Sodium Chloride → Ethyl 1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

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Reaction Conditions

Reaction Steps

Ethyl 4-chloro-1,6-diethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate [0.75 g, 2.66 mmol, 1.0 equivalent] was dissolved in 1-methyl-2-pyrrolidinone (NMP, 4 ml). 4-Amino-tetrahydro-2H-pyran acetate (0.51 g, 3.19 mmol, 1.2 equivalents) was added in one portion to the stirred solution at room temperature. The reaction mixture was stirred for 15 minutes and then potassium carbonate (1.10 g, 7.99 mmol, 3.0 equivalents) was added in one portion. The reaction mixture was heated to and at 100° C. for 16 hours, and then cooled before partitioning between ethyl acetate (25 ml) and water (25 ml) whereupon an emulsion formed. To this biphase mixture/emulsion was added brine, followed by water (20 ml) and then ethyl acetate (20 ml), to aid separation. The two layers were separated and the aqueous layer washed with ethyl acetate (20 ml). The organic layers were combined and washed with 1M aqueous hydrochloric acid (3×25 ml). To the combined aqueous layers was added ethyl acetate (25 ml); the resulting biphasic mixture was stirred vigorously, and then 10M aqueous sodium hydroxide solution (14.5 ml) was added to this stirred mixture until the pH of the now-warm mixture was measured to be about 13. The mixture was allowed to separate. The separated aqueous layer washed with ethyl acetate (20 ml). The combined organic layers were washed with water (20 ml) followed by brine (20 ml). The organic layer was concentrated to dryness to give an orange oil which visually appeared to contain sodium chloride or similar crystals. This oil was dissolved in ethyl acetate and washed with a minimal amount of water; separation was poor. The organic layer was separated and concentrated to dryness, to give the title compound as an orange oil (still containing some crystals) which solidified after standing overnight at room temperature (0.58 g, about 63% yield).

Provenance & Evidence