Potassium Fluoride → HCID 58404734, compound

Temperature

100 °C

6-bromo-3-(cyclopropylethynyl)-4-methoxypyrazolo[1,5-a]pyridine (36.0 mg, 0.124 mmol), 1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2-fluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (95.0 mg, 0.247 mmol), tris(dibenzylideneacetone)dipalladium (11.3 mg, 0.012 mmol), potassium fluoride (38.1 mg, 0.655 mmol), and tri-t-butylphosphonium tetrafluoroborate (7.2 mg, 0.025 mmol) were suspended in 1.3 mL of DMF and sparged with Ar for 10 minutes. The mixture was heated to 100° C. for 1 h, then allowed to cool to ambient temperature. Tetra-n-butylammonium fluoride (247 μl 0.247 mmol, 1M in THF) was added and the mixture was allowed to stir for 30 minutes, then additional tetra-n-butylammonium fluoride (247 μl, 0.247 mmol, 1M in THF) was added and the mixture was stirred for 30 minutes more. The reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA (20-100%). The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to give a yellow solid that was slightly impure. The residue was purified by column chromatography on silica gel (methanol/ethylacetate gradient) to give 3-{4-[3-(cyclopropylethynyl)-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-1H-pyrazol-1-yl}-2-fluoropropan-1-ol. 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H); 8.36 (s, 1H); 8.09 (s, 1H); 7.94 (s, 1H); 6.92 (s, 1H); 5.15 (t, 1H); 4.78-4.93 (m, 1H); 4.34-4.46 (m, 2H); 3.96 (s, 3H); 3.50-3.72 (m, 2H); 1.48-1.54 (m, 1H); 0.80-0.87 (m, 2H); 0.66-0.70 (m, 2H). LRMS (ESI) calculated for C19H20FN4O2 [M+H]+, 355.1; found 355.0.

1. customsparged with Ar for 10 minutes
2. temperatureto cool to ambient temperature
3. stirringthe mixture was stirred for 30 minutes more
4. washwashed with saturated aqueous sodium hydrogen carbonate and brine
5. dry with materialthen dried over sodium sulfate
6. filtrationfiltered
7. concentrationconcentrated
8. customThe residue was purified by preparative HPLC Reverse phase (C-18)
9. washeluting with Acetonitrile/Water+0.05% TFA (20-100%)
10. additionThe fractions containing product
11. additiondiluted in ethyl acetate
12. washwashed with aqueous sodium bicarbonate
13. dry with materialdried over sodium sulfate
14. filtrationThe solution was filtered
15. concentrationconcentrated under reduced pressure
16. customto give a yellow solid
17. customThe residue was purified by column chromatography on silica gel (methanol/ethylacetate gradient)

ORD record

ord-fcc8445687ab453ca2a5ef8f3de8fb59

Source dataset

uspto-grants-2013_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08455477B2