Triphenylphosphine → 3-(5-Cyanopyrazin-2-ylamino)-N-(2-morpholinoethyl)isoquinoline-8-carboxamide

HRID 40685Notes

Reaction equation

HRID 40685 reaction equation
Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH:12][C:13]1[N:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1)=[CH:7]2.[NH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49]([O-])(=[O:51])C.[Na+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]([C:16]1[N:17]=[CH:18][C:13]([NH:12][C:8]2[N:9]=[CH:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[C:49]([NH:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:51])=[N:14][CH:15]=1)#[N:20]

Participants

7

Reactant 4

HCID 11776TriphenylphosphineHCID 4082852-MorpholinoethylamineHCID 517045Sodium AcetateHCID 442046545-(8-Bromoisoquinolin-3-ylamino)pyrazine-2-carbonitrile

Product 1

HCID 596363343-(5-Cyanopyrazin-2-ylamino)-N-(2-morpholinoethyl)isoquinoline-8-carboxamideYield 32.5%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 5-(8-bromoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (33 mg, 0.10 mmol), N-(2-aminoethyl)morpholine (26 mg, 0.20 mmol), triphenylphosphine (8 mg, 0.030 mmol), and sodium acetate (3.3 mg, 0.040 mmol) in DMF (1 mL) was degassed by bubbling N2 through the solution for 5 mins. Palladium (II) acetate (6.8 mg, 0.030 mmol) was added and the mixture degassed for a further 5 minutes. Carbon monoxide was then bubbled through the solution for 5 minutes, before the reaction vessel was sealed. The solution was stirred at 80° C. under a balloon of carbon monoxide for 90 minutes and then partitioned between ethyl acetate and aqueous sodium hydrogen carbonate (2.5%). The phases were separated and the aqueous phase washed with ethyl acetate. The combined organic phases were washed with aqueous sodium hydrogen carbonate (2.5%) before being dried (Na2SO4) and then passed sequentially through two PS-Thiol cartridges and concentrated to dryness. Preparative HPLC gave the title compound (5.1 mg, 0.013 mmol, 12%). 1H NMR (d6-DMSO, 400 MHz) δ 11.05 (s, 1H), 9.58 (s, 1H), 8.83 (d, 1H, J=1.2 Hz), 8.73 (d, 1H, J=1.2 Hz), 8.63 (br t, 1H, J=5.8 Hz), 8.56 (s, 1H), 8.00 (d, 1H, J=8.4 Hz), 7.75 (dd, 1H, J=7.1, 8.3 Hz), 7.57 (d, 1H, J=6.8 Hz), 3.62-3.68 (m, 4H), 3.46-3.52 (m, 2H), 2.52-2.58 (m, 2H), 2.46-2.52 (m, 4H, partially obscured by DMSO). LC-MS (2) Rt=1.95 min; m/z (ESI+) 404 (M+H).

Workup

  1. customwas degassed
  2. customby bubbling N2 through the solution for 5 mins
  3. customthe mixture degassed for a further 5 minutes
  4. customCarbon monoxide was then bubbled through the solution for 5 minutes, before the reaction vessel
  5. customwas sealed
  6. custompartitioned between ethyl acetate and aqueous sodium hydrogen carbonate (2.5%)
  7. customThe phases were separated
  8. washthe aqueous phase washed with ethyl acetate
  9. washThe combined organic phases were washed with aqueous sodium hydrogen carbonate (2.5%)
  10. dry with materialbefore being dried (Na2SO4)
  11. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-aa68e9dcbe2847b69ec6f33bd7495f30
Source dataset
uspto-grants-2013_09
Patent number
US08530468B2

Reaction notes

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