Cesium carbonate → 4-(2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)-9-methyl-8-((4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)-9H-purin-6-yl)morpholine

HRID 1946076Notes

Reaction equation

HRID 1946076 reaction equation
Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:3]=1.[CH:31]([C:34]1[NH:38][C:37]2[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=2[N:35]=1)([CH3:33])[CH3:32].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=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]>[CH:31]([C:34]1[N:35]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([CH:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:3]=2)[C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1)([CH3:33])[CH3:32]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 221212-(propan-2-yl)-1H-1,3-benzodiazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 596055882-Chloro-9-methyl-6-morpholin-4-yl-8-[4-(tetrahydropyran-4-yl)piperazin-1-ylmethyl]-9H-purine

Product 1

HCID 596054994-(2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)-9-methyl-8-((4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)-9H-purin-6-yl)morpholineYield 37%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolvent

Procedure

A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-8-[4-(tetrahydropyran-4-yl)piperazin-1-ylmethyl]-9H-purine (180 mg, 0.41 mmol), 2-isopropyl-1H-benzoimidazole (80 mg, 0.50 mmol), Pd2dba3 (11 mg, 0.012 mmol), Xphos (22 mg, 0.046 mmol) and cesium carbonate (201 mg, 0.62 mmol) in DMF (4 mL) was purged with argon gas then subjected to microwave irradiation at 145° C. for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), which was washed with MeOH/DCM before the desired product was eluted with 2 M NH3 in MeOH/DCM. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH 100:0 to 95:5) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 60:40 to 10:90) to afford 564 as a white solid (85 mg, 37%). LCMS (method I): RT=2.61 min, M+H+=560. 1H NMR (CDCl3, 400 MHz) δ 7.89 (d, J=7.6 Hz, 1 H), 7.78 (d, J=7.5 Hz, 1 H), 7.26 (m, 2 H), 4.34 (m, 4 H), 4.03 (d, J=10.1 Hz, 2 H), 3.95 (m, 1 H), 3.86 (m, 7 H), 3.77 (s, 2 H), 3.38 (t, J=11.7 Hz, 2 H), 2.63 (m, 9 H), 1.79 (m, 2 H), 1.60 (m, 2 H), 1.48 (s, 3 H) and 1.46 (s, 3 H)

Workup

  1. customwas purged with argon gas
  2. customirradiation at 145° C. for 30 min
  3. washwas washed with MeOH/DCM before the desired product
  4. washwas eluted with 2 M NH3 in MeOH/DCM
  5. customThe product was collected
  6. concentrationconcentrated in vacuo
  7. customThe resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH 100:0 to 95:5)

Sources & evidence

ORD record
ord-020c4d9f8fbd455fa2b32d09a01f3a4c
Source dataset
uspto-grants-2013_03
Patent number
US08394796B2

Reaction notes

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