Diisopropylamine → 3-Cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acid methyl ester

Temperature

-78 °C

A solution of diisopropylamine (1.5 mL, 10.67 mmol) in dry tetrahydrofuran (24 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (4.3 mL, 10.67 mmol). The resulting reaction mixture was stirred at −78° C. for 45 min and then treated dropwise with a solution of (3-fluoro-4-trifluoromethyl-phenyl)-acetic acid methyl ester (2.40 g, 10.16 mmol) in a small amount of tetrahydrofuran. The reaction mixture was allowed to stir at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (2.24 g, 10.67 mmol) in a small amount of dry tetrahydrofaran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (10 mL) and then partitioned between water (75 mL) and ethyl acetate (75 mL). The layers were shaken and separated. The aqueous layer was further extracted with ethyl acetate (75 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 5/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acid methyl ester (2.69 g, 83%) as a colorless oil: EI-HRMS m/e calcd for C16H18F4O2 (M+) 318.1243, found 318.1250.

1. customThe resulting reaction mixture
2. stirringto stir at −78° C. for 1 h, at which time
3. temperatureto warm to 25° C. where it
4. stirringwas stirred for 15 h
5. customThe reaction mixture was quenched with a saturated aqueous ammonium chloride solution (10 mL)
6. custompartitioned between water (75 mL) and ethyl acetate (75 mL)
7. stirringThe layers were shaken
8. customseparated
9. extractionThe aqueous layer was further extracted with ethyl acetate (75 mL)
10. washThe combined organic layers were washed with a saturated aqueous sodium chloride solution
11. dry with materialdried over magnesium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacuo

ORD record

ord-a596ca4e6dc54c399c89e1634c8d70b6

Source dataset

uspto-grants-2001_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06320050B1