反応 #674295

ord-a37fc8f051724aec9244c9a4b3868890

反応方程式

O=C([O-])[O-].[Na+].[Na+]
Na2CO3
N#N
N2
CC(C)(C)OC(=O)N1CC2(CC(n3cc(Br)cn3)C2)C1
tert-Butyl 6-(4-bromo-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate
CC(Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N)c1c(Cl)ccc(F)c1Cl
(±)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
N#N
N2
CC(Oc1cc(-c2cnn(C3CC4(C3)CN(C(=O)OC(C)(C)C)C4)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
(±)-tert-butyl 6-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate
収率 45.0%

溶媒

反応条件

温度
90°CELSIUS
詳細条件
See reaction.notes.procedure_details.

後処理

  1. 1
    その他It was degassed again
  2. 2
    workup.ADDITIONrefilled with N2 (2 times)
  3. 3
    温度(heating bath) for 16 hrs
  4. 4
    温度The reaction mixture was cooled to room temperature
  5. 5
    workup.ADDITIONH2O (30 mL) was added
  6. 6
    抽出The aqueous phase was extracted with EtOAc (30 mL) and DCM (3×30 mL)
  7. 7
    乾燥The combined organic phase was dried over anhydrous Na2SO4
  8. 8
    濃縮concentrated by evaporation in vacuo
  9. 9
    その他to give black residue which
  10. 10
    その他was purified by CombiFlash (40 g silica gel column, Hexane/EtOAc)

実験手順

tert-Butyl 6-(4-bromo-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (145 mg, 0.42 mmol) and (±)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (268 mg, 0.63 mmol) were added to a round bottom flask. It was vacuumed and refilled with N2 (3 times). DME (2.0 mL) and a solution of Na2CO3 (2.0 M, 1.0 mL) were sequentially added. It was vacuumed and refilled with N2 (3 times). Pd(PPh3)2Cl2 (14.7 mg, 0.021 mmol) was added. It was degassed again refilled with N2 (2 times). The mixture was stirred at 90° C. (heating bath) for 16 hrs. The reaction mixture was cooled to room temperature and H2O (30 mL) was added. The aqueous phase was extracted with EtOAc (30 mL) and DCM (3×30 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated by evaporation in vacuo to give black residue which was purified by CombiFlash (40 g silica gel column, Hexane/EtOAc) to afford (±)-tert-butyl 6-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (106 mg, 45%) as a off-white solid.

出典

DOI: 10.6084/m9.figshare.5104873.v1特許: US09226923B2uspto-grants-2016_01