Lithium diisopropylamide → 3-Cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid

Temperature

-78 °C

A solution of freshly prepared lithium diisopropylamide (35.32 mL of a 0.31M stock solution, 10.95 mmol) cooled to −78° C. was treated with (4-fluoro-3-trifluoromethyl-phenyl)-acetic acid (1.11 g, 5.0 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (12.42 mL, 3:1). The resulting solution was then stirred at −78° C. for 1 h. Iodomethylcyclopentane (1.16 g, 5.52 mmol) was then added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.2 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 24 h. This solution was then quenched by the slow addition of the reaction mixture to a 2N aqueous hydrochloric acid solution (50 mL). The product was extracted into ethyl acetate (1×300 mL) and diethyl ether (1×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (1.28 g, 84.3%) as a white solid: mp 65-68° C.; EI-HRMS m/e calcd for C15H16F4O2 (M+) 305.1165, found 305.1174.

1. stirringThe reaction 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 24 h
4. customThis solution was then quenched by the slow addition of the reaction mixture to a 2N aqueous hydrochloric acid solution (50 mL)
5. extractionThe product was extracted into ethyl acetate (1×300 mL) and diethyl ether (1×50 mL)
6. dry with materialThe combined organic layers were dried over sodium sulfate
7. filtrationfiltered
8. concentrationconcentrated in vacuo

ORD record

ord-4b1c649d464a4b5f9d40ef54269f1be9

Source dataset

uspto-grants-2003_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06610846B1