Background and overview[1]
2-Hydroxy-5-trifluoromethylbenzoic acid is an organic intermediate that can be prepared by the reaction of 2-methoxy-5-(trifluoromethyl)benzoic acid and iodocyclohexane.
Preparation[1]
Place 2-methoxy-5-(trifluoromethyl)benzoic acid (5.00g, 22.71mmol) in a flask containing iodocyclohexane (29.4mL, 227mmol) and DMF (25mL). The reaction mixture was refluxed for 4 h, cooled, and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography eluting with 0-100% EtOAc in isohexane to afford the title compound, 2-hydroxy-5-trifluoromethylbenzoic acid. 1HNMR (MHz, CDCl3) δ10.70 (1H, s), 8.29 (1H, d), 7.80 (1H, dd), 7.15 (1H, d ).
Apply[1]
2-Hydroxy-5-trifluoromethylbenzoic acid can be used to prepare tert-butyl 2-(2-(hydroxymethyl)-4-(trifluoromethyl)phenoxy)acetate: add 2- Hydroxy-5-trifluoromethylbenzoic acid (6.50 g, 31.5 mmol) was placed in a flask containing THF (50 mL) and cooled on ice. Borane tetrahydrofuran complex (47.3 mL, 47.3 mmol) was added, and the reaction mixture was stirred at 50°C for 6 h. The reaction mixture was quenched carefully with 1 M HCl (50 mL) and partitioned between EtOAc and water. The organic phase was washed with water and brine, dried over MgSO4, filtered and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography eluting with 0-100% EtOAc in isohexane to give 2-(hydroxymethyl)-4-(trifluoromethyl)phenol; 2-(hydroxymethyl)-4 – (Trifluoromethyl)phenol (4.70 g, 24.46 mmol) was placed in a flask containing dry MeCN (100 mL). tert-Butyl 2-bromoacetate (5.25g, 26.9mmol) was added followed by potassium carbonate (16.9g, 122mmol) and the reaction mixture was stirred at room temperature overnight. K2CO3 was filtered out, washed with MeCN, and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography eluting with 0-100% EtOAc in isohexane to give the title compound 2-(2-(hydroxymethyl)-4-(trifluoromethyl)phenoxy)acetic acid tert-butyl ester; 1HNMR (MHz, DMSO-d6) δ7.70 (1H, d), 7.58 (1H, dd), 7.01 (1H, d), 5.30 (1H, t), 4.81 (2H, s), 4.60 (2H, d), 1.41 (9H, s).
Main reference materials
[1] CN201480051343.9 Autocrine motility factor inhibitor containing heteroaromatic ring-benzyl-amide-ring core
