Cesium carbonate → 2-methyl-2-(4-((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-4-morpholinofuro[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide

HRID 1945816Notes

Reaction equation

HRID 1945816 reaction equation
Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[O:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:30][C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=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]>[CH3:22][C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[O:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([N:32]4[C:33]5[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=5[N:35]=[C:31]4[CH3:30])=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)([CH3:23])[C:19]([NH2:21])=[O:20]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 119842-MethylbenzimidazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 596055422-[4-(2-Chloro-4-morpholin-4-ylfuro[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide

Product 1

HCID 596053282-methyl-2-(4-((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-4-morpholinofuro[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamideYield 67%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
110 °C

Procedure

A mixture of 2-[4-(2-chloro-4-morpholin-4-ylfuro[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (500 mg, 1.18 mmol), 2-methyl-1H-benzoimidazole (180 mg, 1.36 mmol), Pd2dba3 (27 mg, 0.029 mmol), Xphos (57 mg, 0.12 mmol) and cesium carbonate (580 mg, 1.78 mmol) in 1,4-dioxane (10 mL) was heated at 110° C. for 18 h. The reaction mixture was cooled to ambient temperature, then loaded onto an Isolute® SCX-2 cartridge, 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, EtOAc:MeOH; gradient from 100:0 to 70:30) followed by trituration from hot EtOAc to afford 240 as a white solid (408 mg, 67%). LCMS (Method G): RT=5.23 min, M+H+=519. 1H NMR (CDCl3, 400 MHz) δ 8.03-7.98 (m, 1 H); 7.73-7.69 (m, 1 H); 7.28-7.23 (m, 2 H); 7.05 (bs, 1 H); 6.76 (s, 1 H); 5.27 (bs, 1 H); 4.08 (t, J=4.7 Hz, 4 H); 3.89 (t, J=4.7 Hz, 4 H); 3.76 (s, 2 H); 2.90 (s, 3 H); 2.62 (m, 8 H) and 1.24 (s, 6 H)

Workup

  1. temperatureThe reaction mixture was cooled to ambient temperature
  2. washwas washed with MeOH/DCM before the desired product
  3. washwas eluted with 2 M NH3 in MeOH/DCM
  4. customThe product was collected
  5. concentrationconcentrated in vacuo
  6. customThe resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; gradient from 100:0 to 70:30)

Sources & evidence

ORD record
ord-f230b8d536034b39894151519028b396
Source dataset
uspto-grants-2013_03
Patent number
US08394796B2

Reaction notes

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