Hydrazine hydrate (1:1) → 6-[2-Amino-6-(methylthio)-4-pyrimidinyl]-1H-indazol-3-amine

Temperature

100 °C

To 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (16.5 g, 66.6 mmol) and 4-chloro-6-(methylthio)-2-pyrimidinamine (11.7 g, 66.6 mmol) were added 1,4-dioxane (300 mL) and saturated aqueous NaHCO3 (150 mL) and the mixture was degassed with nitrogen gas for 15 minutes into a sealable tube. Pd(Ph3P)4 (2.3 g, 2.0 mmol) was added, the tube was sealed, and the reaction mixture was stirred overnight at 100° C. The mixture was cooled to room temperature and poured onto water where a precipitate was formed. The mixture was filtered and the solid was transferred to a sealable tube. Dioxane (300 mL) was added followed by hydrazine monohydrate (32.7 mL, 666 mmol) and the reaction mixture was stirred overnight at 100° C. into the sealed tube. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was poured onto water and filtered again. The aqueous filtrate was poured onto a separatory funnel and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. To the resulting residue was added 1,4-dioxane (100 mL) and the mixture was sonicated for 30 minutes. The solids were filtered affording the crude title compound (11.5 g) as a yellow solid. The filtrate was concentrated and the resulting residue was dissolved in dioxane and purified via flash chromatography on SiO2 (gradient: 99:1:0.1 CHCl3/CH3OH/NH4OH to 90:10:1 CHCl3/CH3OH/NH4OH) to afford the title compound (4.5 g) as a pale yellow solid. LC-MS (ES) m/z=273 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.53 (s, 3H), 5.41 (s, 2H), 6.70 (s, 2H), 7.06 (s, 1H), 7.58 (dd, J=8.5, 1.1 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.98 (s, 1H), 11.60 (s, 1H).

1. customthe mixture was degassed with nitrogen gas for 15 minutes into a sealable tube
2. customthe tube was sealed
3. temperatureThe mixture was cooled to room temperature
4. additionpoured onto water where a precipitate
5. customwas formed
6. filtrationThe mixture was filtered
7. customthe solid was transferred to a sealable tube
8. additionDioxane (300 mL) was added
9. stirringthe reaction mixture was stirred overnight at 100° C. into the sealed tube
10. temperatureto cool to room temperature
11. filtrationfiltered
12. additionThe filtrate was poured onto water
13. filtrationfiltered again
14. additionThe aqueous filtrate was poured onto a separatory funnel
15. extractionextracted with EtOAc (3×)
16. washThe combined organic layers were washed with brine
17. dry with materialdried (MgSO4)
18. filtrationfiltered
19. concentrationconcentrated
20. additionTo the resulting residue was added 1,4-dioxane (100 mL)
21. customthe mixture was sonicated for 30 minutes
22. filtrationThe solids were filtered
23. customaffording the crude title compound (11.5 g) as a yellow solid
24. concentrationThe filtrate was concentrated
25. dissolutionthe resulting residue was dissolved in dioxane
26. custompurified via flash chromatography on SiO2 (gradient: 99:1:0.1 CHCl3/CH3OH/NH4OH to 90:10:1 CHCl3/CH3OH/NH4OH)

ORD record

ord-5aa95c3f51da47039bb761f857fd6a36

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08697685B2