Cesium carbonate → 2-(1-(2-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)ethyl)piperidin-4-yl)propan-2-ol

HRID 1923084Notes

Reaction equation

HRID 1923084 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][CH:17]([C:20]([OH:23])([CH3:22])[CH3:21])[CH2:16][CH2:15]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[CH3:30][C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1.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]>[CH3:11][N:8]1[C:7]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]([OH:23])([CH3:21])[CH3:22])[CH2:16][CH2:15]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:32]1[C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=[C:31]1[CH3:30])=[N:3][C:4]=2[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 119842-MethylbenzimidazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 596057382-{1-[2-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]piperidin-4-yl}propan-2-ol

Product 1

HCID 596053122-(1-(2-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)ethyl)piperidin-4-yl)propan-2-olYield 43.8%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
150 °C

Procedure

A mixture of 2-{1-[2-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]-piperidin-4-yl}propan-2-ol (47 mg, 0.11 mmol), 2-methylbenzimidazole (16 mg, 0.12 mmol), Pd2(dba)3 (2.5 mg, 2.5 mol %), Xphos (5.0 mg, 10 mol %) and Cs2CO3 (54 mg, 0.17 mmol) in dioxane (1.0 mL) was purged with argon gas then heated at 150° C., for 30 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (RediSep amine cartridge, 0-5% MeOH in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 30-50%) to give 344 (25 mg, 43%) as a white solid. LCMS: (Method G): RT 5.64 min; [M+H]+ 519.3. 1H NMR (400 MHz, CHCl3-d): δ 8.09-8.04 (m, 1 H), 7.73-7.69 (m, 1 H), 7.29-7.24 (m, 2 H), 4.48-4.16 (m, 4 H), 3.87 (t, J=4.7 Hz, 4 H), 3.79 (s, 3 H), 3.23-1.05 (m, 4 H), 2.93 (s, 3 H), 2.93-2.75 (m, 2 H), 2.11 (s, 3 H), 1.90-1.75 (m, 2 H), 1.55-1.25 (m, 3 H), 1.20 (s, 6 H)

Workup

  1. customwas purged with argon gas
  2. washwashed with MeOH
  3. washthe desired product eluted with 2 M NH3 in MeOH
  4. customThe resulting residue was purified by flash chromatography (RediSep amine cartridge, 0-5% MeOH in DCM)

Sources & evidence

ORD record
ord-333075d25c1c4826896e9bfe3dacd1b9
Source dataset
uspto-grants-2012_05
Patent number
US08173650B2

Reaction notes

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