18-Crown-6 → 1-phenyl-7H-pyrazolo[5,4-b]pyridin-6-one

To a semi-solid mixture of 18-crown-6 (4.31 g, 16 mmol) and THF (30 ml) at −40° C. under nitrogen was added bis(2,2,2-trifluoroethyl)-(methoxycarbonylmethyl)phosphonate (0.69 ml, 3.26 mmol) followed by a solution of potassium bis(trimethylsilyl)amide in toluene (6.52 ml of a 0.5M solution, 3.26 mmol). A solution of 5-amino-1-phenyl-1H-pyrazole-4-carboxaldehyde (0.61 g, 3.26 mmol) in THF (10 ml+5 ml washings) was then added via cannula and the resulting mixture was stirred for 20 h, allowing to warm to room temperature. The reaction mixture was partitioned between saturated aqueous ammonium chloride solution and diethyl ether. The aqueous phase was extracted a second time with diethyl ether, and the combined organic extracts were washed with brine, dried (MgSO4) and concentrated. The crude material was dissolved in THF (20 ml), under nitrogen, and the resulting solution cooled to 0° C. A solution of potassium bis(trimethylsilyl)amide in toluene (13.0 ml of a 0.5M solution, 6.5 mmol) was added dropwise and the reaction mixture was stirred for 17 h during which time it was allowed to warm to room temperature. The reaction mixture was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The aqueous phase was extracted a second time with ethyl acetate, and the combined organic extracts were washed sequentially with 0.5M aqueous hydrochloric acid and brine before being dried (MgSO4) and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with 30% ethyl acetate-hexane to give 1,7-dihydro-1-phenylpyrazolo[3,4-b]pyridin-6-one (0.49 g, 71%). δH (400 MHz; CDCl3) 6.50 (1H, d, J=9), 7.29-7.33 (1H, m), 7.42-7.45 (2H, m), 7.71-7.73 (2H, m), 7.85 (1H, d, J=9), 7.91 (1H, s).

1. customThe reaction mixture was partitioned between saturated aqueous ammonium chloride solution and diethyl ether
2. extractionThe aqueous phase was extracted a second time with diethyl ether
3. washthe combined organic extracts were washed with brine
4. dry with materialdried (MgSO4)
5. concentrationconcentrated
6. dissolutionThe crude material was dissolved in THF (20 ml), under nitrogen
7. temperaturethe resulting solution cooled to 0° C
8. additionA solution of potassium bis(trimethylsilyl)amide in toluene (13.0 ml of a 0.5M solution, 6.5 mmol) was added dropwise
9. stirringthe reaction mixture was stirred for 17 h during which time it
10. temperatureto warm to room temperature
11. customThe reaction mixture was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate
12. extractionThe aqueous phase was extracted a second time with ethyl acetate
13. washthe combined organic extracts were washed sequentially with 0.5M aqueous hydrochloric acid and brine
14. dry with materialbefore being dried (MgSO4)
15. concentrationconcentrated in vacuo
16. customThe crude material was purified by chromatography on silica eluting with 30% ethyl acetate-hexane

ORD record

ord-389beb37c0574658a963b5e16ea9a1e7

Source dataset

uspto-grants-2003_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06541484B2