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

HRID 1945972

Reaction equation

HRID 1945972 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][C:17]([CH3:21])([OH:20])[CH2:16][CH2:15]3)[N:8]2[CH3:11])=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.[CH2:28]([C:30]1[NH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29].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]>[CH2:28]([C:30]1[N:31]([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][C:17]([CH3:21])([OH:20])[CH2:16][CH2:15]4)[N:8]3[CH3:11])=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:3]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 158072-EthylbenzimidazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 596059071-[2-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]-4-methylpiperidin-4-ol

Product 1

HCID 596057341-(2-(2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)ethyl)-4-methylpiperidin-4-olYield 82.9%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
120 °C

Procedure

A mixture of 1-[2-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]-4-methylpiperidin-4-ol (45 mg, 0.11 mmol), 2-ethylbenzimidazole (18 mg, 0.13 mmol), Pd2(dba)3 (2.6 mg, 2.5 mol %), Xphos (5.4 mg, 10 mol %) and Cs2CO3 (56 mg, 0.17 mmol) in dioxane (1.0 mL) was purged with argon gas then heated at 120° 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 in MeOH. The resulting residue was purified by flash chromatography (Si—PCC, 0-10% 2 M NH3/MeOH in DCM) to give 452 (46 mg, 80%) as a pale orange solid. LCMS: (Method I): RT 2.46 min; [M+H]+ 505.2. 1H NMR (400 MHz, CHCl3-d): δ 8.01-7.96 (m, 1 H), 7.77-7.73 (m, 1 H), 7.28-7.22 (m, 2 H), 4.47-4.19 (m, 4 H), 3.88-3.83 (m, 4 H), 3.78 (s, 3 H), 3.34 (q, J=7.5 Hz, 2 H), 3.15-3.05 (m, 2 H), 2.98-2.80 (m, 2 H), 2.78-2.73 (m, 2 H), 2.65-2.57 (m, 2 H), 1.69-1.65 (m, 4 H), 1.44 (t, J=7.5 Hz, 3 H), 1.33-1.27 (s, 3 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 (Si—PCC, 0-10% 2 M NH3/MeOH in DCM)

Sources & evidence

ORD record
ord-6088c0da57014359a93618b5a28ef923
Source dataset
uspto-grants-2013_03
Patent number
US08394796B2

Linked notes

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