Reaction Steps
Preparation of 5-Methoxy-2-methyl-phenol (compound 1A) 2-Hydroxy-4-methoxy-benzaldehyde (3 g, 19.7 mmol), ammonium formate (6.2 g, 99 mmol) and palladium/carbon (900 mg @10%) were added to 26 ml glacial acetic acid and heated at 110° C. for 1 h. The reaction was cooled, filtered, and diluted with water (100 ml). The crude product was extracted with chloroform (3×50 ml), washed with water, brine, and dried over anhydrous sodium sulfate. The resulting solution was concentrated and used for the next step without further purification. MS m/z 139 (M+1). Step 2. Preparation of 5-Methoxy-2-methyl-4-thiocyanato-phenol (compound 1B) The product from Example 1A (3.5 g, 25 mmol), sodium thiocyanate (6.48 g, 80 mmol), and sodium bromide (2.6 g, 25 mmol) were dissolved in 30 ml anhydrous methanol. Bromine (4.4 g, 28 mmol) was added drop wise over 15 minutes and allowed to stir at ambient temperature for 1 h. Brine was added (50 ml) and the crude product was extracted into ethyl acetate (3×100 ml). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, decanted, and concentrated to afford the title product in good purity. 400 MHz 1H NMR (DMSO-d6) δ 10.13 (s, 1H), 7.25 (s, 1H), 6.54 (s, 1H), 3.77 (s, 3H), 2.0 (s, 3H); MS m/z 196 (M+1). Step 3. Preparation of (5-Methoxy-2-methyl-4-thiocyanato-phenoxy)-acetic acid methyl ester (compound 1C) The product from Example 1B (620 mg, 3.2 mmol), methyl bromoacetate (854 mg, 3.5 mmol), and cesium carbonate (3.1 g, 9.6 mmol) were stirred in 10 ml anhydrous acetonitrile at ambient temperature for 1 h. The reaction was filtered through Celite®, concentrated, and purified using normal phase chromatography. 400 MHz 1H NMR (DMSO-d6) δ 7.33 (s, 1H), 6.72 (s, 1H), 4.93 (s, 2H), 3.84 (s, 3H), 3.66 (s, 3H), 2.09 (s, 3H); MS m/z 268 (M+1). Step 4. Preparation of (4Mercapto-5-methoxy-2-methyl-phenoxy)-acetic acid methyl ester (compound 1D) The product from Example 1C (1.1 g, 4.1 mmol) and dithiothreitol (824 mg, 5.4 mmol) were dissolved in 20 ml methanol with 2.5 ml water. The solution was refluxed for 4 h, cooled, concentrated, and purified by normal phase chromatography. 400 MHz 1H NMR (DMSO-d6) δ 7.02 (s, 1H), 6.54 (s, 1H), 4.79 (s, 2H), 4.41 (s, 1H), 3.72 (s, 3H), 3.64 (s, 3H), 2.02 (s, 3H); MS m/z 243 (M+1). Step 5. Preparation of 4-Bromomethyl-biphenyl (compound 1E) Biphenyl-4-yl methanol (500 mg, 2.72 mmol) phosphorus tribromide (809 mg, 2.99 mmol), and lithium bromide (260 mg, 2.99 mmol) were dissolved in 10 ml DMF and stirred at ambient temperature for 1 h. Water (10 ml) was added and the crude product was extracted into dichloromethane, dried over anhydrous sodium sulfate, filtered through silica gel, and concentrated. MS m/z 167 (M+1-Br). Step 6. Preparation of [4-(Biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-acetic acid methyl ester (compound 1F) The product from Example 1D (100 mg, 0.38 mmol), the product from Example 1E (92 mg, 0.38 mmol) and cesium carbonate (250 mg, 0.76 mmol) were added to 5 ml acetonitrile and stirred at ambient temperature for 4 hr. The reaction was filtered through Celite®, concentrated and purified through normal phase chromatography. MS m/z 409 (M+1). Step 7. Preparation of [4-(Biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-acetic acid (compound 1) The product from Example 1F (101 mg) was dissolved in 10 ml THF/water solution (10:1). Lithium hydroxide monohydrate (300 mg) was added and stirred for 30 minutes. 2 Normal aqueous HCl was added to pH<5 and then washed with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, decanted, and concentrated. The title product was recrystallized from chloroform/hexanes. mp 60-62° C.; 400 MHz 1H NMR (DMSO-d6) δ 12.94 (br(s), 1H), 7.58 (d, 2H, J=8 Hz), 7.52 (d, 2H, J=8 Hz), 7.39 (t, 2H, J=7.2 Hz), 7.30 (m, 3H), 7.02 (s, 1H), 6.52 (s, 1H), 4.69 (s, 2H), 4.01 (s, 2H), 3.73 (s, 3H), 2.01 (s, 3H). MS m/z 393 (M−1). Anal. Calc'd for C32H22O4S.3H2O C, 69.05; H, 5.07; found: C, 69.04; H, 5.35.
