Hydrochloric Acid → 3-Fluoro-4-[(1E,3E)-5-oxo-1,3-pentadienyl]benzonitrile

0.5 ml (0.77 mmol) of a 1.53 N hexane solution of butyllithium were added dropwise to a solution of 209 mg (0.77 mmol) of diethyl 4-cyano-2-fluorobenzylphosphonate [which was obtained in Step 1(i) above) in 4 ml of anhydrous tetrahydrofuran at −78° C. with stirring. The mixture was stirred at −78° C. for 30 minutes. At the end of this time, a solution of 100 mg (0.77 mmol) of commercially available fumaraldehyde mono-dimethylacetal in 2 ml of anhydrous tetrahydrofuran was added to the mixture, and the resulting mixture was stirred at −78° C. for 2 hours. The cooling bath was then removed and the mixture was stirred in an ice bath for a further 15 minutes. 3.9 ml (0.39 mmol) of 0.1 N hydrochloric acid were added to the reaction mixture and the mixture was then stirred for 30 minutes in the ice bath and then for 1 hour at ambient temperature. At the end of this time, a saturated aqueous sodium hydrogen carbonate solution was added to the mixture in an ice bath. The resulting mixture was partitioned between ethyl acetate and water, the organic layer was washed with water and with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The crystalline residue thus obtained was recrystallized from a mixture of ethyl acetate and hexane to afford 127 mg (yield 87%) of the title compound as pale yellow crystals.

1. stirringThe mixture was stirred at −78° C. for 30 minutes
2. stirringthe resulting mixture was stirred at −78° C. for 2 hours
3. customThe cooling bath was then removed
4. stirringthe mixture was stirred in an ice bath for a further 15 minutes
5. customThe resulting mixture was partitioned between ethyl acetate and water
6. washthe organic layer was washed with water and with aqueous sodium chloride solution
7. dry with materialdried over anhydrous magnesium sulfate
8. concentrationconcentrated under reduced pressure
9. customThe crystalline residue thus obtained
10. customwas recrystallized from a mixture of ethyl acetate and hexane

ORD record

ord-4a41f75cd9174c9582c2884218055a5b

Source dataset

uspto-grants-2002_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06391903B1