Cesium carbonate → 4-(2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9-methyl-8-((3-(1,1-dioxo-thiomorpholino)azetidin-1-yl)methyl)-9H-purin-6-yl)morpholine

HRID 1945910Notes

Reaction equation

HRID 1945910 reaction equation
Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]4)[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:3]=1.[CH3:31][C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=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]>[CH3:31][C:32]1[N:36]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH:15]([N:17]5[CH2:18][CH2:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22]5)[CH2:16]4)[N:8]3[CH3:11])=[C:4]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:3]=2)[C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[N:33]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 119842-MethylbenzimidazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 596058222-Chloro-8-[3-(1,1-Dioxo-1-thiomorpholin-4-yl)azetidin-1-ylmethyl]-9-methyl-6-morpholin-4-yl-9H-purine

Product 1

HCID 596058464-(2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9-methyl-8-((3-(1,1-dioxo-thiomorpholino)azetidin-1-yl)methyl)-9H-purin-6-yl)morpholineYield 84%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
145 °C

Procedure

A mixture of 2-chloro-8-[3-(1,1-Dioxo-1-thiomorpholin-4-yl)azetidin-1-ylmethyl]-9-methyl-6-morpholin-4-yl-9H-purine (125 mg, 0.27 mmol), 2-methylbenzimidazole (402 mg, 0.30 mmol), tris(dibenzylideneacetone)dipalladium (13 mg, 0.01 mmol), Xphos (13 mg, 0.02 mmol) and Cs2CO3 (179 mg, 0.55 mmol) in dioxane (4 mL) was purged with argon then heated at 145° C. for 30 min in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM then eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%) followed by an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH to give 355 as a cream solid (125 mg, 84%). LCMS (Method G): RT 4.73 min, [M+H]+ 552.2. 1H NMR (CDCl3, 400 MHz): δ 8.10-8.05 (m, 1 H); 7.73-7.67 (m, 1 H); 7.29-7.24 (m, 2 H); 4.35 (m, 4 H); 3.90-3.82 (m, 9 H); 3.59 (m, 2 H); 3.28 (m, 1 H); 3.11-3.04 (m, 6 H); 2.94 (s, 3 H) and 2.87-2.82 (m, 4 H)

Workup

  1. customwas purged with argon
  2. washwashed with MeOH/DCM
  3. washthen eluted with 2M NH3/MeOH
  4. customThe resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%)
  5. washwas washed with MeOH/DCM
  6. washthe product eluted with 2M NH3/MeOH

Sources & evidence

ORD record
ord-a8cbe7c98efb4e1aa745e00559353fbb
Source dataset
uspto-grants-2013_03
Patent number
US08394796B2

Reaction notes

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