Hydrogen chloride-ethyl acetate → Hydrochloric Acid

To a solution of 5-fluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]pyridine obtained in Reference Example 9 (81.2 g, 0.33 mol) in methanol (250 mL), a 4M solution of HCl-EtOAc (0.25 L, 0.96 mol) was added, and the resulting mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, then EtOAc (500 mL) was added to the residue, and the resulting mixture was heated to reflux for 1 hour. The reaction mixture was allowed to cool to room temperature, then ice-cooled, and then the precipitate was filtered out and dried to obtain a hydrochloride (colorless solid) of the title compound. Water (700 mL) and EtOAc (350 mL) were added to the obtained hydrochloride, and the resulting mixture was stirred for 30 minutes and then separated. The obtained organic layer was extracted with 1.2M hydrochloric acid (100 mL) three times. The aqueous layers were combined and the pH was adjusted to 12 with an 8M aqueous solution of NaOH, and then the organic layer was extracted with CHCl3. The extracted organic layer was passed through an ISOLUTE Phase Separator, and the solvent was distilled off under reduced pressure. Diisopropyl ether (300 mL) was added to the obtained residue, and the resulting mixture was heated to reflux for 2 hours. The reaction mixture was allowed to cool at room temperature, then ice-cooled, and then the precipitate was filtered out and dried to obtain the title compound (44.9 g) (pale pink solid).

1. distillationThe solvent was distilled off under reduced pressure
2. additionEtOAc (500 mL) was added to the residue
3. temperaturethe resulting mixture was heated
4. temperatureto reflux for 1 hour
5. temperatureto cool to room temperature
6. temperatureice-cooled
7. filtrationthe precipitate was filtered out
8. customdried

ORD record

ord-1a1cb954b329453dbf91d2d2d02589d4

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09266870B2