5-Chloro-1H-pyrazolo[4,3-b]pyridine

Uses

5-Chloro-1H-pyrazolo[4,3-b]pyridine is an intermediate used to prepare 2-aryl or heteroaryl indole derivatives as ASIC channel modulators for treating pain, bone diseases, and other disorders.

Synthesis

6-Chloro-2-methylpyridin-3-amine (12.8 g, 0.09 mol) was used as starting material and dissolved in chloroform (500 mL). Acetic anhydride (34.0 mL, 0.36 mol) and potassium acetate (10.6 g, 0.11 mol) were added sequentially, and the reaction mixture was stirred and reacted at 60 °C for 2 hours. Subsequently, isoamyl nitrite (27.8 mL, 0.21 mol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (2.4 g, 8.90 mmol) were added to the reaction system, and the reaction continued to be stirred at 60 °C overnight. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure and the resulting crude product was dissolved in a solvent mixture of methanol (225 mL) and water (50 mL), cooled to 0 °C and potassium carbonate (45 g) was added in batches. The mixture was stirred at 0 °C for 10 min, then brought to room temperature and continued stirring for 3 h. The mixture was then cooled to room temperature and stirred for 3 h. The reaction solution was then mixed with potassium carbonate. Water was added to the reaction solution and stirred at room temperature for 1 h. The precipitate was collected and washed with cold water and hexane. The resulting solid was dried in a vacuum oven at 50 °C overnight to afford the target product 5-chloro-1H-pyrazolo[3,4-b]pyridine (13.6 g, 97% yield) as a white solid.LRMS (m/z): 154,156 ([M+H]+, [M+3]+).1H-NMR (300 MHz, CDCl3)δ: 7.35 (d, 1H), 7.84 (dd, 1H), 8.26 (d, 1H), 10.39 (s, 1H).

References

[1] Patent: WO2017/220431, 2017, A1. Location in patent: Page/Page column 35
[2] Patent: CN108003161, 2018, A. Location in patent: Paragraph 0745; 0747-0749