反应详情

温度

-12 °C

To a mixture of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (20.6 kg) and 2-amino-5-cyano-N,3-dimethylbenzamide (14.1 kg) in acetonitrile (114 kg) was added 3-picoline (22.2 kg). The mixture was cooled to −10 to −14° C., and then methanesulfonyl chloride (10.6 kg) was slowly added so that the temperature did not exceed 5° C. After reaction completion as ascertained by HPLC and NMR analyses, the mixture was worked up by successively adding water (72.6 kg) and concentrated hydrochloric acid (7.94 kg) at such a rate that the temperature did not exceed 5° C. After being maintained at a temperature not exceeding 5° C. for about 30 minutes, the reaction mixture was filtered to collect the solid product, which was successively washed with acetonitrile-water (2:1, 2×12.3 kg) and acetonitrile (2×10.4 kg). The solid was then dried at about 50° C. under reduced pressure and a flow of nitrogen gas to give the title product as a white crystalline solid, which was directly used in the present formulation Examples and Comparative Examples. With a moderate rate of heating (heating to about 150° C. over 5 minutes and then decreasing rate of heating from about 4-5° C./minute to about 3° C./minute to reach 210° C. over about 15 minutes more) to facilitate volatilization of loosely entrained solvents from the solid product, melting occurred in the range between 204 and 210° C.

1. customdid not exceed 5° C
2. customAfter reaction completion
3. customdid not exceed 5° C
4. temperatureAfter being maintained at a temperature not
5. filtrationthe reaction mixture was filtered
6. customto collect the solid product, which
7. washwas successively washed with acetonitrile-water (2:1, 2×12.3 kg) and acetonitrile (2×10.4 kg)
8. customThe solid was then dried at about 50° C. under reduced pressure