4-(1-Piperidylmethyl)phenylboronic Acid → 5-(4-Piperidin-1-ylmethyl-phenyl)-2-fluoro-[3,4']bipyridinyl-3'-ylamine

HRID 1888537Notes

Reaction equation

HRID 1888537 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH2:15])[C:5]([F:8])=[N:6][CH:7]=1.[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C.[F-].[K+].O.CO.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:2]3[CH:3]=[C:4]([C:9]4[CH:14]=[CH:13][N:12]=[CH:11][C:10]=4[NH2:15])[C:5]([F:8])=[N:6][CH:7]=3)=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1

Participants

9

Reactant 2

HCID 230053434-(1-Piperidylmethyl)phenylboronic AcidHCID 582663945-Bromo-2-fluoro-[3,4]bipyridinyl-3'-ylamine

Product 1

HCID 582665135-(4-Piperidin-1-ylmethyl-phenyl)-2-fluoro-[3,4']bipyridinyl-3'-ylamineYield 65%

Reagents, catalysts & solvents 6

HCID 178418476HCID 178418476, compoundCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolventHCID 522689Potassium FluorideSolvent

Conditions

Temperature
100 °C

Procedure

A degassed mixture of 5-bromo-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (861 mg, 3.21 mmol), 4-piperidin-1-ylmethyl-phenyl boronic acid (816 mg, 3.72 mmol) and bis(triphenylphosphine)palladium(II) chloride (169 mg, 0.241 mmol) in acetonitrile (14 mL) and 1N aqueous potassium fluoride solution (8.0 mL) was heated under microwave irradiation at 100° C. for 25 minutes. The cooled reaction mixture was diluted with water and 20% methanol in DCM, the layers separated, and the aqueous phase extracted into 20% methanol in DCM. The combined organic phase was concentrated in vacuo, and the resultant residue dissolved in DCM/methanol, absorbed onto celite, and purified by flash chromatography (silica, 100 g column, Biotage, 0-20% methanol in DCM) to afford the title compound as a dark orange foam (753 mg, 65%). 1H NMR (DMSO-D6, 400 MHz): 8.58 (s, 1H), 8.20 (d, J=7.1 Hz, 1H), 8.13 (s, 1H), 7.84 (d, J=4.8 Hz, 1H), 7.74 (m, 2H), 7.43 (m, 2H), 7.07 (d, J=4.9 Hz, 1H), 5.31 (s, 2H), 3.29 (s, 2H), 2.35 (m, 4H), 1.51 (m, 4H), 1.40 (m, 2H). LCMS (Method B): RT=1.27 min, M+H+=363.

Workup

  1. customThe cooled reaction mixture
  2. customthe layers separated
  3. extractionthe aqueous phase extracted into 20% methanol in DCM
  4. concentrationThe combined organic phase was concentrated in vacuo
  5. dissolutionthe resultant residue dissolved in DCM/methanol
  6. customabsorbed onto celite
  7. custompurified by flash chromatography (silica, 100 g column, Biotage, 0-20% methanol in DCM)

Sources & evidence

ORD record
ord-9549b8c86aa74a7c9d2afd174b57a14f
Source dataset
uspto-grants-2013_08
Patent number
US08501765B2

Reaction notes

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