Reaction Steps
Preparation of 2-((1E)buta-1,3-dienyl)-1-methoxybenzene (compound 100A) Methyltriphenylphosphonium bromide (42.9 g, 0.12 mol) was suspended in 400 ml of anhydrous THF under nitrogen and cooled to −78° C. Sodium hydride (60% in mineral oil, 6.0 g, 0.15 mol) was added portionwise. The reaction mixture was allowed to warm up slowly to room temperature and stirred at the same temperature for 1 h, then 2-methoxycinnamaldehyde (16.2 g, 0.10 mol) in 200 ml of THF was added dropwise at room temperature, and stirred at the same temperature for 3 h. Water (200 ml) and diethyl ether (800 ml) were added. The organic layer was separated, dried over sodium sulfate, concentrated, and purified using normal phase chromatography to afford the title product. 400 MHz 1H NMR (CDCl3) δ 7.48-6.56 (m, 7H), 5.32 (d, 1H), 5.16 (d, 11H), 3.84 (s, 3H). Step 2. Preparation of 2-butyl-1-methoxybenzene (compound 100B) A mixture of the product from example 100A (12.8 g, 0.08 mol) and palladium/carbon (10%, 50% water, 12 g) in 400 ml of ethyl acetate was hydrogenated at 50 psi, at room temperature overnight, then filtered through Celite®, and concentrated to give 100B. 400 MHz 1H NMR (CDCl3) δ 7.16 (m, 2H), 6.85 (m, 2H), 3.81 (s, 3H), 2.61 (m, 2H), 1.57 (m, 2H), 1.38 (m, 2H), 0.92 (t, 3H). Step 3. Preparation of 2-butylphenol (compound 100C) To a stirred solution of the product from example 100B (13.1 g, 0.08 mol) in 400 ml of dichloromethane at −78° C. was added dropwise a solution of boron tribromide (100.2 g, 0.4 mol) in 200 ml of dichloromethane. After the completion of addition of boron tribromide, the reaction mixture was maintained at −78° C. for 1 h, then allowed to reach room temperature and stirred at the same temperature overnight. The mixture was cooled to 0° C., and carefully quenched with 100 ml of water. The mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated to give 100C. 400 MHz 1H NMR (CDCl3) δ 7.10 (m, 2H), 6.86 (m, 1H), 6.78 (d, 1H), 4.61 (brs, 1H), 2.61 (m, 2H), 1.60 (m, 2H), 1.40 (m, 2H), 0.96 (t, 3H). Step 4. Preparation of (3-butyl-4-hydroxyphenyl)thiocarbonitrile (compound 100D) The title compound was prepared in the manner analogous to Example 1B with the product from example 100C (2.38 g, 0.016 mol), sodium thiocyanate (5.14 g, 0.063 mol), sodium bromide (1.63 g, 0.016 mol), and bromine (2.8 g, 0.017 mol) in methanol. 400 MHz 1H NMR (CDCl3) δ 7.30 (m, 2H), 6.81 (d, 1H), 5.49 (brs, 1H), 2.60 (m, 2H), 1.59 (m, 2H), 1.38 (m, 2H), 0.95 (t, 3H). Step 5. Preparation of methyl 2-(2-butyl-4-cyanothiophenoxy)acetate (compound 100E) The title compound was prepared in the manner analogous to Example 1C with the product from example 100D (2.80 g, 0.014 mol), methyl bromoacetate (2.28 g, 0.015 mol), and cesium carbonate (6.60 g, 0.020 mol), in 100 ml of acetonitrile. 400 MHz 1H NMR (CDCl3) δ 7.38 (m, 2H), 6.72 (d, 1H), 4.66 (s, 2H), 3.80 (s, 3H), 2.67 (m, 2H), 1.57 (m, 2H), 1.38 (m, 2H), 0.98 (t, 3H). Step 6. Preparation of methyl 2-(2-butyl-4-sulfanylphenoxy) acetate (compound 100F) The title compound was prepared in the manner analogous to Example 1D with the product from example 100E (2.79 g, 10.0 mol), dithiothreitol (3.08 g, 20.0 mmol), and 0.2 M potassium dihydrogenphosphate (15 ml) in 60 ml of methanol. 400 MHz 1H NMR (CDCl3) δ 7.11 (m, 2H), 6.60 (d, 1H), 4.61 (s, 2H), 3.81 (s, 3H), 3.36 (s, 1H), 2.63 (m, 2H), 1.57 (m, 2H), 1.38 (m, 2H), 0.98 (t, 3H). Step 7. Preparation of methyl 2-[2-butyl-4-({4-[4-(trifluoromethyl)phenyl]phenyl}methylthio)phenoxy]acetate (compound 100G) The title compound was prepared in the manner analogous to Example 1F using 100F and 1-(bromomethyl)-4-[4-(trifluoromethyl)phenyl]benzene prepared from and phosphorous tribromide and (4′-trifluoromethyl-biphenyl-4-yl)-methanol in a manner analogous to Example 3B. 400 MHz 1H NMR (CDCl3) δ 7.68 (m, 4H), 7.51 (d, 2H), 7.29 (d, 2H), 7.15 (m, 2H), 6.60 (d, 1H), 4.62 (s, 2H), 4.04 (s, 2H), 3.79 (s, 3H), 2.60 (m, 2H), 1.55 (m, 2H), 1.35 (m, 2H), 0.88 (t, 3H). Step 8. Preparation of 2-[2-butyl-4-({4-[4-(trifluoromethyl)phenyl]phenyl}methylthio)phenoxy]acetic acid (compound 100) The title compound was prepared in the manner analogous to Example 1 with the product from example 100G. mp 155-157° C.; 400 MHz 1H NMR (DMSOd-6) δ 7.88 (d, 2H), 7.80 (d, 2H), 7.65 (d, 2H), 7.38 (d, 2H), 7.17 (dd, 1H), 7.09 (d, 1H), 6.79 (d, 1H), 4.65 (s, 2H), 4.17 (s, 2H), 2.50 (m, 2H), 1.43 (m, 2H), 1.22 (m, 2H), 0.81 (t, 3H). MS m/z 473 (M−1). Anal. Calc'd for C26H25O3SF3: C, 65.81; H, 5.31; Found: C, 65.95; H, 5.36.
