反应详情

温度

-70 °C

Isopropylmagnesium chloride-LiCl (37.9 ml, 36.5 mmol) was added portion wise (in overall 10 min) to a solution of 3-bromo-6-methyl-2-pyridinecarbonitrile (4 g, 20.30 mmol) in THF (150 ml) cooled to −70° C. (internal temperature). The reaction was kept to that temperature for 15 min. Then it was allowed to gently warm up to −40° C. in overall 1 hour. Then, it was cooled to −78° C. and zinc chloride (3.32 g, 24.36 mmol) was added. The resulting mixture was allowed to warm up to room temperature in 1 hour. Pd(Ph3P)4 (2.346 g, 2.030 mmol), 2-chloropyrimidine (3 g, 26.2 mmol) were added and the mixture was refluxed (external temperature 100° C.) until complete consumption of starting chloropyrimidine (3 hours). The reaction mixture was cooled to room temperature and poured into water (200 ml) cooled to 10° C. It was then extracted with EtOAc (5×200 mls). The collected organic phases, containing large amount of colloid material and water, were washed with brine (200 ml). The water phase was filtered over a gouch, and the solid material was washed with further EtOAc 2×300 mls). The collected organic phases were dried overnight over Na2SO4, filtered and concentrated to give (7 g) the crude material which was purified (Biotage Sp1 over a 240 g Silica Anolgix column, with a 25 g pre-column) to give the title compound D18 as yellow solid (1.8 g). UPLC (Acid GEN_QC_SS): rt=0.58 minutes, peak observed: 197 (M+1). C11H8N4 requires 196.

1. temperatureto gently warm up to −40° C. in overall 1 hour
2. temperatureThen, it was cooled to −78° C.
3. temperatureto warm up to room temperature in 1 hour
4. temperaturethe mixture was refluxed (external temperature 100° C.)
5. customuntil complete consumption of starting chloropyrimidine (3 hours)
6. temperatureThe reaction mixture was cooled to room temperature
7. additionpoured into water (200 ml)
8. temperaturecooled to 10° C
9. extractionIt was then extracted with EtOAc (5×200 mls)
10. additionThe collected organic phases, containing large amount of colloid material and water
11. washwere washed with brine (200 ml)
12. filtrationThe water phase was filtered over a gouch
13. washthe solid material was washed with further EtOAc 2×300 mls)
14. dry with materialThe collected organic phases were dried overnight over Na2SO4
15. filtrationfiltered
16. concentrationconcentrated
17. customto give (7 g) the crude material which
18. customwas purified (Biotage Sp1 over a 240 g Silica Anolgix column