Cesium carbonate → (R)-2-(1-((2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-(3-methylmorpholino)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol

HRID 1946161Notes

Reaction equation

HRID 1946161 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][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@H:24]2[CH3:29])[N:3]=1.[CH2:30]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31].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]>[CH2:30]([C:32]1[N:33]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@H:24]3[CH3:29])[N:3]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 158072-EthylbenzimidazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 596059482-{1-[2-Chloro-9-methyl-6-((R)-3-methylmorpholin-4-yl)-9H-purin-8-ylmethyl]piperidin-4-yl}propan-2-ol

Product 1

HCID 59605429(R)-2-(1-((2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-(3-methylmorpholino)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-olYield 43.6%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
110 °C

Procedure

A mixture of 2-{1-[2-chloro-9-methyl-6-((R)-3-methylmorpholin-4-yl)-9H-purin-8-ylmethyl]piperidin-4-yl}propan-2-ol (120 mg, 0.28 mmol), 2-ethylbenzimidazole (46 mg, 0.31 mmol), tris(dibenzylideneacetone)dipalladium (7 mg, 2.5 mol %), XPhos (14 mg, 10 mol %) and Cs2CO3 (139 mg, 0.43 mmol) in dioxane (3 mL) was purged with argon then heated at 110° C. for 4 h in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) followed by (Si—PCC, MeOH:DCM, 0-10%) affording 781 as a white solid (65 mg, 43%). LCMS (method I): RT 2.64 min, [M+H]+ 533.3. 1H NMR (CDCl3, 400 MHz): δ 8.03-8.02 (1 H, m), 7.76-7.75 (1 H, m), 7.30-7.25 (2 H, m), 4.06-4.05 (1 H, m), 3.88 (3 H, s), 3.83 (2 H, s), 3.73 (2 H, s), 3.70-3.55 (2 H, m), 3.36 (2 H, q, J=7.48 Hz), 2.99-2.96 (2 H, m), 2.16-2.06 (2 H, m), 1.81-1.71 (2 H, m), 1.58 (2 H, brd s), 1.48-1.42 (6 H, m), 1.43-1.27 (3 H, m), 1.19 (6 H, s)

Workup

  1. customwas purged with argon
  2. washwas washed with MeOH
  3. washthe product eluted with 2M NH3/MeOH/DCM
  4. customThe resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%)

Sources & evidence

ORD record
ord-760199da932148599d63aa476dae9b30
Source dataset
uspto-grants-2013_03
Patent number
US08394796B2

Reaction notes

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