Hydrochloric Acid → HCID 87458383, compound

To a suspension of sodium hydride (640 mg, 16 mmol, 60%) in DMF (20 mL) was added (2-fluorophenyl)methanol (1.9 g, 15 mmol) at 0° C. After being stirred at room temperature for 30 min, 6-chloronicotinonitrile (2.6 g, 19 mmol) was added to the mixture. The mixture was stirred at room temperature for 14 hours. The mixture was poured into saturated ammonium chloride aqueous solution, and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (19:1 (v/v)) to give the intermediate. The intermediate was dissolved into dichloromethane (30 mL). DIBAL-H (6.3 mL, 6.4 mmol, 0.99 M) was added to the mixture at −78° C. After being stirred at −78° C. for 4 hours, methanol (2 mL) was added to the mixture. 1N hydrochloric acid (0.5 mL) was added to the mixture at room temperature. The mixture was stirred at room temperature for 1 hour. Sat. sodium bicarbonate aqueous solution was added to the mixture until the pH was neutrized. The organic layer was extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in dichloromethane (20 mL). Copper(II) sulfate (2.3 g, 14 mmol) followed by (R)-(+)-2-methyl-2-propanesulfinamide (700 mg, 5.8 mmol) were added to the mixture respectively and the mixture was stirred for 18 hours at room temperature. The reaction mixture was filtrated off through a pad of Celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (4:1 (v/v)) to give 155 mg (3% yield) of the title compound as a white solid:

1. stirringThe mixture was stirred at room temperature for 14 hours
2. extractionthe aqueous phase was extracted with ethyl acetate (twice)
3. dry with materialThe combined organic layers were dried over magnesium sulfate
4. concentrationconcentrated in vacuo
5. customThe residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (19:1 (v/v))
6. customto give the intermediate
7. stirringAfter being stirred at −78° C. for 4 hours
8. stirringThe mixture was stirred at room temperature for 1 hour
9. extractionThe organic layer was extracted with dichloromethane
10. dry with materialdried over sodium sulfate
11. concentrationconcentrated in vacuo
12. dissolutionThe residue was dissolved in dichloromethane (20 mL)
13. additionwere added to the mixture respectively
14. stirringthe mixture was stirred for 18 hours at room temperature
15. filtrationThe reaction mixture was filtrated off through a pad of Celite
16. concentrationthe filtrate was concentrated in vacuo
17. customThe residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (4:1 (v/v))

ORD record

ord-12d6be7dea1a40b1ab83043629440c5d

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09101616B2