1346528-50-4

20511-15-3

1093211-85-8

1885-14-9

1346528-50-4

3-Amino-4-chloropyridine (35.0 g, 272 mmol) and toluene (740 mL) were added to a 2 L three-necked Morton flask equipped with a mechanical stirrer, thermocouple, and a charging funnel under nitrogen protection. The resulting brown solution was cooled to 2°C. Pyridine (25.3 mL, 310 mmol) was added all at once, followed by the dropwise addition of phenyl chloroformate (32.6 mL, 259 mmol) over a 30-minute period, controlling the reaction temperature to not more than 5°C. After stirring at 2-5 °C for 7 h, the reaction mixture was transformed into a thick yellow suspension. A pre-cooled aqueous solution of K2CO3 (53.6 g, 388 mmol) (216 mL) was added within 3 min, during which the maximum internal temperature was 6 °C. Solid 1-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)piperazine (66.3 g, 259 mmol) was then added over 1 min. The mixture was slowly warmed to room temperature and stirred for 15 hours. After addition of water (200 mL), the toluene layer was separated and extracted with 1.8 M aqueous HCl (600 mL). The aqueous phase was washed with toluene (2 x 300 mL). Methanol (500 mL) was added to the aqueous layer and the solution was cooled to 5°C. The pH was adjusted to 8-9 by dropwise addition of 50 wt% NaOH solution (~50 mL) and the internal temperature was controlled not to exceed 17°C. The resulting suspension was stirred at 5 °C for 2 h. The product was collected by filtration and washed with MeOH/H2O (1:1, 70 mL). The solid was dried in a vacuum oven at 50 °C for 24 h to afford N-(4-chloro-3-pyridinyl)-4-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-1-piperazinecarboxamide as a yellow/green solid (73 g, 69% yield). To a 1L three-neck Morton flask equipped with a stir bar, thermocouple and reflux condenser was added the crude product, N-(4-chloro-3-pyridinyl)-4-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-1-piperazinecarboxamide (98 g, 239 mmol) and isopropyl acetate (318 mL). The suspension was heated to 65 °C, activated carbon (10.0 g) was added and stirred at 65 °C for 1 hour. The mixture was then heated to 80°C and rapidly filtered through a diatomaceous earth pad. The filtrate was slowly cooled to room temperature and placed in an ice bath for 30 minutes. The solid was collected by filtration, washed with cold isopropyl acetate (10 mL) and dried to give the product (72 g, 73% yield). The crude product (191 g, 465 mmol) and isopropyl acetate (705 mL) were added to a 2 L three-neck Morton flask equipped with a mechanical stirrer, thermocouple and reflux condenser. The suspension was heated to 65 °C, activated carbon (11.2 g) was added and stirred at 65 °C for 1 hour. The mixture was then heated to 75°C and rapidly filtered. The filtrate was slowly cooled to room temperature overnight and then placed in an ice bath for 30 minutes. The solid was collected by filtration, washed with cold isopropyl acetate (40 mL) and dried in a vacuum oven at 50 °C for 72 h to give a light yellow solid product (161 g, 84% yield). MS (ESI+): m/z calculated for C18H17ClF2N4O3 [M+H]+ 411.1, found 411.1. Elemental analysis calculated for C18H17ClF2N4O3: C, 52.63; H, 4.17; N, 13.64. Found: C, 52.73; H, 4.15; N, 13.62. 1H NMR (600 MHz, CDCl3) δ: 9.36 (s, 1H), 8.19 (d, J = 5.2 Hz, 1H), 7.29 (dd, J = 5.3, 0.3 Hz, 1H), 7.13 (d, J = 0.9 Hz, 1H), 7.02- 6.98 (m, 5H), 6.84 (s, 1H), 3.58-3.54 (m, 4H), 3.53 (s, 2H), 2.54-2.48 (m, 4H); 13C NMR (151 MHz, CDCl3) δ: 153.49, 144.02, 143.88, 143.28, 142.98, 134.05, 133.09, 131.05 133.09, 131.66 (t, JC-F = 254.6 Hz), 131.55, 123.89, 123.53, 110.03, 109.02, 62.28, 52.47, 44.23.