5-Chloromethyl-3-(4-trifluoromethyl-phenyl)-isoxazole → {2-Methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-phenoxy}-acetic Acid

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Reaction Steps

Preparation of 5-chloromethyl-3-(4-trifluoromethyl-phenyl)-isoxazole (compound 45A) A solution of 4-trifluoromethyl-benzaldehyde oxime (8.9 g, 47.1 mmol) in 100 mL DCM was added to a rapidly stirred solution of propargyl chloride (47.1 mmol), triethyl amine (4.71 mmol) and 91 mL of commercial bleach (6.5% by weight) all in 50 mL DCM at 0° C. After 1 hour the layers were separated and the organic layer dried (Na2SO4), and concentrated in vacuo. Purification by flash column chromatography (gradient elution: 5% EtOAc/hexane to 25% EtOAc/hexane) gave the title compound (2.9 g, 23%) MS m/z 262 (M+1). Step 2. Preparation of {2-Methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-phenoxy}-acetic acid methyl ester (compound 45B) The title compound was prepared in a manner analogous to Example 1F using 45A and 2C. MS m/z 438 (M+1). Step 3. Preparation of {2-Methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-3-phenoxy}-acetic acid (compound 45) The title compound was prepared in a manner analogous to Example 1 using 45B. IR cm−1: 1747; 400 MHz 1H NMR (DMSO-d6) δ 12.97 (br(s), 1H), 7.99 (d, 2H, J=8.0 Hz), 7.81 (d, 2H, J=8.0 Hz), 7.21 (s, 1H), 7.16 (d, 1H, J=8.5 Hz), 6.86 (s, 1H), 6.74 (d, 1H, J=8.5 Hz), 4.63 (s, 2H), 4.30 (s, 2H), 2.09 (s, 3H); MS m/z 424 (M+1).

Provenance & Evidence