Uses
2,5-Dichloro-4-pyridinecarboxaldehyde, is an intermediate in the preparation of various pharmaceutical compounds. It is used in the synthesis of 2-Amino-5-aryl-pyridines as selective CB2 agonists.
Synthesis
General procedure for the synthesis of 2,5-dichloropyridine-4-carbaldehyde from 2,5-dichloropyridine and N,N-dimethylformamide: First, 2,5-dichloropyridine (27.0 g, 180 mmol) was dissolved in THF (65 mL), which was added via cannulae to a pre-cooled LDA solution at -78°C (100 mL of a 1.8 M solution of 180 mmol, dissolved in THF (80 mL)). After stirring the mixture at -78 °C for 30 min, a solution of DMF (21.1 mL, 271 mmol) in THF (25 mL) was added slowly via syringe. The reaction was kept at -78 °C for 3 h of continued stirring, followed by slow warming to room temperature. The reaction solution was slowly poured into a mixture of ice (800 mL) and hydrochloric acid (150 mL) and stirred for 20 minutes. The pH was adjusted to 9-10 with 3.0 M NaOH solution, followed by extraction with ether (2 x 500 mL). The organic layers were combined, dried and concentrated with MgSO4 to give the crude product as a light yellow solid. This solid was suspended in n-hexane with a small amount of EtOAc and boiled for 5 min before decanting the liquid and evaporating the solvent to give a yellow solid. Finally, purification by Biotage fast chromatography (using a 65i silica gel column loaded with DCM/EtOAc followed by heptane elution with an elution gradient of 20% EtOAc/heptane, 8 column volumes, and then kept at 5 column volumes) afforded the target compound, 2,5-dichloro pyridine-4-carboxaldehyde (17.9 g, 56% yield), as a light yellow solid.1H NMR ( 400 MHz, DMSO-d6) δ 7.85 (s, 1H), 8.76 (s, 1H), 10.22 (s, 1H).
References
[1] Patent: WO2011/27249, 2011, A2. Location in patent: Page/Page column 58
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 23, p. 6578 - 6581
[3] Patent: WO2006/50506, 2006, A1. Location in patent: Page/Page column 132
[4] Patent: WO2005/73232, 2005, A1. Location in patent: Page/Page column 34
