Cesium carbonate → 4-(6-((2,2-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)methyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)thieno[3,2-d]pyrimidin-4-yl)morpholine

HRID 1946167Notes

Reaction equation

HRID 1946167 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[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:21][O:20][CH2:19]4)[CH2:14][C:13]3([CH3:23])[CH3:22])=[CH:8][C:6]=2[N:7]=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+]>CN(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]>[NH3:3].[CH3:19][OH:20].[CH3:22][C:13]1([CH3:23])[CH2:14][N:15]([CH:18]2[CH2:21][O:20][CH2:19]2)[CH2:16][CH2:17][N:12]1[CH2:11][C:9]1[S:10][C:5]2[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:3][C:2]([N:33]3[C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[N:36]=[C:32]3[CH2:30][CH3:31])=[N:7][C:6]=2[CH:8]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 158072-EthylbenzimidazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 575067452-Chloro-6-(2,2-dimethyl-4-oxetan-3-ylpiperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine

Product 2

HCID 21705897Ammonia methanolHCID 575067444-(6-((2,2-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)methyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)thieno[3,2-d]pyrimidin-4-yl)morpholineYield 53%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
150 °C

Procedure

A mixture of 2-chloro-6-(2,2-dimethyl-4-oxetan-3-ylpiperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (136 mg, 0.31 mmol), 2-ethylbenzimidazole (48 mg, 0.33 mmol), tris(dibenzylideneacetone)dipalladium (8 mg, 3 mol %), XPhos (14 mg, 9 mol %) and Cs2CO3 (143 mg, 0.44 mmol) in DMF (4 mL) was purged with argon then heated at 150° C. for 30 min in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-5%) then (Si—PCC, 2M NH3/MeOH:DCM, 0-2%) affording 792 as a cream solid (45 mg, 26%). LCMS (method I): RT 2.78 min [M+H]+ 548.3. 1H NMR (CDCl3, 400 MHz): δ 7.97-7.96 (1 H, m), 7.75-7.74 (1 H, m), 7.32-7.22 (3 H, m), 4.66 (2 H, t, J=6.47 Hz), 4.59 (2 H, t, J=6.08 Hz), 4.04 (4 H, t, J=4.72 Hz), 3.91-3.86 (6 H, m), 3.46-3.45 (1 H, m), 3.33 (2 H, q, J=7.48 Hz), 2.64 (2 H, t, J=4.98 Hz), 2.33 (2 H, s), 2.14 (2 H, s), 1.42 (3 H, t, J=7.47 Hz), 1.20 (6 H, s)

Workup

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

Sources & evidence

ORD record
ord-6d20b617fa074ae38d39c0590557469e
Source dataset
uspto-grants-2013_03
Patent number
US08394796B2

Reaction notes

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