反应详情

温度

5 °C

A 300 L vessel was flushed with nitrogen. Acetic acid (40.0 L) was charged, and then 7.312 kg (37.84 moles) of (5-amino-1H-pyrazol-4-yl)-thiophen-2-yl-methanone and 10.000 kg (37.84 moles) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-acetamide were added consecutively. The mixture was heated to 120° C. (±5° C.) with stirring. The reaction was controlled by HPLC until completion (<1% of each starting material), which typically occurs in 4 hours. The reaction mass was cooled to 60-70° C. 2-Propanol (80.0 L) was charged to reaction mixture, cooled to 40-45° C. and aged for at least 1 hour. The mixture was cooled over approximately 2.5 hours to 0-5° C. and aged for at least 2 hours. Solids were filtered and washed twice with 10.0 L of chilled 2-propanol. The solid product was dried under vacuum at 50° C. (±5° C.) to remove residual solvents (<0.5% w/w of acetic acid and <0.5% w/w of 2-propanol). N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide was obtained as a crystalline material (12.686 kg). Yield 85%. Purity ≧95%.

1. customA 300 L vessel was flushed with nitrogen
2. additionAcetic acid (40.0 L) was charged
3. temperatureThe reaction mass was cooled to 60-70° C
4. temperaturecooled to 40-45° C. and aged for at least 1 hour
5. temperatureThe mixture was cooled over approximately 2.5 hours to 0-5° C. and aged for at least 2 hours
6. filtrationSolids were filtered
7. washwashed twice with 10.0 L of chilled 2-propanol
8. customThe solid product was dried under vacuum at 50° C. (±5° C.)
9. customto remove residual solvents (<0.5% w/w of acetic acid and <0.5% w/w of 2-propanol)