反应详情

温度

80 °C

(S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II (33.0 g, 75 mmol) was charged to a suitably sized reactor, followed by n-propanol (337 g), water (450 g), 2-aminopyrimidin-5-ylboronic acid III (12.5 g, 90 mmol) and dipotassium hydrogen phosphate (39.2 g, 225 mmol). The resulting mixture was degassed by vacuum/argon purge three times. Bis(triphenylphosphine)palladium (II) chloride (0.079 g, 0.112 mmol) was added and the slurry was again degassed by vacuum/argon purge three times. The mixture was heated within 2 h to 65° C. and stirred for 10 hours. The organic phase was separated and slowly filtered over a preheated pressure filter loaded with a ZETACARBON® R55SP pad (Cuno Inc., a 3M Company, Meriden Conn.). The filter unit was washed with a warm (80° C.) n-propanol (45 mL). Water (750 mL) were added to the filtrate and the resulting suspension was cooled to 10° C., aged for 1 h and filtered. The filter cake was washed with water (150 g) and dried under reduced pressure at 45° C. to afford (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one, GDC-0980, Formula I as a white solid (30.1 g, 79%).

1. customThe resulting mixture was degassed by vacuum/argon
2. custompurge three times
3. customthe slurry was again degassed by vacuum/argon
4. custompurge three times
5. temperatureThe mixture was heated within 2 h to 65° C.
6. customThe organic phase was separated
7. filtrationslowly filtered over a preheated pressure
8. filtrationfilter
9. washThe filter unit was washed with
10. additionWater (750 mL) were added to the filtrate
11. temperaturethe resulting suspension was cooled to 10° C.
12. waitaged for 1 h
13. filtrationfiltered
14. washThe filter cake was washed with water (150 g)
15. customdried under reduced pressure at 45° C.