Triethylamine → (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester

Participants

Reaction Conditions

Reaction Steps

A solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester hydrochloride (Novabiochem, 500 mg, 2.25 mmol) in acetonitrile (20 mL) was placed in a flask and treated with 2-bromomethyl-3-fluoro-benzoic acid methyl ester (557 mg, 2.25 mmol) and triethylamine (660 μL, 4.74 mmol). The reaction mixture was then heated at reflux (82° C.) overnight for 16 h. After this time, the reaction mixture was diluted with water (5 mL) and concentrated in vacuo to remove the acetonitrile. The remaining material was then diluted with another portion of water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were then dried over magnesium sulfate, filtered to remove the drying agent and the filtrate concentrated in vacuo. The crude material was purified using an Analogix Intelliflash 280 chromatography system (RS-40 silica gel column, 10-25% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester (411 mg, 57%) as a clear colorless oil: [α]30D=−17.3° (c=0.30, methylene chloride); HR-ES(+) m/e calcd for C18H22NO3F [M+H]+ 320.1657, observed 320.1656; 1H NMR (300 MHz, DMSO-d6) δ 7.54-7.63 (m, 2H), 7.42-7.54 (m, 1H), 4.96 (dd, J=4.53, 11.47 Hz, 1H), 4.49-4.65 (m, 2H), 3.63 (s, 3H), 1.48-1.99 (m, 7H), 0.74-1.23 (m, 6H).

Provenance & Evidence