(alpha,alpha,alpha-Trifluoro-4-tolyl)acetic acid → 3-Cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic acid

Temperature

-78 °C

A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (4-trifluoromethyl-phenyl)-acetic acid (693 mg, 3.4 mmol) in tetrahydrofuran/hexamethylphosphoramide (8.5 mL, 3:1). The resulting solution was stirred at −78° C. for 30 min. lodomethylcyclopentane (784 mg, 3.7 mmol) was then added in hexamethylphosphoramide (1 mL). The mixture was stirred at <78° C. for 4 h. The reaction was then warmed to 25° C and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL). The excess solvent was removed in vacuo. The residue was acidified to pH=1 with a 1N aqueous hydrochloric acid solution. The mixture was then poured into water (150 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic acid (634.9 mg, 65%) as a white solid: mp 94-95° C.; EI-HRMS m/e calcd for C15H17F3O2 (M+) 309.1079, found 309.1072.

1. stirringThe mixture was stirred at <78° C. for 4 h
2. temperatureThe reaction was then warmed to 25° C
3. stirringwas stirred at 25° C. for 16 h
4. customThe reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL)
5. customThe excess solvent was removed in vacuo
6. additionThe mixture was then poured into water (150 mL)
7. extractionextracted with ethyl acetate (3×100 mL)
8. dry with materialThe combined organic layers were dried over sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated in vacuo

ORD record

ord-e3eb57840692455fab7bb1d4b01790d4

Source dataset

uspto-grants-2003_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06610846B1