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To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.37 g, 3.86 mmol, Intermediate 10: step d) was added THF (45 mL) at room temperature which resulted in a colorless homogeneous mixture. The solution was cooled to -78 C. and then n-BuLi (2.5 M in hexanes, 1.8 mL, 4.5 mmol) was added dropwise. The color of the solution became a reddish-brown color. After 4 minutes, <strong>[2644-93-1]1,3,5-<strong>[2644-93-1]trimethyl-1H-pyrazole-4-carbaldehyde</strong></strong> (300 mg, 2.17 mmol, in 3 mL THF) was introduced and the color of the mixture changed from reddish-brown to a yellow-greenish color over 5 minutes. The mixture was allowed to warm to 0 C. over 45 minutes at which time the reaction was quenched with aqueous NH4Cl solution. The mixture was diluted further with water and extracted with EtOAc (3*150 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a light orange foam. FCC on silica gel (2% MeOH-DCM increasing to 8% MeOH-DCM) afforded the title compound as a light yellow amorphous solid. 1H NMR (500 MHz, CDCl3) delta ppm 8.23 (s, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.56-7.47 (m, 3H), 7.40 (d, J=8.1 Hz, 2H), 6.01 (d, J=3.0 Hz, 1H), 4.35 (s, 2H), 4.06 (s, 3H), 3.70 (s, 3H), 2.14 (s, 3H), 2.12 (s, 3H), 2.09 (d, J=3.3 Hz, 1H). MS (ESI): mass calcd. for C25H23ClF3N3O2, 489.1; m/z found, 490.1 [M+H]+. |
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Example 34a: (4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)qinolin-6-yl)(1,3,5-trimethyl-1H-pyrazol-4-yl)methanolTo a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.37 g, 3.86 mmol, Intermediate 10: step d) was added THF (45 mL) at room temperature which resulted in a colorless homogeneous mixture. The solution was cooled to -78 C and then n- BuLi (2.5 M in hexanes, 1.8 mL, 4.5 mmol) was added dropwise. The color of the solution became a reddish-brown color. After 4 minutes, <strong>[2644-93-1]1,3,5-<strong>[2644-93-1]trimethyl-1H-pyrazole-4-carbaldehyde</strong></strong> (300 mg, 2.17 mmol, in 3 mL THF) was introduced and the color of the mixture changed from reddish-brown to a yellow-greenish color over 5 minutes. The mixture was allowed to warm to 0 C over 45 minutes at which time the reaction was quenched with aqueous NH4Cl solution. The mixture was diluted further with water and extracted with EtOAc (3 x 150 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a light orange foam. FCC on silica gel (2% MeOH-DCM increasing to 8% MeOH-DCM) afforded the title compound as a. light yellow amorphous solid. 1H NM (500 MHz, CDCl3) delta ppm 8.23 (s, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.56 - 7.47 (m, 3H), 7.40 (d, J= 8.1 Hz, 2H), 6.01 (d, J = 3.0 Hz, 1H), 4.35 (s, 2H), 4.06 (s, 3H), 3.70 (s, 3H), 2.14 (s, 3H), 2.12 (s, 3H), 2.09 (d, J = 3.3 Hz, 1H). MS (ESI): mass calcd. for C25H23ClF3N3O2, 489.1 ; m/z found, 490.1 [M+H]+. Example 34a was purified by chiral SFC (Stationary phase: Chiralpak AD-H 5 mum 250 x 21 mm, Mobile phase: 15% EtOH + 0,2% TEA, 85% CO2). The first eluting enantiomer was 34b and the seco d eluting enantiomer was Example 34c. |
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At room temperature for 6-bromo-4-chloro-2-methoxy-3 - (4 - (trifluoromethyl) benzyl) quinoline (1.37 g, 3.86 mmol, Intermediate 10: step d) comprises that the flask, THF It was added (45 mL) to obtain a colorless, homogeneous mixture.Cooling the solution to -78 Next,ndropwise -BuLi (2.5 M, 1.8 mL, 4.5 mmol in hexane).The color of the solution was reddish brown.4 minutes after, 1,3,5-trimethyl -1H-pyrazole-4-carbaldehyde (300 mg, 2.17 mmol, 3 mL of THF) was introduced to he a mixture of red-brown color over 5 min It was in turn greenish yellow.The mixture was warmed to 0 over 45 minutes and, at this time the reaction NH4was quenched with aqueous solution of Cl.The mixture was diluted further with water and extracted with EtOAc (3 × 150 mL).The combined organics were washed with brine, MgSO4dried, filtered, and concentrated to give a light orange foam.Silica gel by FCC on (2% MeOH-DCM, increased to 8% MeOH-DCM), to give the title compound as a pale yellow non-crystalline solid. |
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