Diethyl Oxalate → Ethyl 2,4-dioxo-4-[4-(trifluoromethyl)phenyl]butanoate

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Preparation of 5-(4-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic acid ethyl ester (compound 42A) Sodium hydride (1.6 g, 63.7 mmol, 95%) was added to a solution of 1(4-trifluoromethyl-phenyl)-ethanone (10.0 g, 53.1 mmol) and oxalic acid diethyl ester (8.7 mL, 63.7 mmol) in 75 mL dry DMF at 0° C. The reaction was allowed to come to room temperature and then heated to 45° C. for 45 minutes. The reaction was then cooled, concentrated in vacuo, and the residue taken up in EtOAc. The organic layer was then washed with 2 M HCl (1×100 mL), dried (Na2SO4) and the solvent removed in vacuo. Purification by flash column chromatography (gradient elution: 5% EtOAc/hexane to 55% EtOAc/hexane) gave the intermediate 2,4-dioxo-4-(4-trifluoromethyl-phenyl)-butyric acid ethyl ester (12.2 g, 80%) which was then taken up in EtOH and refluxed in the presence of hydroxyl amine hydrochloride (10.2 g, 132.3 mmol) for 3H. The reaction was then cooled, diluted with EtOAc, washed with dilute NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo. Recrystallization from EtOAc/hexane gave 5.2 g of the title compound. MS m/z 286 (M+1). Step 2. Preparation of [5-(4-Trifluoromethyl-phenyl)-isoxazol-3-yl]-methanol (compound 42B) The title compound was prepared in a manner analogous to Example 40B using 42A. MS m/z 244 (M+1). Step 3. Preparation of 3-chloromethyl-5-(4-trifluoromethyl-phenyl)-isoxazole (compound 42C) The title compound was prepared in a manner analogous to Example 3B using 42B. MS m/z 262 (M+1). Step 4. Preparation of {2-methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-acetic acid methyl ester (compound 42 The title compound was prepared in a manner analogous to Example 1F using 42C and 2C. MS m/z 438 (M+1). Step 5. Preparation of {2Methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-acetic acid (compound 42) The title compound was prepared in a manner analogous to Example 1 using 42D. IR cm−1:1746, 1326; 400 MHz 1H NMR (DMSO-d6) δ 12.97 (br(s), 1H), 8.02 (d, 2H, J=8.0 Hz), 7.83 (d, 2H, J=8.0 Hz), 7.20 (s, 1H), 7.15 (s, 2H), 6.71 (d, 1H, J=8.5 Hz), 4.63 (s, 2H), 4.14 (s, 2H), 2.08 (s, 3H); MS m/z 424 (M+1). Anal. Calc'd for C20H16F3NO4S C, 56.73; H, 3.81; N, 3.31 found: C, 56.59; H, 3.58; N, 3.22.

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