Methane → Grapiprant

Participants

Reaction Steps

To a clean and dry 12 L 3-neck round-bottom flask were charged 2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanamine (422 g, 1.43 moles) and CH2Cl2 (3.37 L). Tosyl isocyanate (217 mL, 1.43 moles) dissolved in CH2Cl2 (851 mL) was added to the reaction keeping the temperature below 21° C. and was stirred for at least 90 minutes. The reaction was deemed complete by HPLC and activated charcoal (DARCO KB-B, 4.2 g) was added. The resulting slurry was filtered through a 0.5-micron filter into a speck free 5 L 3-neck round-bottom flask and the filter washed with CH2Cl2 (421 mL). The reaction was atmospherically concentrated to a minimum stirable volume and displacement continued with speck freed acetone until an internal temperature of 58° C. to 62° C. was achieved and final volume was ˜1.3 L. The reaction was cooled to at least 30° C. and seed of N-[({2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide Polymorph Form A was added. The reaction was allowed to granulate between 20° C. and 25° C. for at least 10 hours. After cooling reaction to 0° C. to 5° C. and granulating for at least 2 hours, the reaction was filtered on a speck free filter. The solids were washed two times with speck free acetone (1.68 L) cooled to 0° C. to 5° C. The wet-cake was returned to a speck free 12 L 3-neck round-bottom flask and speck free ethyl acetate (4.4 L) was added. The slurry was heated to at least 75° C. and held for at least 2 hours. The reaction was cooled to at least 30° C. and the solids were filtered on a speck free filter. The solids were washed with speck free ethyl acetate (1.6 L). The wet-cake was returned to the same speck free 12 L 3-neck round-bottom flask and speck free ethyl acetate (4.4 L) was added. The slurry was heated to at least 75° C. and held for at least 2 hours. The reaction was cooled to at least 30° C. and the solids were filtered on a speck free filter. The solids were washed with speck free ethyl acetate (1.6 L). The product was dried at 45° C. to 50° C. for at least 24 hours to yield 289 g the title product, Polymorph Form A (41.4% yield, 98.68% purity by HPLC).

Provenance & Evidence