Bromide ion → HCID 21891474, compound

Temperature

0 °C

Part C: 6-(4-Chloro-butyl)-1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile (0.148 g, 0.412 mmol) and potassium bromide (0.982 g, 8.24 mmol) were dissolved in acetone (25 mL) and refluxed overnight. The reaction was concentrated, quenched with water (100 mL), extracted with ethyl acetate (3×100 mL), washed with brine (1×100 mL), dried over MgSO4, concentrated, and purified by flash chromatography using 0–100% ethyl acetate/hexanes gradient as eluent to afford 0.136 g (82%). 2-Piperidone (0.136 g, 0.340 mmol) was dissolved in N,N-dimethylformamide (7 mL) and the reaction was cooled to 0° C. Sodium hydride (60%, 0.040 g, 1.01 mmol) was added and the reaction was stirred at 0° C. for 30 min. The bromide intermediate (0.136 g, 0.34 mmol) dissolved in N,N-dimethylformamide (8 mL) was added, and the reaction was stirred at rt overnight. The reaction was quenched with 1N hydrochloric acid (100 mL), extracted with ethyl acetate (3×100 mL), washed with water (100 mL), washed with brine (1×100 mL), dried over MgSO4, concentrated, and purified by flash chromatography using 0–100% ethyl acetate/hexanes gradient as the eluent. Further purification by reverse-phase HPLC and freeze-drying afforded 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-butyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile (0.060 g, 42%). The carbonitrile (0.060 g, 0.141 mmol), 1N sodium hydroxide (10 mL), hydrogen peroxide (30%, 10 mL), and catalytic tetrabutyl hydrogen sulfate were dissolved in methylene chloride (10 mL) and stirred overnight at rt. The reaction was quenched with 1N sodium hydroxide (20 mL), concentrated to about 10 mL of solution, water (100 mL) added, extracted with ethyl acetate (3×100 mL), washed with brine (1×100 mL), dried over MgSO4, concentrated, and purified by reverse phase HPLC and freeze-dried to afford the title compound (0.034 g, 54%): 1H NMR (CHCl3) δ 7.45 (d, j=8.8 Hz, 2H), 6.97 (d, j=8.8 Hz, 2H), 6.82 (s, 3H), 5.44 (s, 3H), 3.85 (s, 3H), 3.65 (t, j=7.0 Hz, 2H), 3.49 (t, j=7.0 Hz, 2H), 3.36 (t, j=6.8 Hz, 2H), 3.22 (t, j=7.0 Hz, 4H), 2.38–2.34 (m, 2H), 1.79–1.76 (m, 4H), 1.64–1.57 (m, 4H) ppm; Mass Spec 440.3(M+H)+.

1. temperaturerefluxed overnight
2. concentrationThe reaction was concentrated
3. customquenched with water (100 mL)
4. extractionextracted with ethyl acetate (3×100 mL)
5. washwashed with brine (1×100 mL)
6. dry with materialdried over MgSO4
7. concentrationconcentrated
8. custompurified by flash chromatography
9. customto afford 0.136 g (82%)
10. additionwas added
11. stirringthe reaction was stirred at rt overnight
12. customThe reaction was quenched with 1N hydrochloric acid (100 mL)
13. extractionextracted with ethyl acetate (3×100 mL)
14. washwashed with water (100 mL)
15. washwashed with brine (1×100 mL)
16. dry with materialdried over MgSO4
17. concentrationconcentrated
18. custompurified by flash chromatography
19. customFurther purification by reverse-phase HPLC
20. customfreeze-drying

ORD record

ord-5be03f9879b046a29a116a9184e47bf5

Source dataset

uspto-grants-2006_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07135469B2