反应详情

Stir together 3′-chloro-4-(1-phenyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (177 mg, 0.50 mmol), 4-(cyanomethyl)benzene boronic acid (97 mg, 0.60 mmol), potassium carbonate (166 mg, 1.20 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.006 g, 0.003 mmol) and water (1 mL), in N,N-dimethylacetamide (2 mL) at room temperature under nitrogen, then heat at 120° C. for 3 hr. Cool to room temperature, add water (20 mL) and extract with DCM (3×20 mL). Pass the combined DCM extracts through an IST Phase Separator Frit®, concentrate and purify (silica gel chromatography, eluting with 5:95 to 15:85 methanol:DCM). Dry in a vacuum oven over night, then further purify by low pH reverse phase HPLC. Form the free base by passing through an SCX-2® ion exchange cartridge washing with methanol then eluting with 2 M ammonia in methanol and concentrate. Dissolve the solid in acetonitrile and convert to the hydrochloride salt by adding 2 M aq HCl solution. Add water and lyophilize to give the title compound as a bright yellow solid (136 mg, 58%). MS (ES): m/z=436 [M+H]+.

1. extractionextract with DCM (3×20 mL)
2. concentrationconcentrate
3. custompurify
4. wash(silica gel chromatography, eluting with 5:95 to 15:85 methanol:DCM)
5. customDry in a vacuum oven over night
6. customfurther purify by low pH reverse phase HPLC
7. washwashing with methanol
8. washthen eluting with 2 M ammonia in methanol
9. concentrationconcentrate
10. dissolutionDissolve the solid in acetonitrile
11. additionby adding 2 M aq HCl solution