General Steps:
Example 2.5: Synthesis of 4-{4-[(4-chloro-3-trifluoromethylphenylcarbamoyl)-methyl]-2-methylphenoxy}-pyridine-2-carboxylic acid methylamide
1) Synthesis of methyl (4-hydroxy-3-methylphenyl)acetate
(4-Methoxy-3-methylphenyl)acetonitrile (3.3 g, 20.4 mmol) was dissolved in dichloromethane (20 mL), cooled to -78 °C, and a dichloromethane (30 mL) solution of boron tribromide (5.8 mL, 61.2 mmol) was added dropwise over a period of 30 min. The reaction mixture was slowly warmed to room temperature and stirred for 20 hours. Purification step: methanol (50 mL) was added dropwise at 0°C and the solution was washed with water (2 x 50 mL). The aqueous phase was back-extracted with dichloromethane (5 x 50 mL), the organic layers were combined and dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by fast column chromatography (Combi Flash RF, Si-60, 120g column, gradient CH/EE 100:0 to 75:25 for 29 min, then isocratic 75:25 for 13 min at a flow rate of 85 mL/min with UV 254 nM and 280 nM detection) to give (4-hydroxy-3-methylphenyl)acetic acid methyl ester (1.8 g, 8 mmol) as a colorless oil.
2) Synthesis of (4-hydroxy-3-methylphenyl)acetic acid
Methyl (4-hydroxy-3-methylphenyl)acetate (1.8g, 8mmol) was dissolved in 2M sodium hydroxide solution (20mL) and stirred at room temperature for 1.5 hours. The reaction mixture was adjusted to pH 4 with 6M hydrochloric acid solution and extracted with dichloromethane (4 x 70 mL). The organic layers were combined, dried over anhydrous sodium sulfate and the solvent was evaporated to give (4-hydroxy-3-methylphenyl)acetic acid (1.3 g, 7.9 mmol) as a white solid.
3) Synthesis of N-(4-chloro-3-trifluoromethylphenyl)-2-(4-hydroxy-3-methylphenyl)acetamide
5-Amino-2-chlorobenzotrifluoride (455.2 mg, 2.3 mmol) and (4-hydroxy-3-methylphenyl)acetic acid (429.7 mg, 2.3 mmol) were dissolved in anhydrous DMF (9 mL). HOBT (463.3 mg, 3 mmol), EDCI (490.783 mg, 2.6 mmol) and 4-methylmorpholine (0.27 mL, 2.6 mmol) were added to initiate the reaction, and the reaction was stirred at 60 °C for 24 hours. Water (30 mL) and dichloromethane (30 mL) were added and the phases were separated. The aqueous layer was washed with brine (15 mL) and the organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The crude product was purified by fast column chromatography (Combi Flash RF, Si-60, 40g column, gradient CH/EE 100:0 to 50:50 for 16 min, then isocratic 50:50 for 8 min at a flow rate of 40 mL/min with UV 254 nM and 280 nM detection) to afford N-(4-chloro-3-trifluoromethylphenyl)-2-(4-hydroxy -3-methylphenyl)acetamide (243 mg, 0.5 mmol) as a yellow oil.
4) Synthesis of 4-{4-[(4-chloro-3-trifluoromethylphenylcarbamoyl)-methyl]-2-methylphenoxy}-pyridine-2-carboxylic acid methylamide
A solution of N-(4-chloro-3-trifluoromethylphenyl)-2-(4-hydroxy-3-methylphenyl)acetamide (243 mg, 0.5 mmol) in anhydrous DMF (1.1 mL) was treated with potassium tert-butoxide (64 mg, 0.6 mmol) and stirred at room temperature for 2 hours. 4-Chloro-pyridine-2-carboxylic acid formamide (104 mg, 0.6 mmol) and potassium carbonate (35.9 mg, 0.3 mmol) were added and the suspension was heated to 130 °C and reacted for 1 day. The reaction mixture was cooled to room temperature and water (5 mL) and dichloromethane (15 mL) were added to separate the phases. The organic layer was washed with water (15 mL), brine (15 mL), dried over anhydrous sodium sulfate and the solvent was evaporated. The crude product was purified by fast column chromatography (Combi Flash RF, Si-60, 24g column, gradient CH/EE 100:0 to 35:65 for 21 min, then isocratic 35:65 for 6 min at a flow rate of 35 mL/min with UV 254 nM and 280 nM detection) to afford 4-{4-[(4-chloro-3-trifluoromethylphenylcarbamoyl )-methyl]-2-methylphenoxy}-pyridine-2-carboxylic acid methylamide (82.5 mg, 0.2 mmol) as a yellow solid.
HPLC/MS analytical conditions: A: H2O + 0.05% HCOOH | B: MeCN + 0.04% HCOOH, T: 30°C | Flow rate: 2 mL/min | Column: Chromolith RP-18e 50-4.6 mm | MS: 85-800 amu, 4% -> 100% B: 0->2.8 min | 100% B : 2.8->3.3 min | Rt = 2.526 min [M+H] 478.1
1H NMR (300 MHz, DMSO-d6) δ ppm = 10.63 (s, 1H), 8.82-8.66 (m, 1H), 8.49 (d, J=5.7 Hz, 1H), 8.28-8.15 (m, 1H), 7.92-7.81 (m, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.41- 7.32 (m, 1H), 7.33-7.23 (m, 2H), 7.17-7.04 (m, 2H), 3.72 (s, 2H), 2.78 (d, J=4.8 Hz, 3H), 2.09 (s, 3H).
