Cesium carbonate → (R)-3-(1-(Dimethylamino)propan-2-yloxy)-5-(8-methoxyisoquinolin-3-ylamino)pyrazine-2-carbonitrile

HRID 40689Notes

Reaction equation

HRID 40689 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.FC(F)(F)S(O[C:49]1[N:50]=[CH:51][C:52]2[C:57]([CH:58]=1)=[CH:56][CH:55]=[CH:54][C:53]=2[O:59][CH3:60])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:69][C:70]1[N:71]=[C:72]([O:78][C@H:79]([CH3:84])[CH2:80][N:81]([CH3:83])[CH3:82])[C:73]([C:76]#[N:77])=[N:74][CH:75]=1>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]>[CH3:83][N:81]([CH3:82])[CH2:80][C@H:79]([O:78][C:72]1[C:73]([C:76]#[N:77])=[N:74][CH:75]=[C:70]([NH:69][C:49]2[N:50]=[CH:51][C:52]3[C:57]([CH:58]=2)=[CH:56][CH:55]=[CH:54][C:53]=3[O:59][CH3:60])[N:71]=1)[CH3:84]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 56926516(R)-5-amino-3-((1-(dimethylamino)propan-2-yl)oxy)pyrazine-2-carbonitrileHCID 59636363HCID 59636363, compound

Product 1

HCID 44204749(R)-3-(1-(Dimethylamino)propan-2-yloxy)-5-(8-methoxyisoquinolin-3-ylamino)pyrazine-2-carbonitrileYield 2%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
130 °C

Procedure

A mixture of tris(dibenzylideneacetone)dipalladium (0) (7.9 mg, 0.009 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (10 mg, 0.017 mmol) in toluene (1 mL) and DMF (1 mL) was degassed under a stream of nitrogen gas with stirring for 15 minutes. 8-Methoxyisoquinolin-3-yl trifluoromethanesulfonate (26.6 mg, 0.087 mmol), cesium carbonate (28 mg, 0.087 mmol) and (R)-5-amino-3-(1-(dimethylamino)propan-2-yloxy)pyrazine-2-carbonitrile (19 mg, 0.087 mmol) were added and the mixture degassed for a further 5 minutes. The mixture was heated at 130° C. for 30 minutes in a microwave reactor and then partitioned between ethyl acetate and aqueous sodium hydrogen carbonate (2.5%). The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with aqueous sodium hydrogen carbonate (2.5%) and brine, then dried (Na2SO4) and passed sequentially through 2 PS-Thiol cartridges and concentrated to dryness. Preparative HPLC afforded the title compound (0.62 mg, 0.00016 mmol, 2%). 1H NMR (d6-DMSO, 400 MHz) δ 9.34 (s, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 7.69-7.65 (m, 1H), 7.37 (d, 1H, J=8.3 Hz), 6.99 (d, 1H, J=7.6 Hz), 5.53-5.47 (m, 1H), 4.02 (s, 3H), 2.68-2.63 (m, 1H), 2.57-2.53 (m, 1H), 2.21 (s, 6H), 1.46 (d, 3H, J=6.3 Hz). LC-MS (2) Rt=3.18 min; m/z (ESI+) 379 (M+H).

Workup

  1. customwas degassed under a stream of nitrogen gas
  2. customthe mixture degassed for a further 5 minutes
  3. custompartitioned between ethyl acetate and aqueous sodium hydrogen carbonate (2.5%)
  4. extractionThe aqueous phase was extracted with ethyl acetate
  5. washthe combined organic phases were washed with aqueous sodium hydrogen carbonate (2.5%) and brine
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-7e14da3bfe96490ab70f0b11b2c6030e
Source dataset
uspto-grants-2013_09
Patent number
US08530468B2

Reaction notes

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