p-Toluenesulfonic acid → 3-(1-(Dimethylamino)propan-2-yloxy)-5-(isoquinolin-3-ylamino)pyrazine-2-carbonitrile

HRID 40665

Reaction equation

HRID 40665 reaction equation
Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:12][C:13]1[N:14]=[C:15]([O:21][CH:22]([CH3:27])[CH2:23][N:24]([CH3:26])[CH3:25])[C:16]([C:19]#[N:20])=[N:17][CH:18]=1.CC(C)([O-])C.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:26][N:24]([CH3:25])[CH2:23][CH:22]([O:21][C:15]1[C:16]([C:19]#[N:20])=[N:17][CH:18]=[C:13]([NH:12][C:2]2[N:3]=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:14]=1)[CH3:27]

Participants

8

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 6409683-ChloroisoquinolineHCID 23676156Sodium t-butoxideHCID 596363285-Amino-3-(1-(dimethylamino)propan-2-yloxy)pyrazine-2-carbonitrile

Product 1

HCID 441823893-(1-(Dimethylamino)propan-2-yloxy)-5-(isoquinolin-3-ylamino)pyrazine-2-carbonitrileYield 7.2%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
140 °C

Procedure

A mixture of palladium (II) acetate (24 mg, 0.11 mmol) and (±)-2,2″-bis(diphenylphosphino)-1,1″-binaphthalene (140 mg, 0.22 mmol) in toluene (2 mL) was degassed under a stream of nitrogen gas with stirring for 10 minutes. After addition of 3-chloroisoquinoline (59 mg, 0.36 mmol), 5-amino-3-(1-(dimethylamino)propan-2-yloxy)pyrazine-2-carbonitrile (80 mg, 0.36 mmol) in DMF (0.5 mL), and sodium tert-butoxide (42 mg, 0.43 mmol), the mixture was degassed for a further 5 minutes and then heated at 140° C. for 30 minutes in a microwave reactor. Upon cooling, the mixture was diluted with methanol and isolated by SPE using a MP-TsOH cartridge, washing with methanol and then eluting with 2 M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. Preparative HPLC gave the title compound (8.9 mg, 0.026 mmol, 7%). 1H NMR (d6-DMSO, 400 MHz) δ 9.22 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8.09 (d, 1H, J=9.1 Hz), 7.84 (d, 1H, J=8.1 Hz), 7.77-7.73 (m, 1H), 7.58-7.54 (m, 1H), 5.53-5.49 (m, 1H), 2.67-2.63 (m, 1H), 2.34-2.32 (m, 1H), 2.21 (s, 6H), 1.46 (d, 3H, J=6.3 Hz). LC-MS (2) Rt=2.93 min m/z (ESI−) 347 (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
  4. additionthe mixture was diluted with methanol
  5. customisolated by SPE
  6. washwashing with methanol
  7. washeluting with 2 M ammonia in methanol
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-eae530f7f3ea4be8931bbe83a55f6179
Source dataset
uspto-grants-2013_09
Patent number
US08530468B2

Linked notes

Loading…