Cesium carbonate → 4-((2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-3-isopropylpiperazin-2-one

HRID 1946109Notes

Reaction equation

HRID 1946109 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][NH:16][C:15](=[O:19])[CH:14]3[CH:20]([CH3:22])[CH3:21])[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH2:29]([C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30].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]>[CH2:29]([C:31]1[N:32]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH:14]4[CH:20]([CH3:21])[CH3:22])[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:3]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 158072-EthylbenzimidazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 596053464-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)-3-isopropylpiperazin-2-one

Product 1

HCID 596058104-((2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-3-isopropylpiperazin-2-oneYield 78%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
110 °C

Procedure

A mixture of 4-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)-3-isopropylpiperazin-2-one (198 mg, 0.49 mmol), 2-ethylbenzimidazole (78 mg, 0.53 mmol), Pd2(dba)3 (11.1 mg, 2.5 mol %), Xphos (23.1 mg, 10 mol %) and Cs2CO3 (237 mg, 0.16 mmol) in dioxane (4 mL) was purged with argon gas then heated at 110° C., for 17 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 column chromatography (Si—PCC, 0-10% MeOH in EtOAc) to give 648 (196 mg, 78%) as a white solid. LCMS: (Method I): RT 3.37 min, [M+H]+ 518.2 1H NMR (400 MHz, CDCl3d): δ 8.05-8.00 (m, 1 H), 7.79-7.75 (m, 1 H), 7.30-7.23 (m, 2 H), 6.02 (s, 1 H), 4.50-3.96 (m, 4 H), 4.09 (d, J=13.6 Hz, 1 H), 3.94 (d, J=13.6 Hz, 1 H), 3.89 (s, 3 H), 3.87 (t, J=4.80 Hz, 4 H), 3.63-3.54 (m, 1 H), 3.37 (q, J=7.5 Hz, 2 H), 3.34-3.28 (m, 1 H), 3.13-3.04 (m, 1 H), 3.03 (d, J=5.5 Hz, 1 H), 2.74-2.66 (m, 1 H), 2.25-2.14 (m, 1 H), 1.46 (t, J=7.5 Hz, 3 H), 1.11 (d, J=6.8 Hz, 3 H), 1.03 (d, J=6.8 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 column chromatography (Si—PCC, 0-10% MeOH in EtOAc)

Sources & evidence

ORD record
ord-c6d2fd5c69c44383af668742f32508af
Source dataset
uspto-grants-2013_03
Patent number
US08394796B2

Reaction notes

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