Diisopropylamine → 2-(3-Chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid methyl ester

Temperature

-78 °C

A solution of diisopropylamine (4.86 mL, 34.70 mmol) in dry tetrahydrofuran (212.3 mL) was cooled to −78° C. and then treated with a 2.5M solution of n-butyllithium in hexanes (13.88 mL, 34.70 mmol). The resulting reaction mixture was stirred at −78° C for 15 min and then slowly treated with a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (7.28 g, 31.55 mmol) in dry tetrahydrofuran (23.6 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (9.43 mL). The resulting bright yellow solution was allowed to stir at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (7.95 g, 37.86 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7.08 mL) was slowly added. The reaction mixture was allowed to warm to 25° C. where it was stirred overnight. The reaction mixture was then quenched with a saturated aqueous ammonium chloride solution (20 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (5.74 g, 58.1%) as a colorless oil.

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 overnight
5. customThe reaction mixture was then quenched with a saturated aqueous ammonium chloride solution (20 mL)
6. customthe layers were separated
7. extractionThe aqueous layer was extracted with ethyl acetate (3×20 mL)
8. dry with materialThe combined organic layers were dried over sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated in vacuo

ORD record

ord-1ba4c8c103384e63bfa21405135ecc81

Source dataset

uspto-grants-2002_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06441184B1