p-Toluenesulfonic acid → HCID 44204355, compound

HRID 40666Notes

Reaction equation

HRID 40666 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.Cl[C:44]1[N:45]=[CH:46][C:47]2[C:52]([CH:53]=1)=[CH:51][CH:50]=[CH:49][C:48]=2[Cl:54].[NH2:55][C:56]1[N:57]=[C:58]([O:64][C@@H:65]2[CH2:69][CH2:68][NH:67][CH2:66]2)[C:59]([C:62]#[N:63])=[N:60][CH:61]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O)(=O)=O)=CC=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]>[Cl:54][C:48]1[CH:49]=[CH:50][CH:51]=[C:52]2[C:47]=1[CH:46]=[N:45][C:44]([NH:55][C:56]1[N:57]=[C:58]([O:64][C@@H:65]3[CH2:69][CH2:68][NH:67][CH2:66]3)[C:59]([C:62]#[N:63])=[N:60][CH:61]=1)=[CH:53]2

Participants

9

Reactant 5

HCID 6101p-Toluenesulfonic acidHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 596364133,8-DichloroisoquinolineHCID 67017477(R)-5-amino-3-(pyrrolidin-3-yloxy)pyrazine-2-carbonitrile

Product 1

HCID 44204355HCID 44204355, compoundYield 4%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
130 °C

Procedure

A mixture of tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.025 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (29 mg, 0.05 mmol) in toluene (1.5 mL) was degassed under a stream of nitrogen gas with stirring for 10 minutes. 3,8-Dichloroisoquinoline (50 mg, 0.252 mmol), (R)-5-amino-3-(pyrrolidin-3-yloxy)pyrazine-2-carbonitrile (85 mg, 0.278 mmol) in DMF (0.5 mL) and caesium carbonate (165 mg, 0.505 mmol) were added and the mixture was degassed for a further 5 minutes, then heated at 130° 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 combined basic fractions were concentrated in vacuo. Preparative HPLC gave (R)-5-(8-chloroisoquinolin-3-ylamino)-3-(pyrrolidin-3-yloxy)pyrazine-2-carbonitrile (3.8 mg, 0.01 mmol, 4%). 1H NMR (d4-MeOD) δ 9.42 (d, 1H, J=0.9 Hz), 8.52 (s, 1H), 8.32 (d, 1H, J=5.3 Hz), 7.85 (d, 1H, J=8.3 Hz), 7.66-7.62 (m, 1H), 7.59-7.57 (m, 1H), 5.89-5.86 (m, 1H), 3.67-3.65 (m, 2H), 3.50-3.46 (m, 2H), 2.52-2.47 (m, 2H). LC-MS (2) Rt=2.65 min; m/z (ESI−) 365 (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. concentrationThe combined basic fractions were concentrated in vacuo

Sources & evidence

ORD record
ord-00f448283c2344af947f7dc8cf7b1fbd
Source dataset
uspto-grants-2013_09
Patent number
US08530468B2

Reaction notes

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