Lithium Hexamethyldisilazide → 5-(3-(2-(Methylthio)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-amine

Temperature

65 °C

To a brown solution of tris(dibenzylideneacetone)dipalladium (o) (0.68 g, 0.75 mmol), 2-(dicyclohexylphosphino)biphenyl (0.50 g, 1.4 mmol), and 4-(2-(6-chloropyridin-3-yloxy) pyridin-3-yl)-2-(methylthio)pyrimidine (1.9 g, 5.7 mmol) in 15 mL dioxane was added solid lithium bis(trimethylsilyl) amide (2.9 g, 17 mmol). Argon was bubbled through the reaction for 1 min, and then it was sealed and heated to 65° C. for 3.5 days. The reaction was cooled to ambient temperature, diluted with water, and acidified to a pH of about 1 with stirring, then brought to pH of about 5 with 6N NaOH. Dichloromethane was added and reaction was filtered through 2 cm Celite® in a frit, rinsing with MC and water. The layers were separated, and the organic layer was dried over anhyd. Na2SO4, filtered, and concentrated in vacuo. The material was diluted in 100 mL MC, and extracted 3×100 mL 1 N HCl. The aqueous layers were cooled to 0° C. and basified with 6 N NaOH to about pH of 10. The aqueous layer was extracted 3×100 mL with MC. The organic layers were combined, dried over anhdrous sodium sulfate, filtered, and concentrated in vacuo to a brown oil. The oil residue was purified by silica gel chromatography, 120 g, 0-50% MC-90/10 MC/MeOH, to afford 5-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-amine as a yellow solid. MS m/z=312 [M+H]+. Calc'd for C15H13N5OS: 311.4.

1. customArgon was bubbled through the reaction for 1 min
2. customit was sealed
3. temperatureThe reaction was cooled to ambient temperature
4. additiondiluted with water
5. additionDichloromethane was added
6. customreaction
7. filtrationwas filtered through 2 cm Celite® in a frit
8. washrinsing with MC and water
9. customThe layers were separated
10. customthe organic layer was dried over anhyd
11. filtrationNa2SO4, filtered
12. concentrationconcentrated in vacuo
13. additionThe material was diluted in 100 mL MC
14. extractionextracted 3×100 mL 1 N HCl
15. temperatureThe aqueous layers were cooled to 0° C. and basified with 6 N NaOH to about pH of 10
16. extractionThe aqueous layer was extracted 3×100 mL with MC
17. dry with materialdried over anhdrous sodium sulfate
18. filtrationfiltered
19. concentrationconcentrated in vacuo to a brown oil
20. customThe oil residue was purified by silica gel chromatography, 120 g, 0-50% MC-90/10 MC/MeOH

ORD record

ord-c8e5ecc692f649779c1dc3df47d7d4db

Source dataset

uspto-grants-2011_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07868177B2