1H-Pyrrolo[3,2-b]pyridine-2-carboxylic acid

Uses

1H-Pyrrolo[3,2-b]pyridine-2-carboxylic Acid is a useful organic reagent for synthesis of substituted 4- and 6-azaindoles and indolecarboxamides as H4 receptor ligands.

Synthesis

General procedure for the synthesis of 4-azaindole-2-carboxylic acid from ethyl 4-azaindole-2-carboxylate: 3-amino-2-chloropyridine (150 mg, 1.17 mmol), ethyl pyruvate (0.25 mL, 2.00 mmol), pyridinium p-toluenesulfonate (73 mg, 0.29 mmol), and tetraethoxysilane (0.26 mL, 1.18 mmol) were suspended in 0.4 mL of pyridine and stirred at 20 °C for 24 hours. Tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) and N,N-dicyclohexylmethylamine (0.35 mL, 2.06 mmol) were subsequently added, and the reaction mixture was placed in a microwave reactor, heated to 160 °C, and held for 20 min. After completion of the reaction, the reaction mixture was diluted with 100 mL of dichloromethane and extracted twice with 50 mL of half-saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (P3) to afford ethyl 1H-pyrrolo[3,2-b]pyridine-2-carboxylate (190 mg, 1.00 mmol). The ester was dissolved in a mixture of 17 mL ethanol and 5 mL water and lithium hydroxide (120 mg, 5.00 mmol) was added. After 16 hours of reaction, the pH of the reaction mixture was adjusted to 4 and the solvent was evaporated under vacuum. The crude product was purified by acidic ion exchange resin (Strata-X-C, Phenomenex) to afford 4-azaindole-2-carboxylic acid (155 mg, 82% yield). Product purity >95%; mass spectrum (ESI) m/z 163 (M + H)+; 1H NMR (DMSO) δ (ppm) 13.34 (br, 1H), 8.77 (d, J = 5.3 Hz, 1H), 8.53 (d, J = 8.3 Hz, 1H), 7.73 (dd, J = 5.4 Hz, J = 8.3 Hz, 1H), 7.33 ( br, 1H); 13C NMR (500 MHz, DMSO) δ (ppm) 161.4 (s), 138.0 (s), 136.1 (s), 135.8 (s), 132.7 (s), 128.6 (s), 119.6 (s), 101.2 (s).

References

[1] European Journal of Medicinal Chemistry, 2012, vol. 54, p. 660 - 668
[2] Patent: WO2004/104001, 2004, A2. Location in patent: Page 42-43