1-(4-Bromophenyl)-4-methylpiperazine → [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine

Participants

Reaction Steps

To a solution of 1-(4-bromo-phenyl)-piperazine (1.47 g, 6.10 mmol) and acetic acid (0.42 mL, 7.4 mmol) in methanol (25 mL) was added 37% formaldehyde in water/methanol (56.7:37:6.3, water:formaldehyde:methanol, 5.6 mL, 180 mmol). The mixture was stirred at room temperature for 18 hours. The suspension was cooled to 5° C. in an ice/water bath and Sodium cyanoborohydride (4.98 g, 79.2 mmol) was added in small portions. The mixture was stirred and warmed to room temperature for 18 hours. The mixture was slowly poured into saturated aqueous ammonium chloride (200 mL) and stirred for 1 hour. The mixture was extracted with dichloromethane (3×75 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to an oily solid. The material was placed under high vacuum for 18 hours to yield a white solid (1.54 g). 1-(4-Bromo-phenyl)-4-methyl-piperazine was isolated as a white solid (1.54 g, 99%) and was used without further purification. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.36-7.31 (m, 2H), 6.82-6.76 (m, 2H), 3.20-3.15 (m, 4H), 2.60-2.55 (m, 4H), 2.36 (s, 3H). MS=255, 257 (MH)+. 32b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (73.0 mg, 0.286 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (29.0 mg, 0.0530 mmol) as the ligand in a manner analogous to Step 2d. The reaction product was isolated as pale yellow solid (0.022 g, 18%). MP=242-244° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (dd, J=6.7, 1.1 Hz, 1H), 8.25-8.20 (m, 2H), 8.10-8.06 (m, 2H), 7.63 (dd, J=7.4, 1.1 Hz, 1H), 7.51-7.46 (m, 2H), 7.01-6.95 (m, 2H), 6.67 (s, 1H), 3.20-3.15 (m, 4H), 3.10 (s, 3H), 2.62-2.58 (m, 4H), 2.36 (s, 3H). MS=463 (MH)+.

Provenance & Evidence