Cesium carbonate → 4-(8-((2,2-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)methyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine

HRID 1946145Notes

Reaction equation

HRID 1946145 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[CH2:22][O:21][CH2:20]4)[CH2:15][C:14]3([CH3:24])[CH3:23])[N:8]2[CH3:11])=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:3]=1.[CH2:31]([C:33]1[NH:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)[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+]>O1CCOCC1.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]>[CH3:24][C:14]1([CH3:23])[CH2:15][N:16]([CH:19]2[CH2:22][O:21][CH2:20]2)[CH2:17][CH2:18][N:13]1[CH2:12][C:7]1[N:8]([CH3:11])[C:9]2[C:5]([N:6]=1)=[C:4]([N:25]1[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1)[N:3]=[C:2]([N:34]1[C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=[C:33]1[CH2:31][CH3:32])[N:10]=2

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 158072-EthylbenzimidazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 596060072-Chloro-8-(2,2-dimethyl-4-oxetan-3-ylpiperazin-1-ylmethyl)-9-methyl-6-morpholin-4-yl-9H-purine

Product 1

HCID 596061684-(8-((2,2-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)methyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholineYield 48%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
150 °C

Procedure

A mixture of 2-chloro-8-(2,2-dimethyl-4-oxetan-3-ylpiperazin-1-ylmethyl)-9-methyl-6-morpholin-4-yl-9H-purine (90 mg, 0.21 mmol), 2-ethylbenzimidazole (32 mg, 0.22 mmol), tris(dibenzylideneacetone)dipalladium (5 mg, 2.5 mol %), XPhos (9 mg, 10 mol %) and Cs2CO3 (95 mg, 0.29 mmol) in dioxane (1 mL) was purged with argon then heated at 150° C. for 1 h in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 1-3%) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 5-98%) affording 740 (54 mg, 48%). LCMS (method I): RT 2.62 min [M+H]+ 546.2. 1H NMR (CDCl3, 400 MHz): δ 8.01-8.01 (1 H, m), 7.75-7.74 (1 H, m), 7.31-7.22 (2 H, m), 4.64 (2 H, t, J=6.47 Hz), 4.57 (2 H, t, J=6.07 Hz), 4.34 (4 H, brd s), 3.90 (3 H, s), 3.86 (6 H, t, J=4.78 Hz), 3.36-3.35 (3 H, m), 2.52 (2 H, s), 2.24 (2 H, s), 2.11 (2 H, s), 1.45 (3 H, t, J=7.48 Hz), 1.24 (6 H, s)

Workup

  1. customwas purged with argon
  2. washwas washed with MeOH
  3. washthe product eluted with 2M NH3/MeOH
  4. customThe resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 1-3%)

Sources & evidence

ORD record
ord-e502c30001a44111be1f26ea3b985016
Source dataset
uspto-grants-2013_03
Patent number
US08394796B2

Reaction notes

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