Tetrahydrofuran → 5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline

HRID 751288Notes

Reaction equation

HRID 751288 reaction equation
C1COCC1.[N:6]1[C:15]2[C:10](=[C:11](OS(C(F)(F)F)(=O)=O)[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][CH:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[C:31](B(O)O)=[C:32]2[CH2:37][CH2:36][CH2:35][N:33]2[N:34]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C.C1COCC1>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[C:31]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:10]=2[N:9]=[CH:8][CH:7]=[N:6]3)=[C:32]2[CH2:37][CH2:36][CH2:35][N:33]2[N:34]=1

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 11430Potassium CarbonateHCID 58611956Trifluoro-methanesulfonic Acid Quinoxalin-5-yl EsterHCID 59710031(2-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid

Product 1

HCID 104482875-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxalineYield 7%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 21974620tetrahydrofuran N,N-dimethylformamideSolvent

Procedure

Add THF (2.2 mL) to trifluoro-methanesulfonic acid quinoxalin-5-yl ester (292 mg, 1.05 mmol) and purge the solution with nitrogen for 10 min. Add tris(dibenzylideneacetone)dipalladium(0) (80 mg, 0.087 mmol) and bis(1,2-bis(diphenylphosphino)ethane)palladium(0) (78 mg, 0.087 mmol), purge the reaction with nitrogen for 2 min, and stir the reaction at room temperture for 20 min. Add 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5; 200 mg, 0.87 mmol) in 1:1 DMF/THF (2 mL) and stir for 10 min. Add 2.0M aqueous potassium carbonate (1.04 mL, 2.1 mmol) and heat the reaction to 65° C. Add additional tris(dibenzylideneacetone)dipalladium(0) (80 mg, 0.087 mmol) after 1 h and 3 h. Stir the reaction at 65° C. for 18 h, filter through Celite® with methanol/chloroform, and concentrate in vacuo. Purify by flash column chromatography followed by reverse-phase preparative HPLC. Concentrate the pure fractions from the preparative HPLC in vacuo, take up in methanol, treat with MP-carbonate beads, filter, and concentrate in vacuo to provide the title compound (11 mg, 7%) as a clear, colorless oil. MS APCI+ m/e 314 (M+1). 1H NMR (DMSO-d6) δ 8.78 (m, 1H), 8.68 (m, 1H), 8.54 (m, 1H), 8.08 (m, 1H), 7.72 (m, 3H), 7.53 (m, 1H), 7.22 (m, 1H), 4.37 (m, 2H), 2.95 (m, 2H), 2.64 (m, 2H). HPLC: 98.6%, Rt=13.5 min. TLC (SiO2): Rf0.2 (1:3 [80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane).

Workup

  1. custompurge the solution with nitrogen for 10 min
  2. customthe reaction with nitrogen for 2 min
  3. customthe reaction at room temperture for 20 min
  4. temperatureheat
  5. customthe reaction to 65° C
  6. custom3 h
  7. stirringStir
  8. customthe reaction at 65° C. for 18 h
  9. filtrationfilter through Celite® with methanol/chloroform
  10. concentrationconcentrate in vacuo
  11. customPurify by flash column chromatography
  12. concentrationConcentrate the pure fractions from the preparative HPLC in vacuo
  13. additiontreat with MP-carbonate beads
  14. filtrationfilter
  15. concentrationconcentrate in vacuo

Sources & evidence

ORD record
ord-7028b8bd2a2c4a90a3b1b414095077a2
Source dataset
uspto-grants-2008_07
Patent number
US07405299B2

Reaction notes

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