Methanol → (R)-3-cyclopentyl-2-(4-methanesulfonyl-3-methoxy-phenyl)-propionic acid

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Reaction Conditions

Reaction Steps

In a round bottom flask under argon was placed methanol (50 mL) and to it was added in small portions sodium metal (1.15 g, 45.35 mmol). This was stirred at 25° C. for 1 h. It was then concentrated in vacuo and azeotroped with acetonitrile. To this solid residue under argon was then added 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO200058293, Example 12, 3.00 g, 9.07 mmol) in dimethylsulfoxide (25 mL). This was then stirred and heated at 75° C. for 1 h. Let the solution cool back to 25° C. and then diluted it with water (120 mL). The solution was then filtered through celite and washed with water. The pH of the filterate was then adjusted pH=2 using a 1 N aqueous hydrochloric acid solution. It was then extracted with ethyl acetate (200 mL) and dried using sodium sulfate. The solution was filtered and concentrated in vacuo. The crude racemic material was then separated into the chiral components by supercritical fluid chromatography (SFC) on a Berger MultiGram II Supercritical Fluid Chromatography (SFC) system (Mettler-Toledo AutoChem Berger Instruments, Newark, Del.) (Chiral column: Daicel OJ-H, 250 mm×30 mm i.d., 5 μm-particle size, temperature: 35° C., flow rate of 70 mL/min, and 100 bar back pressure, 12% of a 1:1 ethanol/acetonitrile as mobile phase modifier and UV Detection: 220 nm) to afford (R)-3-cyclopentyl-2-(4-methanesulfonyl-3-methoxy-phenyl)-propionic acid (second compound to elute, 1.31 g, 44%) as a white foam: [α]31589=−47.4° (c=0.23, methanol); ES-HRMS m/e calcd for C16H22O5S (M+H)+ 327.1261, observed 327.1262; 1H NMR (300 MHz, DMSO-d6) δ 1.10 (m, 2H, CH2), 1.36-1.81 (m, 8H, 4×CH2), 2.00 (m, 1H, CH), 3.22 (s, 3H, SO2CH3), 3.66 (t, J=7.7 Hz, 1H, ArCHCO), 3.95 (s, 3H, OCH3), 7.10 (dd, Jm=1.4 Hz, Jo=8.1 Hz, 1H, Ar), 7.22 (d, Jm=1.4 Hz, 1H, Ar), 7.74 (d, Jo=8.1 Hz, 1H, Ar), 12.56 (s, 1H, CO2H).

Provenance & Evidence