Acetic Acid → 2-(3-(4-(7-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(oxetan-3-yl)azetidin-3-yl)acetonitrile

Participants

Reaction Steps

To a suspension of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62, 78.4 mg, 0.181 mmol) in dry MeOH (1.0 mL) was sequentially added 3-oxetanone (39.2 mg, 0.544 mmol) and acetic acid (0.30 mL). The mixture was stirred at ambient temperature for 5 minutes and sodium cyanoborohydride (72.0 mg, 1.29 mmol) was added slowly in portions over 5 minutes. The mixture was stirred at ambient temperature for 16 hours and additional 3-oxetanone (2.0 equivalents) was added. Stirring was continued for 4 hours and the mixture concentrated to dryness. The residual solids were partitioned into DCM and 1M K2CO3 (3 mL each) and 1M NaOH was added to adjust the pH to 13. The mixture was stirred until both layers were homogeneous, the DCM layer was removed and the aqueous layer was extracted with DCM. The DCM extracts were combined and dried over Na2SO4. The solution was eluted through a silica gel plug eluting with DCM, 10% MeOH/EtOAc, and then 20% (9:1 MeOH/NH4OH)/EtOAc. The 20% pool was concentrated to give a colorless glass. The glass was dissolved in minimal DCM and treated with hexanes to give a granular white precipitate. The suspension was concentrated to afford the title compound (54 mg, 72% yield) as a white solid. MS (apci) m/z=416.2 (M+H).

Provenance & Evidence