Methyl 2-(3,4-dichlorophenyl)acetate → 2-(3,4-Dichloro-phenyl)-3-[2-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester

Participants

Reaction Conditions

Reaction Steps

A solution of freshly prepared lithium diisopropylamide (10.4 mL of a 0.31M stock solution, 3.22 mmol) cooled to −78° C. was treated with 3,4-dichlorophenylacetic acid methyl ester (prepared as in Example 1, 642 mg 2.93 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7.33 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. A solution of 2-(2-iodomethyl-cyclopentyloxy)-tetrahydropyran (1.0 g, 3.22 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL) was then added. The reaction mixture was stirred at −78° C. for 2 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL). This mixture was poured into water (100 mL) and extracted with methylene chloride (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-[2-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (880 mg, 74.8%) as a pale yellow oil: EI-HRMS m/e calcd for C20H26Cl2O4 (M+) 400.1208 found 400.1203.

Provenance & Evidence