PYRAZOLO[1,5-A]PYRIDIN-2-OL

Synthesis

1b) Synthesis of 2-hydroxypyrazolo[1,5-a]pyridine (C4f): the method was carried out with reference to the literature (Ochi, M.; Miyasaka, T.; Kanada, K.; Arakawa, K. Bull. Chem. Soc. Japan, 1976, 49, 1980-1984). At 0 °C, 4.14 g (36.6 mmol) of hydroxylamine-O-sulfonic acid was dissolved in 13.8 mL of water, neutralized with 2.6 N KOH solution, and added slowly and dropwise to 26.2 mL (0.172 mol) of ethyl 2-pyridylacetate. The reaction mixture was stirred at room temperature for 30 hours. Subsequently, the mixture was extracted with dichloromethane and the aqueous layer was adjusted to pH 9 with 10% Na2CO3 solution and extracted again with dichloromethane. Next, the aqueous layer was adjusted to pH 5 with acetic acid and extracted with dichloromethane. The organic layers were combined, dried with MgSO4 and concentrated. The crude product was purified by fast chromatography (hexane/EtOAc = 90:10) to give 607 mg (39%) of white solid product. Melting point: 127-128 °C. MS (APCI): m/z 135 (M + 1)+. 1H NMR (DMSO-d6, 360 MHz) δ (ppm): 5.72 (d, J = 0.8 Hz, 1H, H-3); 6.63 (ddd, J = 6.8 Hz, 6.8 Hz, 1.4 Hz, 1H, H-6); 7.08 (ddd , J = 8.9 Hz, 6.8 Hz, 1.1 Hz, 1H, H-5); 7.35 (ddd, J = 8.9 Hz, 1.4 Hz, 0.8 Hz, 1H, H-4); 8.32 (dd, J = 6.8 Hz, 1.1 Hz, 1H, H-7); 10.40 (s, 1H, OH).

References

[1] Patent: EP1972628, 2008, A1. Location in patent: Page/Page column 31
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 11, p. 4861 - 4875