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

HRID 1923254Notes

Reaction equation

HRID 1923254 reaction equation
Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH2:16][CH2:15]3)[N:8]2[CH3:11])=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=1.[CH2:32]([C:34]1[NH:35][C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1)[CH3:33].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]>[CH2:32]([C:34]1[N:35]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][N:17]([CH:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[CH2:16][CH2:15]4)[N:8]3[CH3:11])=[C:4]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:3]=2)[C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1)[CH3:33]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 158072-EthylbenzimidazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 596052282-Chloro-9-methyl-6-morpholin-4-yl-8-{2-[4-(tetrahydropyran-4-yl)piperazin-1-yl]ethyl}-9H-purine

Product 1

HCID 596061014-(2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-8-(2-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)ethyl)-9H-purin-6-yl)morpholineYield 71.5%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
120 °C

Procedure

A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-8-{2-[4-(tetrahydropyran-4-yl)piperazin-1-yl]ethyl}-9H-purine (37 mg, 0.08 mmol), 2-ethylbenzimidazole (13 mg, 0.09 mmol), Pd2(dba)3 (1.9 mg, 2.5 mol %), Xphos (3.9 mg, 10 mol %) and Cs2CO3 (37 mg, 0.11 mmol) in dioxane (1.5 mL) was purged with argon gas then heated at 120° C., for 19 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 30-90%) to give 557 (32 mg, 70%) as a pale beige solid. LCMS: (Method I): RT 2.42 min; [M+H]+ 560.3. 1H NMR (400 MHz, CHCl3-d): δ 8.01-7.97 (m, 1 H), 7.77-7.72 (m, 1 H), 7.29-7.22 (m, 2 H), 4.56-4.21 (m, 4 H), 4.04 (dd, J=11.4, 4.2 Hz, 2 H), 3.86 (t, J=4.7 Hz, 4 H), 3.77 (s, 3 H), 3.38-3.34 (m, 2 H), 3.34 (q, J=7.5 Hz, 2 H), 3.13-3.00 (m, 2 H), 3.00-2.87 (m, 2 H), 2.82-2.58 (m, 6 H), 2.57-2.42 (m, 1 H), 1.88-1.75 (m, 2 H), 1.71-1.55 (m, 4 H), 1.44 (t, J=7.5 Hz, 3 H)

Workup

  1. customwas purged with argon gas
  2. washwashed with MeOH
  3. washthe desired product eluted with 2 M NH3/MeOH in DCM
  4. customThe resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 30-90%)

Sources & evidence

ORD record
ord-51afd73ae1694325b5377f198deeaac1
Source dataset
uspto-grants-2012_05
Patent number
US08173650B2

Reaction notes

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