84% |
Stage #1: With pyridine In toluene at 2 - 5℃; for 7.5 h; Inert atmosphere Stage #2: at 6 - 20℃; for 15 h; |
A 2 L, three-neck Morton flask equipped with a mechanical stirrer, thermocouple, and addition funnel under a nitrogen atmosphere was charged with 3-amino-4-chloropyridine (35.0 g, 272 mmol) and toluene (740 mL). The brown solution was cooled to 2 °C. Pyridine (25.3 mL, 310 mmol) was added in one portion, followed by the dropwise addition of phenyl chloroformate (32.6 mL, 259 mmol) over 30 min. The maximum internal temperature was 5 °C. After stirring at 2-5 °C for 7 h the reaction mixture became a thick yellow suspension. A cooled solution of K2CO3 (53.6 g, 388 mmol) in water (216 mL) was added over 3 min, during which the maximum internal temperature was 6 °C. 1 -(2,2-Difluoro-benzo[1 ,3]dioxol-5-ylmethyl)-piperazine (66.3 g, 259 mmol) was then added as a solid over 1 min. The mixture was allowed to warm slowly to room temperature and stirred for 15 h. Water (200 ml_) was added and the toluene layer was separated and extracted with aqueous HCI (1 .8 M, 600 ml_). The aqueous extract was washed with toluene (2 x 300 ml_). MeOH (500 ml_) was added to the aqueous layer and the solution was cooled to 5 °C. The pH was adjusted to pH 8-9 with the addition of NaOH solution (50 wtpercent, ca. 50 ml_). The addition was at such a rate that the internal temperature did not exceed 17 °C. The resulting suspension was stirred at 5 °C for 2 h. The product was collected by filtration and rinsed with MeOH/H2O (1 :1 , 70 ml_). The solid was dried in vacuum oven at 50 °C for 24 h to afford the title compound as a yellow/green solid (73 g, 69percent).A 1 L, three-neck Morton flask equipped with a stir bar, thermocouple, and reflux condenser was charged with crude 4-(2,2-difluoro-benzo[1 ,3]dioxol- 5-ylmethyl)-piperazine-1 -carboxylic acid (4-chloro-pyridin-3-yl)-amide (98 g, 239 mmol) and isopropyl acetate (318 ml_). The suspension was heated to 65 °C, treated with activated charcoal (10.0 g) and stirred at 65 °C for 1 h. The mixture was then heated to 80 °C and quickly filtered through a thin celite pad. The filtrate was slowly cooled to room temperature and then placed in an ice bath for 30 min. The solid was collected by filtration, rinsed with cold iPrOAc (10 ml_), and dried to give product 4-(2,2-difluoro-benzo[1 ,3]dioxol-5-ylmethyl)- piperazine-1 -carboxylic acid (4-chloro-pyridin-3-yl)-amide as a yellow solid (72 g, 73percent).A 2 L, three-neck Morton flask equipped with a mechanical stirrer, thermocouple, and reflux condenser was charged with crude product 4-(2,2- difluoro-benzo[1 ,3]dioxol-5-ylmethyl)-piperazine-1 -carboxylic acid (4-chloro- pyridin-3-yl)-amide (191 g, 465 mmol) and isopropyl acetate (705 ml_). The suspension was heated to 65 °C, treated with activated charcoal (1 1 .2 g) and stirred at 65 °C for 1 h. The mixture was then heated to 75 °C and quickly filtered. The filtrate was slowly cooled to room temperature overnight and then placed in an ice bath for 30 min. The solid was collected by filtration, rinsed with cold iPrOAc (40 ml_), and dried in vacuum oven at 50 °C for 72 h. The product 4-(2,2-difluoro-benzo[1 ,3]dioxol-5-ylmethyl)-piperazine-1 -carboxylic acid (4-chloro-pyridin-3-yl)-amide was obtained as a slightly yellow solid (161 g, 84percent). MS (ESI+): calcd for Ci8Hi7CIF2N4O3 m/z 410.1 , found 41 1 .1 (M+H)+. Anal. Calcd for Ci8H17CIF2N4O3: C, 52.63; H, 4.17; N, 13.64. Found: C, 52.73; H, 4.15; N, 13.62; 1 H NMR (600 MHz, CDCI3) δ: 9.36 (s, 1 H), 8.19 (d, J = 5.2 Hz, 1 H), 7.29 (dd, J = 5.3, 0.3 Hz, 1 H), 7.13 (d, J = 0.9 Hz, 1 H), 7.02-6.98 (m, 5 2H), 6.84 (s, 1 H), 3.58-3.54 (m, 4H), 3.53 (s, 2H), 2.54-2.48 (m, 4H); 13C NMR (151 MHz, CDCIs) δ: 153.49, 144.02, 143.88, 143.28, 142.98, 134.05, 133.09, 131 .66 (t, JC-F = 254.6 Hz), 131 .55, 123.89, 123.53, 1 10.03, 109.02, 62.28, 52.47, 44.23. |