反应详情

In a dry 3 neck 2 L flask equipped with a dry addition funnel, thermometer and stir bar was added 3-bromo-2-fluoro-4-iodopyridine (83.4 g, 276 mmol) followed by 300 mL of anhydrous THF under an atmosphere of nitrogen. The solution was cooled to −70° C. in 2-propanol/dry ice bath. A solution of isopropylmagnesium chloride 2.0 M in diethyl ether (145 mL, 290 mmol) was added drop wise over a period of 30 minutes. The solution was then stirred for 30 minutes before zinc (II) chloride 0.5 M in THF (276 mL, 138 mmol) was cannulated in. The solution was warmed to room temperature and stirred for 1 hour. The addition funnel was replaced with a reflux condenser and N4-cyclopentyl-5-iodopyrimidine-2,4-diamine (243, see example 200) (28.00 g, 92.1 mmol) was added, followed by Pd(PPh3)4 (5.32 g, 4.60 mmol). The solution was heated over night at a gentle reflux. After concentrating the solution to 1/10th of the volume under vacuum, it was cooled in an ice bath. To this was added 100 mL of cold saturated NH4Cl, followed by 500 mL of water. 500 mL of 12% isopropanol/DCM was then added and the solution was stirred at room temperature for 1 hour before being filtered through filter paper. The filter cake was washed in succession with water, DCM and 12% 2-propanol/DCM. The filtrate was partitioned in a separation funnel and the aqueous layer was washed with 12% 2-propanol /DCM. The organics were dried over MgSO4 and then concentrated under vacuum. The residue obtained was partially dissolved in DCM with sonication and filtered off to give compound 244 (26.45 g, 81.6%) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.18 (1 H, d, J=4.9 Hz), 7.52 (1 H, s), 7.26 (1 H, dd, J=4.9, 0.7 Hz), 6.34 (2 H, s), 6.12 (1 H, d, J=7.6 Hz), 4.42 (1 H, sxt, J=7.4 Hz), 1.76-1.96 (2 H, m), 1.55-1.68 (2 H, m), 1.31-1.53 (4 H, m)) ppm; LCMS-ESI (POS), M/Z, M+1: Found 352.0.

1. customIn a dry 3 neck 2 L flask
2. customequipped with a dry addition funnel
3. stirringstirred for 1 hour
4. customThe addition funnel was replaced with a reflux condenser
5. temperatureThe solution was heated over night at a gentle reflux
6. concentrationAfter concentrating the solution to 1/10th of the volume under vacuum, it
7. temperaturewas cooled in an ice bath
8. additionTo this was added 100 mL of cold saturated NH4Cl
9. addition500 mL of 12% isopropanol/DCM was then added
10. stirringthe solution was stirred at room temperature for 1 hour
11. filtrationbefore being filtered
12. filtrationthrough filter paper
13. washThe filter cake was washed in succession with water, DCM and 12% 2-propanol/DCM
14. customThe filtrate was partitioned in a separation funnel
15. washthe aqueous layer was washed with 12% 2-propanol /DCM
16. dry with materialThe organics were dried over MgSO4
17. concentrationconcentrated under vacuum
18. customThe residue obtained
19. filtrationfiltered off