p-Toluenesulfonic acid → 4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine

HRID 1945944Notes

Reaction equation

HRID 1945944 reaction equation
[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13](C3CCCCO3)[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16](Cl)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([C:36]1[NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[CH:44][C:38]=2[N:37]=1)[CH3:35].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.C1(C)C=CC(S(O)(=O)=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:17]=[C:16]([N:37]2[C:38]4[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=4[N:40]=[C:36]2[CH2:34][CH3:35])[N:15]=3)[CH2:7][CH2:6]1)([CH3:3])([CH3:4])[CH3:2]

Participants

8

Reactant 6

HCID 6101p-Toluenesulfonic acidHCID 6228DimethylformamideHCID 10796Cesium carbonateHCID 158072-EthylbenzimidazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 596055524-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine

Product 1

HCID 1784374114-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholineYield 38.3%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
145 °C

Procedure

Into a vial was added 4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (126 mg, 0.264 mmol), 2-ethyl-1H-benzo[d]imidazole (40.4 mg, 0.277 mmol), Xphos (16.3 mg, 0.0343 mmol), tris(dibenzylideneacetone)dipalladium(0) (16.4 mg, 0.0179 mmol), and cesium carbonate (172 mg, 0.527 mmol;). The mixture was dissolved in N,N-dimethylformamide (2.02 mL, 0.0261 mol) and heated at 145° C. under pressure for 30 minutes in a microwave reactor. The reaction mixture was filtered and concentrated. The crude residue was dissolved in MeOH (5.0 mL) and para-toluenesulfonic acid (90.8 mg, 0.527 mmol) was added. The reaction was heated overnight at 40° C. The reaction mixture was concentrated to dryness and purified by reverse phase HPLC to give 401 (50.9 mg, 38.3%). [M+H]+=504.3

Workup

  1. filtrationThe reaction mixture was filtered
  2. concentrationconcentrated
  3. dissolutionThe crude residue was dissolved in MeOH (5.0 mL)
  4. temperatureThe reaction was heated overnight at 40° C
  5. concentrationThe reaction mixture was concentrated to dryness
  6. custompurified by reverse phase HPLC

Sources & evidence

ORD record
ord-719abf15747849e7b535de137e13d904
Source dataset
uspto-grants-2013_03
Patent number
US08394796B2

Reaction notes

Loading…