Pyridine → 3-(Cyclopentyloxy)-4-(difluoromethoxy)benzeneacetonitrile

To a solution of (3-cyclopentyloxy-4-difluoromethoxyphenyl)benzaldehyde (3.4 g, 13.4 mmol) in absolute ethanol (33 mL) under an argon atmosphere at room temperature and was added sodium borohydride (1.06 g, 28 mmol). After 20 min, 10% aqueous sodium hydroxide (15 mL) was added, the ethanol was removed in vacuo and the aqueous residue was extracted three times with ether. The organic extract was washed twice with brine, was dried (magnesium sulfate) and evaporated to a pale yellow oil (3.44 g). A solution of this alcohol (1.52 g, 5.89 mmol) and pyridine (0.48 mL, 6 mmol) in alumina-dried chloroform (15 mL) under an argon atmosphere was treated with thionyl chloride (0.52 mL, 7.08 mmol) and the mixture was heated at reflux for 1 h. The solvent was removed, ether was added and the precipitate was removed by filtration. The filtrate was concentrated to a pale yellow oil, which was dissolved in dimethylformamide (10 mL) under an argon atmosphere and treated with sodium cyanide (0.58 g, 11.8 mmol). After stirring at room temperature for 72 h, the mixture was partitioned between 5% aqueous sodium carbonate and ether. The organic extract was washed four times with water, was dried (potassium carbonate) and evaporated. Purification by flash chromatography, eluting with 15-20% ethyl acetate/hexanes, provided a pale yellow solid (3.2 g, 90%): m.p. 39°-41° C.

1. customthe ethanol was removed in vacuo
2. extractionthe aqueous residue was extracted three times with ether
3. extractionThe organic extract
4. washwas washed twice with brine
5. dry with materialwas dried (magnesium sulfate)
6. customevaporated to a pale yellow oil (3.44 g)
7. temperaturethe mixture was heated
8. temperatureat reflux for 1 h
9. customThe solvent was removed
10. additionether was added
11. customthe precipitate was removed by filtration
12. concentrationThe filtrate was concentrated to a pale yellow oil, which
13. dissolutionwas dissolved in dimethylformamide (10 mL) under an argon atmosphere
14. customthe mixture was partitioned between 5% aqueous sodium carbonate and ether
15. extractionThe organic extract
16. washwas washed four times with water
17. dry with materialwas dried (potassium carbonate)
18. customevaporated
19. customPurification by flash chromatography
20. washeluting with 15-20% ethyl acetate/hexanes

ORD record

ord-00bb84c28b3c4af2800c80b851ec2817

Source dataset

uspto-grants-1995_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05449686