Potassium Fluoride → HCID 10070332, compound

HRID 751292Notes

Reaction equation

HRID 751292 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:18])[CH2:14][N:15]([CH3:17])[CH3:16])[CH:6]=[CH:5]2.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[C:26](B(O)O)=[C:27]2[CH2:32][CH2:31][CH2:30][N:28]2[N:29]=1.[F-].[K+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>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].C1COCC1>[CH3:16][N:15]([CH3:17])[CH2:14][C:13]([NH:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[N:10][CH:11]=[C:2]([C:26]3[C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=4)=[N:29][N:28]4[CH2:30][CH2:31][CH2:32][C:27]=34)[CH:3]=2)[N:8]=1)=[O:18]

Participants

7

Reactant 4

HCID 522689Potassium FluorideHCID 2734635Tri-tert-butylphosphine tetrafluoroborate2×HCID 58611972HCID 58611972, compoundHCID 59710031(2-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid

Product 1

HCID 10070332HCID 10070332, compoundYield 5.5%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 8028TetrahydrofuranSolvent

Procedure

Add N-(6-bromo-[1,8]naphthyridin-2-yl)-2-dimethylamino-acetamide (148 mg, 0.48 mmol), 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5; 100 mg, 0.44 mmol), potassium fluoride (84 mg, 1.45 mmol), and THF (1.5 mL) to a flask under nitrogen. Purge the system with nitrogen for 10 min and add tris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.044 mmol) and tri-tert-butylphosphonium tetrafluoroborate (Strem; 25 mg, 0.088 mmol). Purge the system with nitrogen for 2 min then stir for 16 h at room temperature. Add additional tris(dibenzylideneacetone)dipalladium(0) (50 mg, 0.054 mmol) and tri-tert-butylphosphonium tetrafluoroborate (40 mg, 0.138 mmol) and heat the reaction to 65° C. for 9 h. Filter the reaction through Celite®, rinse with chloroform/methanol, and concentrate in vacuo. Purify by flash column chromatography followed by reverse-phase preparative HPLC. Collect the pure fractions from the HPLC, concentrate in vacuo, take up the residue in methanol, and treat with MP-carbonate beads. Filter, concentrate in vacuo, and triturate with hexanes to provide the title compound (10 mg, 5%) as a tan solid. MS ESI+ m/e 414 (M+1). 1H NMR (CDCl3) δ 10.21 (m, 1H), 8.93 (m, 1H), 8.48 (m, 2H), 8.09 (m, 2H), 7.68 (m, 2H), 7.20 (m, 1H), 4.27 (m, 2H), 3.17 (m, 4H), 2.72 (m, 2H), 2.41 (s, 6H). HPLC: 95.1%, Rt=11.21 min. TLC (SiO2): Rf0.3 (1:1 [80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane)

Workup

  1. customPurge the system with nitrogen for 10 min
  2. customPurge the system with nitrogen for 2 min
  3. temperatureheat
  4. customthe reaction to 65° C. for 9 h
  5. filtrationFilter
  6. customthe reaction through Celite®
  7. washrinse with chloroform/methanol
  8. concentrationconcentrate in vacuo
  9. customPurify by flash column chromatography
  10. customCollect the pure fractions from the HPLC
  11. concentrationconcentrate in vacuo
  12. additiontreat with MP-carbonate beads
  13. filtrationFilter
  14. concentrationconcentrate in vacuo
  15. customtriturate with hexanes

Sources & evidence

ORD record
ord-70059814244b459bb87692fcb395239d
Source dataset
uspto-grants-2008_07
Patent number
US07405299B2

Reaction notes

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