Pyridine → JNJ-42165279

Participants

Reaction Conditions

Reaction Steps

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%).

Provenance & Evidence