Pyridine → JNJ-42165279

Temperature

2 °C

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 HCl (1.8 M, 600 mL). The aqueous extract was washed with toluene (2×300 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 wt %, 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, 69%).

1. customA 2 L, three-neck Morton flask equipped with a mechanical stirrer
2. additionthermocouple, and addition funnel under a nitrogen atmosphere
3. customwas 5° C
4. customwas 6° C
5. temperatureto warm slowly to room temperature
6. stirringstirred for 15 h
7. customthe toluene layer was separated
8. extractionextracted with aqueous HCl (1.8 M, 600 mL)
9. extractionThe aqueous extract
10. washwas washed with toluene (2×300 mL)
11. additionMeOH (500 mL) was added to the aqueous layer
12. temperaturethe solution was cooled to 5° C
13. additionThe pH was adjusted to pH 8-9 with the addition of NaOH solution (50 wt %, ca. 50 mL)
14. additionThe addition
15. customdid not exceed 17° C
16. stirringThe resulting suspension was stirred at 5° C. for 2 h
17. filtrationThe product was collected by filtration
18. washrinsed with MeOH/H2O (1:1, 70 mL)
19. customThe solid was dried in vacuum oven at 50° C. for 24 h

ORD record

ord-b493a40a33414c88b691ee789a822178

Source dataset

uspto-grants-2015_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08940745B2