Phosphorus oxychloride → 6-chloro-1-isopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

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Reaction Conditions

Reaction Steps

3-Methyl-1-(1-methylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (1.5 g, 6.38 mmol) was added to a solution of THF (15 mL) followed by addition of phosphorous oxychloride (8.9 mL, 96 mmol), and the contents heated at 105° C. overnight. After cooling to room temperature, the contents were concentrated in vacuo to remove most of the volatiles. The residual contents were slowly poured into a solution of iced water and 1N NaOH (10 mL), and the contents were stirred at room temperature for 24 h, during which time solid precipitation ensued. Additional 1N NaOH was added, upon which the solids went into solution. After stirring at room temperature for an additional 30 min., the contents were cooled in an ice bath and the mixture slowly acidified to pH=3-4 by slow addition of 6N HCl, to afford a heterogenous mixture. The mixture was filtered and a white solid set aside. The aq. layer was further extracted with EtOAc and DCM. The combined organic layers dried were dried over MgSO4, filtered and concentrated in vacuo. The resultant light brown solid was triturated in EtOAc/EtOH (1:1) and filtered to afford a first crop of white solid product, which was set aside. The filtrate was again concentrated in vacuo. The residue was diluted with EtOAc, sonicated, treated with hexanes, and filtered. The process was repeated. The isolated solid product crops were dried under vacuum (3 h) and collected as 1.33 g (80%). LCMS E-S (M+H): 254.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (d, 6H), 2.60 (s, 3H), 5.10 (quin, J=6.63 Hz, 1H), 7.50 (s, 1H), 14.17 (br. s., 1H).

Provenance & Evidence