Hydrochloric Acid → 3-cyclopentyl-2-(3,4-dichlorophenyl)propanoic Acid

Temperature

-78 °C

A solution of diisopropylamine (13.36 mL, 101.89 mmol) in tetrahydrofuran (250 mL) was cooled to −78° C. under a nitrogen atmosphere and then treated with a 2.0M solution of n-butyllithium in hexanes (51 mL, 101.89 mmol). The reaction mixture was stirred at −78° C. for 15 min, at which time, a solution of 3,4-dichlorophenyl acetic acid (9.08 g, 44.3 mmol) in tetrahydrofuran (60 mL) and hexamethylphosphoramide (20 mL) was slowly added via a cannula. The bright yellow solution was allowed to stir at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (11.17 g, 53.2 mmol) in hexamethylphosphoramide (10 mL) was added via a cannula. The reaction mixture was stirred at −78° C. for 1 h. The reaction mixture was then allowed to warm to 25° C., where it was stirred for 14 h. The reaction mixture was then acidified to pH=2 by the dropwise addition of a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried with sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, chloroform then 99/1 chloroform/methanol) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (10.28 g, 81%) as a white solid: mp 74.5-76.9° C.; EI-HRMS m/e calcd for C14H16Cl2O2 (M+) 286.0527, found 286.0534.

1. stirringto stir at −78° C. for 1 h, at which time
2. stirringThe reaction mixture was stirred at −78° C. for 1 h
3. temperatureto warm to 25° C.
4. stirringwhere it was stirred for 14 h
5. extractionextracted with ethyl acetate (3×50 mL)
6. dry with materialThe combined organic layers were dried with sodium sulfate
7. filtrationfiltered
8. concentrationconcentrated in vacuo

ORD record

ord-53b217dc8ade43169e1d47859147acbc

Source dataset

uspto-grants-2003_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06528543B1