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

Temperature

100 °C

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).

1. temperaturecooled
2. custombefore partitioning between ethyl acetate (25 ml) and water (25 ml) whereupon an emulsion
3. customformed
4. customseparation
5. customThe two layers were separated
6. washthe aqueous layer washed with ethyl acetate (20 ml)
7. washwashed with 1M aqueous hydrochloric acid (3×25 ml)
8. additionTo the combined aqueous layers was added ethyl acetate (25 ml)
9. stirringthe resulting biphasic mixture was stirred vigorously
10. addition10M aqueous sodium hydroxide solution (14.5 ml) was added to this stirred mixture until the pH of the now-warm mixture
11. customto separate
12. washThe separated aqueous layer washed with ethyl acetate (20 ml)
13. washThe combined organic layers were washed with water (20 ml)
14. concentrationThe organic layer was concentrated to dryness
15. customto give an orange oil which
16. washwashed with a minimal amount of water
17. customseparation
18. customThe organic layer was separated
19. concentrationconcentrated to dryness

ORD record

ord-d071f32838b74bea8a53928dffe25624

Source dataset

uspto-grants-2011_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08003663B2