6-BroMopyrazolo[1,5-a]pyridine

Description

6-BroMopyrazolo[1,5-a]pyridine is a key synthetic building block which, when coupled to an oxazolidinone core via the Suzuki–Miyaura coupling reaction, can be used to construct novel oxazolidinone antimicrobial compounds bearing a fused heteroaromatic C-ring [2].

Uses

6-Bromopyrazolo[1,5-a]pyridine was a useful reagent in discovery of p110a-selective PI3 kinase inhibitors.

Synthesis

The general procedure for the synthesis of 6-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid from ethyl 6-bromopyrazolo[1,5-a]pyridine is as follows: all reactions were carried out under decarboxylation/Vilsmeier conditions or hydrolysis/reduction/re-oxidation unless otherwise indicated. 1. Decarboxylation: Ethyl 6-bromopyrazolo[1,5-a]pyridine-3-carboxylate (1 equiv.) was 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 then extracted twice with CH2Cl2. The organic phases were combined, dried with anhydrous Na2SO4 and concentrated under reduced pressure to give the decarboxylated product. 2. Vilsmeier reaction: Under the protection of nitrogen, the above decarboxylation product was dissolved in anhydrous DMF (2 mL), cooled to 0 °C, and POCl3 (3 equiv.) was added slowly. 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 anhydrous Na2SO4 and concentrated under reduced pressure to give the aldehyde product. Alternative route: 1. Hydrolysis of the ester: Ethyl 6-bromopyrazolo[1,5-a]pyridine-3-carboxylate (1 eq.) was dissolved in a mixture of 1 M NaOH (3 eq.) and EtOH (5 mL) and refluxed for 6 hours. 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. 2. Reduction of carboxylic acid: The above carboxylic acid (1 eq.) was suspended in anhydrous THF (10 mL) under nitrogen protection, CDI (1.5 eq.) was added, and stirred for 18 hours. The resulting solution was added dropwise to a solution of NaBH4 (5 eq.) in water (10 mL) and stirred for 30 min. The reaction solution was quenched with 1 M HCl and stirring was continued for 30 min. The solution was neutralized with saturated aqueous NaHCO3 and extracted twice with CH2Cl2. The organic phases were combined, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography (hexane:EtOAc gradient elution) to give the alcohol product. 3. Reoxidation of alcohols: A suspension of pyrazolo[1,5-a]pyridine-3-methanol (1 eq.) with MnO2 (10 eq.) in CH2Cl2 (2 mL) was stirred 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 aldehyde product.

References

[1] Bioorganic and Medicinal Chemistry,  2012,  vol. 20,  # 1,  p. 69 - 85
[2] Suzuki*, H., Utsunomiya, I., Shudo, K. (2013). Potent Oxazolidinone Antibacterials with Heteroaromatic C-Ring Substructure. ACS Medicinal Chemistry Letters, 4 11, 1074–1078. https://doi.org/10.1021/ml400280z