Reaction Steps
Concentrated sulfuric acid (2.2 mL, 60.0 mmol) was added smoothly over 30 minutes to a slurry of ammonium 2-chloro-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]-propanoate (15.0 g @ 91.4% strength, 33.0 mmol) in methanol (60 mL) and trimethyl orthoformate (10.9 mL, 39.6 mmol), followed by a line wash of methanol (7.5 mL). The reaction mixture was heated to 60° C. for 2 hours to form a dark solution, and then cooled back to 50° C. 2-(4-Hydroxyphenyl)ethyl thiobenzoate (10.4 g @ 97.9%, 39.6 mmol) was added in one portion and the reaction vessel purged with nitrogen. Sodium methoxide (19.0 mL of 25% strength solution in methanol, 82.4 mmol) was added smoothly over 30 minutes followed by a methanol line wash (7.5 mL), and the reaction stirred at 50° C. for 5 hours, during which time a slightly cloudy precipitate formed. The reaction mixture was cooled to 35° C., water (98 mL) was added with vigorous stirring, followed by methyl tert-butyl ether (MTBE) (98 mL), the mixture was stirred for 15 minutes, allowed to settle, and the lower aqueous phase removed and discarded. The remaining MTBE phase was washed with dilute aqueous hydrochloric acid solution (0.03 mL of 32% w/w in 49 mL of water), and then with water (49 mL), both at 35° C. The amount of the product ester in the MTBE solution was assayed by LC and used without further purification in the next stage. HPLC (Rt 10.9 min); m.p. oil; 1H NMR (400 MHz, d6-DMSO) δ 9.20 (1H, s), 7.15-7.24 (6H, m), 7.00 (2H, d, J=8.8 Hz), 6.97 (2H, d, J=8.4 Hz), 6.66 (2H, d, J=8.4 Hz), 4.18 (2H, t, J=7.0 Hz), 3.66 (1H, dd, J=9.2, 6.4 Hz), 3.58 (3H, s), 3.31 (3H, s), 3.05 (1H, dd, J=14.0, 8.8 Hz) 3.00 (2H, t, J=6.8 Hz), 2.85 (1H, dd, J=14.0, 6.8 Hz), 2.77 (2H, t, J=7.2 Hz), 2.61-2.71 (2H, m); 13C NMR (100.6 MHz, d6-DMSO) δ 172.07, 157.14, 155.71, 142.45, 136.37, 135.93, 130.19, 129.35, 128.89, 128.81, 123.29, 115.47, 115.02, 68.48, 51.87, 46.99, 36.90, 36.79, 34.40, 34.35 and 32.68; MS (ES+) 548 (M+NH4+, 70%), 531 (M+H+, 90%), 471 (M-CO2Me+, 100%).
