Dimethylformamide → N-methyl-1-(9-methyl-6-morpholino-8-((4-(oxetan-3-yl)piperidin-1-yl)methyl)-9H-purin-2-yl)-1H-benzo[d]imidazol-2-amine

HRID 1945968Notes

Reaction equation

HRID 1945968 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]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[NH:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1CN.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+].[CH3:80][N:81](C=O)C>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]>[CH3:80][NH:81][C:30]1[N:29]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH2:15][CH:16]([CH:19]5[CH2:20][O:21][CH2:22]5)[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=1

Participants

7

Reactant 5

HCID 6228DimethylformamideHCID 10796Cesium carbonateHCID 1458201H-Benzimidazole-2-methanamineHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 596054062-Chloro-9-methyl-6-morpholin-4-yl-8-(4-oxetan-3-ylpiperidin-1-ylmethyl)-9H-purine

Product 1

HCID 59605901N-methyl-1-(9-methyl-6-morpholino-8-((4-(oxetan-3-yl)piperidin-1-yl)methyl)-9H-purin-2-yl)-1H-benzo[d]imidazol-2-amineYield 45%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Procedure

A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-8-(4-oxetan-3-yl-piperidin-1-ylmethyl)-9H-purine (100 mg, 0.25 mmol), (1H-benzoimidazol-2-yl)methyl-amine (43 mg, 0.29 mmol), Pd2dba3 (6 mg, 0.006 mmol), Xphos (12 mg, 0.025 mmol) and cesium carbonate (121 mg, 0.37 mmol) in DMF (2 mL) was purged with argon gas then subjected to microwave irradiation at 145° C. for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), which was washed with MeOH/DCM before the desired product was eluted with 2 M NH3 in MeOH/DCM. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH 100:0 to 99:1 to 98:2) to afford 447 as a cream foam (58 mg, 45%). LCMS (Method I): RT=2.36 min, M+H+=518. 1H NMR (CDCl3, 400 MHz) δ 8.51 (bs, 1 H); 8.29 (d, J=7.9 Hz, 1 H); 7.51 (d, J=7.9 Hz, 1 H); 7.19 (t, J=7.8 Hz, 1 H); 7.08 (t, J=7.8 Hz, 1 H); 4.75 (dd, J=7.9, 6.1 Hz, 2 H); 4.46 (t, J=6.1 Hz, 2 H); 4.33 (m, 4 H); 3.92-3.85 (m, 7 H); 3.73 (s, 2 H); 3.26 (d, J=4.9 Hz, 3 H); 2.88 (m, 2 H); 2.78-2.69 (m, 1 H); 2.15 (m, 2 H); 1.66 (m, 3 H) and 1.19-1.07 (m, 2 H)

Workup

  1. customwas purged with argon gas
  2. customirradiation at 145° C. for 30 min
  3. washwas washed with MeOH/DCM before the desired product
  4. washwas eluted with 2 M NH3 in MeOH/DCM
  5. customThe product was collected
  6. concentrationconcentrated in vacuo
  7. customThe resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH 100:0 to 99:1 to 98:2)

Sources & evidence

ORD record
ord-9340f5bf8d4d4a1db7131aec8a1a37b1
Source dataset
uspto-grants-2013_03
Patent number
US08394796B2

Reaction notes

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