Nitrogen → HCID 21928167, compound

HRID 1243801Notes

Reaction equation

HRID 1243801 reaction equation
[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][CH:23]([C:25]4[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=4)[OH:24])[CH2:17][CH2:16]3)=[CH:8][C:9]=2[C:11]([F:14])([F:13])[F:12])[S:4][C:3]=1[C:32]([NH2:34])=[O:33].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].N#N.Br[C:61]1[CH:69]=[C:68]2[C:64]([CH2:65][C:66](=[O:70])[NH:67]2)=[CH:63][CH:62]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][CH:23]([OH:24])[C:25]4[CH:30]=[CH:29][C:28]([C:61]5[CH:69]=[C:68]6[C:64]([CH2:65][C:66](=[O:70])[NH:67]6)=[CH:63][CH:62]=5)=[CH:27][N:26]=4)[CH2:17][CH2:16]3)=[CH:8][C:9]=2[C:11]([F:14])([F:13])[F:12])[S:4][C:3]=1[C:32]([NH2:34])=[O:33]

Participants

10

Reactant 6

HCID 947NitrogenHCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 27732896-bromo-2,3-dihydro-1H-indol-2-oneHCID 21064678HCID 21064678, compound

Product 1

HCID 21928167HCID 21928167, compoundYield 12.5%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent2×

Conditions

Temperature
80 °C

Procedure

An N2-purged suspension of 3-Amino-6-{4-[2-(5-bromo-pyridin-2-yl)-2-hydroxy-ethylamino]-piperidin-1-yl}-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (150 mg, 0.268 mmol), bis(pinacolato)diboron (153 mg, 0.590 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-CH2Cl2 complex (33 mg, 0.040 mmol), and potassium acetate (133 mg, 1.34 mmol) in dry DMF (4 ml) was heated at 80° C. for 2.5 h. The crude reaction mixture was then added directly via syringe to a stirring, N2-purged suspension of 6-bromo-2-oxindole (65 mg, 0.295 mmol), tetrakis(triphenylphosphine)palladium(0) (47 mg, 0.040 mmol), and potassium carbonate (74 mg, 0.536 mmol) in dry DMF (6 ml) and water (2 ml) at rt. The sealed mixture was heated to 85° C. for 4 h. The crude reaction was applied direcly to a SiO2 column and purified (0–25% MeOH/CH2Cl2 with NH4OH). Fractions containing desired product were pooled and concentrated. The yellow residue was dissolved in 2 ml DMF and applied to a 2 mm prep plate (Merck) eluting with 10% MeOH/CH2Cl2 with 1% NH4OH. The yellow product crystallized at the origin and the impurities were removed by being carried up the plate. The recovered yellow residue was dissolved in 1 ml DMF, 2 ml MeOH, 5 ml EtOAc, and 5 ml CH2Cl2 and crystallized by the addition of 30 ml hexanes to give 20.5 mg, 11.9% of 3-Amino-6-(4-{2-hydroxy-2-[5-(2-oxo-2,3-dihydro-1H-indol-6-yl)-pyridin-2-yl]-ethylamino}-piperidin-1-yl)-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylic acid amide product. ES+ 612.4 m/z (MH+).

Workup

  1. customAn N2-purged
  2. customThe crude reaction mixture
  3. custompurged
  4. temperatureThe sealed mixture was heated to 85° C. for 4 h
  5. customThe crude reaction
  6. custompurified (0–25% MeOH/CH2Cl2 with NH4OH)
  7. additionFractions containing desired product
  8. concentrationconcentrated
  9. dissolutionThe yellow residue was dissolved in 2 ml DMF
  10. washeluting with 10% MeOH/CH2Cl2 with 1% NH4OH
  11. customThe yellow product crystallized at the origin
  12. customthe impurities were removed
  13. dissolutionThe recovered yellow residue was dissolved in 1 ml DMF
  14. custom2 ml MeOH, 5 ml EtOAc, and 5 ml CH2Cl2 and crystallized by the addition of 30 ml hexanes

Sources & evidence

ORD record
ord-d692eaae658541cb83cf73e3b5492d4f
Source dataset
uspto-grants-2006_10
Patent number
US07119102B2

Reaction notes

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