| 62% |
|
To a 250 mL three-necked flask were charged sodium tert-butoxide (97%, 0.99 g, 10 mmol), and anhydrous tetrahydrofuran (18 mL). The mixture was stirred, and cooled down to about 0 C. A solution of 2-methylpropane-1,2-diol (1.08 g, 12 mmol) in anhydrous tetrahydrofuran (2.0 mL) was added slowly at the internal temperature <5 C. The solution was mixed at <5 C. for 30 minutes, followed by addition of the product (1.59 g, 4.0 mmol) from Part B of Example 1 in anhydrous tetrahydrofuran (36 mL) at <0 C. The resulting mixture was stirred at about 0 C. for 4 hours or until less than 5% of starting material remains. 125 g of 1.5% H3PO4 aqueous solution was added slowly to the reaction mixture at <5 C. The resulting slurry was mixed at about 0 C. for 1 hour, and then allowed to warm up to room temperature. The slurry was stirred at room temperature for 5 hours, and the product collected by filtration. The wet cake was washed with water-acetonitrile (2:1) (20 mL), and dried under vacuum at 50 C. overnight with a slow flow of nitrogen to give a white solid (1.15 g, 62%). MS-ESI: 468 (M+1); 1H-NMR (CDCl3-DMSO-d6) delta 0.94 (3H, t, J=7.4 Hz). 1.25 (6H, s), 1.42 (2H, m), 1.84 (2H, m), 3.90 (2H, s), 4.48 (2H, t, J=7.4 Hz), 7.08 (1H, d, J=8.7 Hz), 7.62 (1H, dd, J=8.7, 2.3 Hz), 7.70 (1H, d, J=5.3 Hz), 8.32 (1H, d, J=2.3 Hz), 8.39 (1H, d, J=5.3 Hz), 8.73 (1H, s); 13C-NMR (CDCl3-DMSO-d6) delta 13.28, 19.53, 25.92, 29.20, 45.20, 68.79, 77.69, 114.07, 116.74, 120.98 (q, J=33 Hz, C-CF3), 123.21 (q, J=268 Hz, CF3), 125.51, 128.12, 128.65, 132.26, 132.64, 134.74, 142.49, 160.56, 164.58, 172.49. |
| 35% |
|
Example 2 IB; N-r(2Z)-3-butviri,31thiazolor4,5-clpyridin-2(3H)-ylidenel-2-(2-hvdroxy-2-methylpropoxy)-5 -(trifluoromethyl)benzamide; The product from Example 21 A (91mg, 1.01 mmol) in THF (2 mL) was treated with NaH (60%) (40.3 mg, 1.01 mmol) at room temperature for 20 minutes. To the above mixture was added the product from Example 2OB (200 mg, 0.5 mmol) in THF (2 mL). After 4 hrs, the reaction mixture was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix Intelliflash280 (SiO2, 0-100 % ethyl acetate in hexanes) to afford 82.4 mg (35 %) of the title compound. 1H NMR (500 MHz, CDCl3) delta ppm 1.04 (t, J=7.63 Hz, 3 H) 1.38 (s, 6 H) 1.48 - 1.55 (m, 2 H) 1.89 - 1.97 (m, 2 H) 4.03 (s, 2 H) 4.54 (t, J=7.32 Hz, 2 H) 4.62 (brs, 1 H) 7.08 (d, J=8.85 Hz, 1 H) 7.66 (d, J=4.58 Hz, 1 H) 7.70 (dd, J=8.54, 2.14 Hz, 1 H) 8.51 (d, J=5.19 Hz, 1 H) 8.51 (s, 1 H) 8.74 (s, 1 H); MS (ESI+) m/z 468 (M+H)+. |
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