反应详情

To a solution of ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, Step A, 275 mg, 1.33 mmol) in anhydrous DMF (5 mL) was added (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (646 mg, 1.46 mmol). The heterogeneous mixture was stirred for 10 minutes before adding DIEA (1.16 mL, 6.6 mmol), followed by addition of (R)-2-chloro-5-fluoro-3-(pyrrolidin-2-yl)pyridine dihydrochloride (363 mg, 1.33 mmol). The reaction was stirred at ambient temperature overnight to reach completion. The mixture was partitioned between 10% citric acid (30 mL) and EtOAc (30 mL), and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic phases were washed successively with water (20 mL), saturated NaHCO3 (20 mL), water (20 mL) and brine (3×20 mL), then dried (Na2SO4) and concentrated to afford the crude product as an orange foam. The crude material was purified on a 25 g Biotage SNAP silica cartridge eluting with 1% MeOH/DCM to afford the desired product as cream-colored foam (0.35 g, 68% yield). MS (apci) m/z=390.0 (M+H).

1. stirringThe reaction was stirred at ambient temperature overnight
2. customThe mixture was partitioned between 10% citric acid (30 mL) and EtOAc (30 mL)
3. extractionthe aqueous layer was extracted with EtOAc (2×20 mL)
4. washThe combined organic phases were washed successively with water (20 mL), saturated NaHCO3 (20 mL), water (20 mL) and brine (3×20 mL)
5. dry with materialdried (Na2SO4)
6. concentrationconcentrated
7. customto afford the crude product as an orange foam
8. customThe crude material was purified on a 25 g Biotage SNAP silica cartridge
9. washeluting with 1% MeOH/DCM