Boronic Acid → 5-Bromo-2-fluoro-[3,4]bipyridinyl-3'-ylamine

HRID 1505997Notes

Reaction equation

HRID 1505997 reaction equation
I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[F:9][C:10]1[C:15](B(O)O)=[CH:14][C:13]([Br:19])=[CH:12][N:11]=1.B(O)O>C(#N)C.[F-].[K+].C(Cl)Cl.O>[Br:19][C:13]1[CH:14]=[C:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH2:8])[C:10]([F:9])=[N:11][CH:12]=1

Participants

8

Reactant 3

HCID 61668Boronic AcidHCID 8191324-Iodopyridin-3-amineHCID 27832425-Bromo-2-fluoropyridine-3-boronic Acid (contains varying amounts of Anhydride)

Product 1

HCID 582663945-Bromo-2-fluoro-[3,4]bipyridinyl-3'-ylamineYield 69%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent2×HCID 522689Potassium FluorideSolvent

Conditions

Temperature
95 °C

Procedure

A mixture of 4-iodo-pyridin-3-ylamine (1.027 g, 4.67 mmol), 2-fluoro-5-bromopyridine-3-boronic acid (2.05 g, 9.33 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (191 mg, 0.233 mmol) in acetonitrile (12 mL) and 1N aqueous potassium fluoride solution (12 mL) was heated at 95° C. for 3 h. The reaction mixture was allowed to cool, treated with additional portions of the boronic acid (0.5 eq) and of catalyst (5.0 mol %), and heated under reflux overnight under a nitrogen atmosphere. The mixture was allowed to cool, diluted with DCM and water, and filtered to remove the solids. The filtrate layers were separated and the aqueous phase was extracted into DCM, and the combined organic phase concentrated in vacuo. The resultant residue was redissolved in 20% methanol in DCM and absorbed onto silica gel for purification by flash chromatography (silica, 100 g column, Biotage, 1-20% methanol in DCM) to afford the title compound as a brown solid (861 mg, 69%). 1H NMR (DMSO-D6, 400 MHz): 8.43 (d, J=1.1 Hz, 1H), 8.18 (dd, J=8.3 Hz, 2.5 Hz, 1H) 8.11 (s, 1H), 7.81 (d, J=4.8 Hz, 1H), 7.01 (d, J=4.8 Hz, 1H), 5.37 (s, 2H). LCMS (Method B): RT=0.95 min, M+H+=268/270.

Workup

  1. temperatureto cool
  2. temperatureheated
  3. temperatureunder reflux overnight under a nitrogen atmosphere
  4. temperatureto cool
  5. filtrationfiltered
  6. customto remove the solids
  7. customThe filtrate layers were separated
  8. extractionthe aqueous phase was extracted into DCM
  9. concentrationthe combined organic phase concentrated in vacuo
  10. dissolutionThe resultant residue was redissolved in 20% methanol in DCM
  11. customabsorbed onto silica gel for purification by flash chromatography (silica, 100 g column, Biotage, 1-20% methanol in DCM)

Sources & evidence

ORD record
ord-79ee88a044194c1cb5d4895c0433c5fe
Source dataset
uspto-grants-2015_12
Patent number
US09216980B2

Reaction notes

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