Pyrazolo[1,5-a]pyridine

Description

Pyrazolo[1,5-a]pyridines, a class of fused heteroaromatic bicyclic compounds, have been investigated for their pharmacological and biological activities. They are used as dopamine D2/D3/D4 antagonists, anti-herpetic agents, p38 kinase inhibitors, PI3 kinase inhibitors, antitubercular agents, EP1 receptor antagonists, 5HT3-antagonists, melatonin receptor (MT1/MT2) ligands, Mcl-1Bcl-xL dual inhibitors, and corticotropin-releasing factor 1 antagonists. Pyrazolo[1,5-a]pyridine has been used as a fluorophore in the research of Zhang et al. and exhibited high quantum yield (0.64, pH 2.4), high selectivity and sensitivity, and extremely short response time[1].

Synthesis

General procedure for the synthesis of pyrazolo[1,5-a]pyridine from ethyl pyrazolo[1,5-a]pyridine-3-carboxylate: to ethyl pyrazolo[1,5-a]pyridine-3-carboxylate (78 g, 410.1 mmol) was added 50% (v/v) aqueous sulfuric acid solution (200 mL, 410.1 mmol) and the reaction mixture was heated to reflux for 215 minutes. Upon completion of the reaction, it was cooled to room temperature and 50% (w/w) NaOH solution (350 mL) was added slowly and dropwise over 60 min under ice bath conditions, keeping the reaction temperature below 35 °C. Subsequently, the reaction mixture was poured into water (1 L) and additional 50% (w/w) NaOH solution (about 75 mL) was added until the mixture was basic. The resulting suspension was stirred until completely dissolved. It was extracted with methyl tert-butyl ether (MTBE, 3 x 250 mL) and the organic phases were combined and washed with water (500 mL) and saturated brine (500 mL) sequentially. The organic layer was dried with anhydrous sodium sulfate (Na2SO4), filtered and concentrated under reduced pressure to afford pyrazolo[1,5-a]pyridine (44.6 g, 92% yield) as a yellow oil. Its NMR hydrogen spectrum (400 MHz, CDCl3) data were as follows: δ 6.51 (1H, d, J = 2 Hz, ArH-3), 6.73 (1H, td, J = 7, 1 Hz, ArH-6), 7.09 (1H, ddd, J = 9, 7, 1 Hz, ArH-5), 7.53 (1H, d, J = 9 Hz, ArH-4), 7.94 (1H, d, J = 9 Hz, ArH-4) 7.94 (1H, d, J = 2 Hz, ArH-2), 8.47 (1H, dd, J = 7, 1 Hz, ArH-7); NMR carbon spectrum (101 MHz, CDCl3) data are as follows: δ 96.73, 111.60, 118.16, 123.14, 128.67, 140.16, 141.80; mass spectrum (ES+) m/z 119 (100, MH+); high-resolution mass spectrum (ESI): MH+, measured value 119.06036, C7H7N2 calculated value 119.06037.

References

[1] Brian A Johns. “Pyrazolo[1,5-a]pyridines: synthetic approaches to a novel class of antiherpetics.” Tetrahedron 59 45 (2003): Pages 9001-9011.