Reaction Steps
A solution of racemic 2-{[2-(4-hydroxyphenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]propanoic acid (45 g @ 80% strength, containing 8% wt/wt benzoic acid, 70 mmol) in ethyl acetate (225 mL, 5 vol) was cooled to 0-5° C. Solid chloromethylene-dimethylammonium chloride (Vilsmeier reagent @ 95% strength, 20.6 g, 161 mmol, 2.3 eq) was added in 4 equal portions over 1.5 hours maintaining a temperature of 0-5° C. The resulting turbid mixture was stirred at the same temperature for 2.5 hours and was subsequently added dropwise to an ice-cold vigorously stirred solution of ethanethiol (7.8 mL, 105 mmol, 1.5 eq.) in aqueous phosphate buffer (pH 7,200 mL). The pH was constantly monitored and kept between 6 and 7.5 by simultaneous addition of 32% NaOH solution. After 30 minutes at low temperature, the batch was allowed to warm to ambient temperature overnight. The organic phase was separated, dried (MgSO4) and concentrated in vacuo to give the crude product as brown oil (43.82 g, 114%). The crude compound was purified by flash chromatography (20:80 to 50:50 EtOAc:iso-hexane; silica) to yield the title compound as a pale yellow oil (31.5 g, 81%). HPLC (Rt 11.6 min); m.p. oil; 1H NMR (400 MHz, d6-DMSO) δ 9.19 (1H, s), 7.18-7.28 (4H, m), 7.14 (2H, d, J=8.1 Hz), 7.00-6.94 (4H, m), 6.65 (2H, d, J=8.4 Hz), 4.15 (2H, t, J=6.8 Hz), 3.87-3.83 (1H, m), 3.29 (3H, s), 3.08 (1H, dd, J=14.0, 8.4 Hz) 2.98 (2H, t, J=6.8 Hz), 2.87 (1H, dd, J=14.0, 7.0 Hz), 2.80-2.67 (4H, m), 2.66-2.60 (2H, m), 1.08 (3H, t, J=7.2 Hz); 13C NMR (100.6 MHz, d6-DMSO) δ 198.14, 157.15, 155.73, 142.45, 136.37, 135.52, 130.14, 129.34, 129.22, 129.07, 123.28, 115.39, 115.04, 68.51, 55.29, 37.14, 36.88, 34.41, 34.34, 32.78, 22.98 and 14.53.
