Pyrazolo[1,5-a]pyridine-2-carboxylic acid

Chemical Properties

White to yellow solid

Synthesis

The general procedure for the synthesis of pyrazolo[1,5-a]pyridine-2,3-dicarboxylic acid from dimethyl pyrazolo[1,5-a]pyridine-2,3-dicarboxylate was as follows: dimethyl pyrazolo[1,5-a]pyridine-2,3-dicarboxylate (3.35 g, 14 mmol) was dissolved in 50% sulfuric acid (110 mL) and the reaction was stirred for 2.5 h at 80 °C. The reaction was completed by cooling to 0 °C and adjusting the pH to 9 with 8 M aqueous sodium hydroxide. Upon completion of the reaction, the reaction solution was cooled to 0 °C and the pH was adjusted to 9 with 8 M aqueous sodium hydroxide, followed by adjusting the pH to 3 with 6 M hydrochloric acid. the resulting suspension was separated by filtration, the crystals were washed with water, and dried under reduced pressure to afford pyrazolo[1,5-a]pyridine-2-carboxylic acid (light brown crystals, 1.88 g, 81% yield). The resulting pyrazolo[1,5-a]pyridine-2-carboxylic acid (941 mg, 5.8 mmol) was dissolved in THF (30 mL) under nitrogen protection and stirred at room temperature. Subsequently, THF solution of borane-THF complex (20 mL, 18 mmol, 0.9 M) was added and the reaction was stirred at 70 °C for 3.5 hours. After the reaction solution was cooled to 0 °C, water was added, stirred for a few moments, then 6 N hydrochloric acid was added and heated to reflux for 1 hour. The solvent was removed by distillation under reduced pressure, methanol was added and the solvent was removed by distillation again. The residue was diluted with ethyl acetate and the organic layer was washed sequentially with 1 N aqueous sodium hydroxide, water and saturated saline, dried with anhydrous sodium sulfate, and the solvent was removed by filtration of the insoluble material followed by distillation under reduced pressure to give pyrazolo[1,5-a]pyridin-2-ylmethanol. Pyrazolo[1,5-a]pyridin-2-ylmethanol was converted to pyrazolo[1,5-a]pyridine-2-carbaldehyde by the method of Reference Examples 13-3. Referring to the method of Reference Examples 1-2, the reaction of pyrazolo[1,5-a]pyridine-2-carbaldehyde and (R)-2-methylpropane-2-sulfinamide is utilized to obtain (R)-2-methyl-N-(pyrazolo[1,5-a]pyridin-2-ylmethylene)propane-2-sulfinamide. Finally, (R)-2-methyl-N-(pyrazolo[1,5-a]pyridin-2-ylmethylene)propane-2-sulfinamide was converted to pyrazolo[1,5-a]pyridine-2-carboxylic acid (yellowish oil, 498 mg, 65% yield) with reference to the methods of Reference Examples 1-3.

References

[1] Patent: EP3404021, 2018, A1. Location in patent: Paragraph 0224
[2] Journal of Medicinal Chemistry, 2001, vol. 44, # 17, p. 2691 - 2694
[3] Journal of Heterocyclic Chemistry, 1981, vol. 18, p. 1149 - 1152
[4] Patent: WO2015/66371, 2015, A1
[5] Patent: CN107778310, 2018, A. Location in patent: Paragraph 0044; 0045