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

HRID 1923149Notes

Reaction equation

HRID 1923149 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.[CH:31]([C:34]1[NH:38][C:37]2[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=2[N:35]=1)([CH3:33])[CH3:32].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]>[CH:31]([C:34]1[N:35]([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:23])(=[O:24])[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:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1)([CH3:33])[CH3:32]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 221212-(propan-2-yl)-1H-1,3-benzodiazoleHCID 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 596059284-(2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)-9-methyl-8-((3-(1,1-dioxo-thiomorpholino)azetidin-1-yl)methyl)-9H-purin-6-yl)morpholineYield 49%

Reagents, catalysts & solvents 2

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

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 (0.162 g, 0.36 mmol), 2-isopropyl-1H-benzoimidazole (0.068 g, 0.43 mmol), Xphos (0.034 g, 0.071 mmol), Pd2(dba)3 (0.017 g, 0.018 mmol) and Cs2CO3 (0.231 g, 0.71 mmol) in dioxane (2 mL) was subjected to microwave irradiation at 145° C. for 45 min. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MEOH:DCM gradient 0:100 to 7.5:92.5) to give 449 as a yellow solid (0.1 g, 49%). LCMS (Method I): RT=2.56 min, [M+H]+ 580.2. 1H NMR (400 MHz, DMSO-d): δ 7.91-7.86 (m, 1 H); 7.66-7.61 (m, 1 H); 7.26-7.21 (m, 2 H); 4.30-4.23 (m, 4 H); 3.97-3.86 (m, 1H); 3.87 (s, 2 H); 3.82-3.71 (m, 7 H); 3.46 (t, J=6.6 Hz, 2 H); 3.26-3.18 (m, 1 H); 3.12-3.08 (m, 4 H); 3.00 (t, J=6.8 Hz, 2 H); 2.74 (m, 4 H); 1.35 (d, J=6.8 Hz, 6 H)

Workup

  1. customirradiation at 145° C. for 45 min
  2. filtrationThe suspension was filtered through Celite
  3. concentrationthe filtrate was concentrated in vacuo
  4. customThe residue was purified by flash chromatography (Si—PPC, MEOH:DCM gradient 0:100 to 7.5:92.5)

Sources & evidence

ORD record
ord-293a62b48bd3441e9e6a3c54e7784beb
Source dataset
uspto-grants-2012_05
Patent number
US08173650B2

Reaction notes

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