Nitrogen → HCID 154494353, compound

Temperature

15 °C

A three-neck round bottom flask, fitted with a mechanical stirrer, an additional funnel, a temperature probe and N2 inlet was charged sequentially with 2-MeTHF (330 mL, 10.5 vol, water content: <300 ppm), 2,4-dichloro-5-methoxy-pyrimidine (16, 30.0 g, 0.164 mol) (FWD Chem, Shanghai, China, or Amfinecom, Inc., St. Petersburg, Va.), and NiCl2(dppp) (1.4 g, 2.6 mmol, 1.6 mol %). The resulting mixture was degassed by evacuation with a reduced pressure followed by purging with nitrogen gas (3 times at room temperature). The resulting mixture was cooled to 15° C. and a solution of 3 M Methyl magnesium chloride in THF (125 mL, 2.25 equiv.) was added via a dropping funnel maintaining the internal temperature at 15-25° C. over a period of 1.5 h (Note: first 6 mL of MeMgCl was added slowly at 15-20° C., and aged for 15 min to activate the catalyst). The dropping funnel was rinsed with 2-MeTHF (15 mL). After addition of the MeMgCl, the reaction was warmed to room temperature over 1 h with the aid of a cooling water-bath. The reaction was stirred for 13 h at room temperature with water-bath cooling (At this point, HPLC indicated the reaction was complete. Magnesium salt was precipitated as a golden yellow colored slurry). The resulting slurry was transferred into the pre-cooled (10° C.) 15% aqueous citric acid solution (300 mL) via cannula at such a rate to maintain the temperature below 30° C., and the biphasic mixture was vigorously stirred for 15 min. The reaction flask was rinsed with 2-MeTHF (60 mL). After stirring for 15 min, ammonium hydroxide (28%, 150 mL) was added keeping the temperature below 30° C. (the pH of the aq. Layer: ˜10). The biphasic mixture was stirred for an additional 15 min. At this point, sodium chloride (83 g) was added and allowed to dissolve (=20 min) After phase separation, the aqueous layer was back-extracted with 2-MeTHF (300 mL). After a phase-cut, the organic layers were combined, concentrated and azeotropically dried (below 40° C.) by 2-MeTHF flush (300 mL). The precipitated inorganic salt was filtered through an in-line CUNO-filter, and rinsed with 120 mL of 2-MeTHF. The rinse was combined with the initial filtrate.

1. customA three-neck round bottom flask, fitted with a mechanical stirrer, an additional funnel
2. customThe resulting mixture was degassed by evacuation with a reduced pressure
3. customby purging with nitrogen gas (3 times at room temperature)
4. temperaturemaintaining the internal temperature at 15-25° C. over a period of 1.5 h (
5. washThe dropping funnel was rinsed with 2-MeTHF (15 mL)
6. additionAfter addition of the MeMgCl
7. temperaturethe reaction was warmed to room temperature over 1 h with the aid of a cooling water-bath
8. temperaturecooling (At this point, HPLC
9. customMagnesium salt was precipitated as a golden yellow colored slurry)
10. temperaturepre-cooled (10° C.) 15% aqueous citric acid solution (300 mL) via cannula at such a rate
11. temperatureto maintain the temperature below 30° C.
12. stirringthe biphasic mixture was vigorously stirred for 15 min
13. washThe reaction flask was rinsed with 2-MeTHF (60 mL)
14. stirringAfter stirring for 15 min
15. additionammonium hydroxide (28%, 150 mL) was added
16. customthe temperature below 30° C.
17. stirringThe biphasic mixture was stirred for an additional 15 min
18. additionAt this point, sodium chloride (83 g) was added
19. dissolutionto dissolve (=20 min)
20. customAfter phase separation
21. extractionthe aqueous layer was back-extracted with 2-MeTHF (300 mL)
22. concentrationconcentrated
23. dry with materialazeotropically dried (below 40° C.) by 2-MeTHF
24. customflush (300 mL)
25. filtrationThe precipitated inorganic salt was filtered through an in-line CUNO-filter
26. washrinsed with 120 mL of 2-MeTHF

ORD record

ord-f13ac4e314f94a0482319ebf045c8ef5

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09416109B2