Hydrochloric Acid → 4-Fluorophenyl-2-(2-Trifluoromethyl-5-Thiazolyl)Ethanone

Temperatur

-70 °C

A solution of 2.4M n-butyl lithium in hexane (6.4 mL, 15.4 mmol) was added to a solution of 2.15 mL (15.4 mmol) of diisopropylamine in 50 mL of dry tetrahydrofuran at -10° C. under nitrogen with stirring over a 2-min period. The resulting solution was cooled to -70° C. and a solution containing 3.18 g (14 mmol) of 2-(trimethylsilyloxy)-2-(4',-fluorophenyl)acetonitriie in 3 mL of dry tetrahydrofuran was added dropwise by means of a syringe pump over a 20-min period under nitrogen with stirring. The resulting bright yellow solution was stirred for an additional 30 min at -70° C. or below and then a solution of 2.92 g (11.9 mmol) of 5-bromomethyl- 2-trifluoromethylthiazole in 5 mL of dry tetrahydrofuran was added over 30 min under nitrogen with stirring to obtain a dark, thick slurry. After a 45-min reaction period this mixture was allowed to warm and was poured into a rapidly stirred mixture consisting of 25 mL of 10 percent aqueous hydrochloric acid and 10 mL of methanol. Aqueous hydrofluoric acid (0.5 mL of 48 percent) was then added and the mixture was stirred until all of the trimethylsilane protecting group was removed. Sufficient 10 percent aqueous sodium hydroxide was added with stirring to adjust the pH to about 10 and after 15 min the phases were separated. The aqueous phase was extracted with 2×30 mL of ether and the combined organic phases were washed with 50 mL of 10 percent aqueous hydrochloric acid and 50 mL of saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was kugelrohr distilled, first at 70° C. and 0.05 torr (6.7 Pa (Pascals)) to remove 4-fluorobenzaldehyde and then at 100°-110° C. and 0.05 torr (6.7 Pa) to distill 2.93 g (85 percent of theory) of the title compound, which was obtained as a waxy yellow solid of 95 percent purity (by gas liquid chromatography). An analytical sample obtained by crystallization from a mixture of hexane and acetone melted at 66.5°-68.5° C.

1. additionwas added dropwise by means of a syringe pump over a 20-min period under nitrogen
2. stirringwith stirring
3. stirringThe resulting bright yellow solution was stirred for an additional 30 min at -70° C. or below
4. stirringwith stirring
5. customto obtain a dark, thick slurry
6. customAfter a 45-min reaction period this mixture
7. temperatureto warm
8. additionwas poured into a rapidly stirred mixture
9. customwas removed
10. additionSufficient 10 percent aqueous sodium hydroxide was added
11. stirringwith stirring
12. customafter 15 min the phases were separated
13. extractionThe aqueous phase was extracted with 2×30 mL of ether
14. washthe combined organic phases were washed with 50 mL of 10 percent aqueous hydrochloric acid and 50 mL of saturated aqueous sodium chloride
15. dry with materialdried over magnesium sulfate
16. concentrationconcentrated by evaporation under reduced pressure
17. customfirst at 70° C. and 0.05 torr (6.7 Pa (Pascals)) to remove 4-fluorobenzaldehyde
18. distillationat 100°-110° C. and 0.05 torr (6.7 Pa) to distill 2.93 g (85 percent of theory) of the title compound
19. customwhich was obtained as a waxy yellow solid of 95 percent purity (by gas liquid chromatography)

ORD-Eintrag

ord-3d8343aea6d24a5f982d97e5402c0d0b

Quelldatensatz

uspto-grants-1995_05

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US05418247