Diisopropylamine → 3-Cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid

Temperature

-78 °C

A solution of diisopropylamine (3.2 mL, 23.16 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL) was cooled to −78° C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (2.3 mL, 23.16 mmol). The resulting reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of 4-(methylthio)phenylacetic acid (2.01 g, 11.03 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL). The reaction mixture was allowed to stir at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (2.55 g, 12.13 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was then stirred at −78° C. for 30 min and then allowed to warm to 25° C. where it was stirred for 24 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1×200 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g, 35%) as a cream solid: mp 91-93° C.; EI-HRMS m/e calcd for C15H20O2S (M+) 264.1184, found 264.1177.

1. customThe resulting reaction mixture
2. stirringto stir at −78° C. for 1 h, at which time
3. stirringThe reaction mixture was then stirred at −78° C. for 30 min
4. temperatureto warm to 25° C. where it
5. stirringwas stirred for 24 h
6. customThe reaction mixture was quenched with water
7. concentrationconcentrated in vacuo
8. customto remove tetrahydrofuran
9. extractionextracted with ethyl acetate (1×200 mL)
10. washThe organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL)
11. dry with materialdried over sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacuo

ORD record

ord-6a80eccdd9704e7cbd4a2321d87a80a5

Source dataset

uspto-grants-2003_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06610846B1