1101120-03-9

68-12-2

1101120-05-1

1. Decarboxylation: The ester compound (1 eq.) is dissolved in 40% aqueous H2SO4 (3 mL) and refluxed for 18 hours. Upon completion of the reaction, the solution was cooled in an ice bath, neutralized to pH 7 with 6 M NaOH and subsequently extracted twice with CH2Cl2. The organic phases were combined, dried with Na2SO4 and concentrated under reduced pressure to give the decarboxylated product. 2. Vilsmeier Formylation: The decarboxylation product was dissolved in anhydrous DMF (2 mL) under N2 protection, cooled to 0 °C and POCl3 (3 eq.) was added. The reaction mixture was gradually warmed to room temperature and stirred for 2 hours. The reaction solution was poured into ice water, the pH was adjusted to 10 with 1 M NaOH and stirred for 1 h. The reaction solution was extracted twice with CH2Cl2. The organic phases were combined, washed twice with water, dried over Na2SO4 and concentrated under reduced pressure to give 3-formylpyrazolo[1,5-a]pyridine-5-carbonitrile. 3. Alternative route - ester hydrolysis: The ester compound (1 eq.) was dissolved in a solution of EtOH (5 mL) in 1 M NaOH (3 eq.) and refluxed for 6 hours. The EtOH was removed under reduced pressure and the residual aqueous phase was acidified to pH 1 with 1 M HCl. The precipitated carboxylic acid was collected by filtration, washed with water and dried. 4. Carboxylic acid reduction: Carboxylic acid (1 eq.) was suspended in anhydrous THF (10 mL) under N2 protection, CDI (1.5 eq.) was added, and the reaction was stirred for 18 hours. The reaction solution was added dropwise to a solution of NaBH4 (5 eq.) in water (10 mL) and stirred for 30 min. The reaction was quenched with 1 M HCl and stirring was continued for 30 min. Neutralize with saturated aqueous NaHCO3 and extract twice with CH2Cl2. The organic phases were combined, dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography (hexane:EtOAc gradient elution) to give the alcohol. 5. Oxidation of alcohol: Pyrazolo[1,5-a]pyridine-3-methanol (1 eq.) was stirred with MnO2 (10 eq.) in CH2Cl2 (2 mL) at room temperature for 4 days. The reaction mixture was filtered through diatomaceous earth, washed with CH2Cl2 and the filtrate was concentrated under reduced pressure to give the target aldehyde.