Hydrazine → HCID 178506291, compound

Temperature

-78 °C

LDA, 2.0 M (15.63 mL, 31.3 mmol, Aldrich) was added to THF (35 ml) that was precooled to −78° C. under argon. The mixture was stirred for 5 min before 5-bromo-2-fluoropyridine (5.0 g, 28.4 mmol, Aldrich) was added dropwise. This mixture was stirred at −78° C. for 1.5 h and then ethyl 2,2,2-trifluoroacetate (5.65 g, 39.8 mmol, Aldrich) was added. The cooling bath was removed and the mixture was stirred for 1 h before 1N HCl and EtOAc were added. The layers were separated and the organic layer was dried with MgSO4, filtered, and concentrated to give a red oil. The oil was dissolved in EtOH (100 mL) and hydrazine (1.78 mL, 56.8 mmol, Aldrich) was added. This mixture was stirred at reflux for 2 h, cooled to RT, and diluted with EtOAc. The mixture was then washed with water, brine, dried (MgSO4), filtered, and concentrated in vacuo to give an oil that was precipitated with DCM. The solid was collected and the filtrate was concentrated and suspended in DCM again. The solid was collected and this time the filtrate was concentrated to give an oil which was purified by silica gel chromatography (0 to 50% EtOAc/hexane) affording 5-bromo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (4.4 g, 59%). MS (ESI, pos. ion) m/z: =266.1 (M+1). A mixture of 5-bromo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (158 mg, 0.59 mmol), bis(pinacolato)diboron (181 mg, 0.71 mmol), Pd(dppf)Cl2 (48.5 mg, 0.06 mmol, Strem) and potassium acetate (233 mg, 2.38 mmol, Aldrich) was capped, degassed and backfilled with argon (3×). Dioxane (5 mL) was added, and the reaction was heated at 100° C. After 22 h, the reaction mixture was cooled to 23° C., and filtered through celite. The crude reaction mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine was concentrated to dryness and taken forward to the next step.

1. customwas precooled to −78° C. under argon
2. additionwas added dropwise
3. customThe cooling bath was removed
4. stirringthe mixture was stirred for 1 h before 1N HCl and EtOAc
5. additionwere added
6. customThe layers were separated
7. dry with materialthe organic layer was dried with MgSO4
8. filtrationfiltered
9. concentrationconcentrated
10. customto give a red oil
11. stirringThis mixture was stirred
12. temperatureat reflux for 2 h
13. temperaturecooled to RT
14. washThe mixture was then washed with water, brine
15. dry with materialdried (MgSO4)
16. filtrationfiltered
17. concentrationconcentrated in vacuo
18. customto give an oil that
19. customwas precipitated with DCM
20. customThe solid was collected
21. concentrationthe filtrate was concentrated
22. customThe solid was collected
23. concentrationthis time the filtrate was concentrated
24. customto give an oil which
25. customwas purified by silica gel chromatography (0 to 50% EtOAc/hexane)

ORD record

ord-038e216a98654f0aa42c62ea45a7514c

Source dataset

uspto-grants-2015_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09090593B2