Cesium carbonate → 1-(6-(5-(6-isopropoxypyrazin-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-amine

温度

80 °C

A mixture of CuI (Aldrich, 26.6 mg, 0.27 mmol), cesium carbonate (Aldrich, 351 mg, 1.08 mmol), 1,1′-bis(diphenylphosphino)ferrocene (14.9 mg, 0.03 mmol), palladium(II) acetate (Strem Chemicals, 3.0 mg, 0.01 mmol), 2-isopropoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine (Combi-Phos, 142 mg, 0.54 mmol), and tert-butyl 1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (compound 1e, 150 mg, 0.27 mmol) in a 5 mL conical microwave vial was sealed, evacuated and back-filled with N2 3×. DMF (2.7 mL) was added, and the reaction mixture was stirred at 80° C. for 16 h. The resulting reaction mixture was cooled to RT, filtered, and concentrated to dryness. The crude product was purified by HPLC (5 to 80% 0.1% TFA:Water:0.1% TFA:ACN over 25 min). The fractions were combined, washed with sat. aq. NaHCO3 and extracted with 20% IPA in chloroform. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to a tan oil. The oil was dissolved in MeOH/DCM before adding 6 N HCl in IPA and stirring at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure before resolubilizing with MeOH and passing through a MeOH washed plug of Si-propylsulfonic acid. The compound was released with 2M NH3 in MeOH (30 mL) to afford 1-(6-(5-(6-isopropoxypyrazin-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-amine as a dark tan solid. MS (ESI, pos. ion) m/z: 431 (M+1).

1. customwas sealed
2. customevacuated
3. additionback-filled with N2 3×
4. additionDMF (2.7 mL) was added
5. customThe resulting reaction mixture
6. temperaturewas cooled to RT
7. filtrationfiltered
8. concentrationconcentrated to dryness
9. customThe crude product was purified by HPLC (5 to 80% 0.1% TFA:Water:0.1% TFA:ACN over 25 min)
10. washwashed with sat. aq. NaHCO3
11. extractionextracted with 20% IPA in chloroform
12. dry with materialThe combined organics were dried over Na2SO4
13. filtrationfiltered
14. concentrationconcentrated under reduced pressure to a tan oil
15. dissolutionThe oil was dissolved in MeOH/DCM
16. additionbefore adding 6 N HCl in IPA
17. stirringstirring at 80° C. for 2 h
18. concentrationThe reaction mixture was concentrated under reduced pressure

ORDレコード

ord-0fdcc7d2316d4df6be21c40b0766f6d7

出典データセット

uspto-grants-2015_07

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09090593B2