Synthesis
Example 25 Synthesis of 1-(3-(3-hydroxy-2-(hydroxymethyl)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-phenyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)urea
Step A: Preparation of (2,2-dimethyl-1,3-dioxan-5-yl)methanol: To a suspension of 2-hydroxymethyl-1,3-propanediol (5.0 g, 47.1 mmol) in THF (100 mL) was added p-toluenesulfonic acid (pTsOH, 269 mg, 1.41 mmol), followed by 2,2-dimethoxypropane (6.72 mL. 54.7 mmol). The reaction mixture was stirred at room temperature for 3 hours, then p-toluenesulfonic acid (200 mg) was added and stirring was continued at room temperature for 48 hours. Upon completion of the reaction, triethylamine (3 mL) was added to neutralize the reaction system and the mixture was subsequently concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol/dichloromethane as eluent to afford (2,2-dimethyl-1,3-dioxan-5-yl) methanol (5.04 g, 73% yield) as a colorless liquid.1H NMR (CDCl3) δ 4.02 (dd, J = 12.0, 4.1 Hz, 2H), 3.74-3.80 (m, 4H), and 1.90 (t, J = 5.1 Hz, 1H), 1.78-1.88 (m, 1H), 1.45 (s, 3H), 1.40 (s, 3H) ppm.
References
[1] Journal of Medicinal Chemistry, 2002, vol. 45, # 26, p. 5694 - 5709
[2] Patent: WO2008/157726, 2008, A1. Location in patent: Page/Page column 210
[3] Patent: EP2103611, 2009, A1. Location in patent: Page/Page column 51-52
[4] Patent: WO2008/124703, 2008, A2. Location in patent: Page/Page column 84
[5] Journal of Medicinal Chemistry, 1990, vol. 33, # 1, p. 187 - 196
