5. temperaturethe mixture was warmed to room temperature
6. washwashed with brine
7. extractionThe combined aqueous layers were extracted again with EtOAc, which
8. washwas washed with brine
9. customDrying
10. custom(MgSO4) of the combined extracts and removal of solvent
11. customgave a brown oil that
12. customwas chromatographed on silica gel (10% CH2Cl2 in hexanes followed by gradient elution to 100% CH2Cl2)

ORD record

ord-c814b0fc3130496ea8bf8ef988907d4e

Source dataset

uspto-grants-2014_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08658641B2