Ethanolamine → 5-(8-(2-Hydroxyethylamino)isoquinolin-3-ylamino)pyrazine-2-carbonitrile

HRID 40681Notes

Reaction equation

HRID 40681 reaction equation
CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:44]1[CH:45]=[CH:46][CH:47]=[C:48]2[C:53]=1[CH:52]=[N:51][C:50]([NH:54][C:55]1[N:56]=[CH:57][C:58]([C:61]#[N:62])=[N:59][CH:60]=1)=[CH:49]2.[CH2:63]([CH2:65][NH2:66])[OH:64].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CN(C=O)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]>[OH:64][CH2:63][CH2:65][NH:66][C:44]1[CH:45]=[CH:46][CH:47]=[C:48]2[C:53]=1[CH:52]=[N:51][C:50]([NH:54][C:55]1[N:56]=[CH:57][C:58]([C:61]#[N:62])=[N:59][CH:60]=1)=[CH:49]2

Participants

8

Reactant 4

HCID 700EthanolamineHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 442046545-(8-Bromoisoquinolin-3-ylamino)pyrazine-2-carbonitrile

Product 1

HCID 442045575-(8-(2-Hydroxyethylamino)isoquinolin-3-ylamino)pyrazine-2-carbonitrileYield 17%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
140 °C

Procedure

A mixture of tris(dibenzylideneacetone)dipalladium (0) (18 mg, 0.020 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (23 mg, 0.040 mmol) in toluene (1 mL) and DMF (1 mL) was degassed under a stream of nitrogen gas with stirring for 15 minutes. 5-(8-Bromoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (65 mg, 0.20 mmol), ethanolamine (61 mg, 1.00 mmol) and caesium carbonate (130 mg, 0.40 mmol) were added and the mixture was degassed for a further 5 minutes, then heated at 140° C. for 40 minutes in a microwave reactor. Upon cooling the reaction mixture was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate (2.5%) and filtered through celite. The aqueous phase was re-extracted with ethyl acetate and then the combined organic phases were washed sequentially with aqueous sodium hydrogencarbonate and brine. The organic phase was dried (Na2SO4) and passed sequentially through two PS-Thiol cartridges and concentrated to dryness. Preparative HPLC gave the title compound (8.14 mg, 0.034 mmol, 17%). 1H NMR (d6-DMSO, 400 MHz) δ 10.94 (br s, 1H), 9.41 (s, 1H), 8.80 (s, 1H), 8.70 (s, 1H), 8.29 (s, 1H), 7.43-7.46 (m, 1H), 6.98 (d, 1H, J=8.4 Hz), 6.70 (br t, 1H), 6.50 (d, 1H, J=7.6 Hz), 4.82 (t, 1H, J=5.8 Hz), 3.65-3.70 (m, 2H), 3.25-3.30 (m, 2H, partially obscured by water signal). LC-MS (2) Rt=2.27 min; m/z (ESI+) 308 (M+H).

Workup

  1. customwas degassed under a stream of nitrogen gas
  2. customthe mixture was degassed for a further 5 minutes
  3. temperatureUpon cooling the reaction mixture
  4. customwas partitioned between ethyl acetate and aqueous sodium hydrogen carbonate (2.5%)
  5. filtrationfiltered through celite
  6. extractionThe aqueous phase was re-extracted with ethyl acetate
  7. washthe combined organic phases were washed sequentially with aqueous sodium hydrogencarbonate and brine
  8. dry with materialThe organic phase was dried (Na2SO4)
  9. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-7fabecbbd3b0425f8d916299eb235101
Source dataset
uspto-grants-2013_09
Patent number
US08530468B2

Reaction notes

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