Cesium carbonate → (2,2-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)(5-(2-ethyl-1H-benzo[d]imidazol-1-yl)-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)methanone

HRID 1923357Notes

Reaction equation

HRID 1923357 reaction equation
Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[N:10]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH2:15][C:14]3([CH3:24])[CH3:23])=[O:12])[S:8][C:6]=2[N:7]=1.[CH2:31]([C:33]1[NH:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)[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+]>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]>[CH3:23][C:14]1([CH3:24])[CH2:15][N:16]([CH:19]2[CH2:22][O:21][CH2:20]2)[CH2:17][CH2:18][N:13]1[C:11]([C:9]1[S:8][C:6]2[N:7]=[C:2]([N:34]3[C:35]4[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=4[N:37]=[C:33]3[CH2:31][CH3:32])[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]=2[N:10]=1)=[O:12]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 158072-EthylbenzimidazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 59606073(5-Chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl)-(2,2-dimethyl-4-oxetan-3-ylpiperazin-1-yl)methanone

Product 1

HCID 59605578(2,2-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)(5-(2-ethyl-1H-benzo[d]imidazol-1-yl)-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)methanone

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
150 °C

Procedure

A mixture of (5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl)-(2,2-dimethyl-4-oxetan-3-ylpiperazin-1-yl)methanone (137 mg, 0.30 mmol), 2-ethylbenzimidazole (47 mg, 0.32 mmol), tris(dibenzylideneacetone)dipalladium (8 mg, 2.5 mol %), XPhos (13 mg, 10 mol %) and Cs2CO3 (140 mg, 0.43 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, 1-2%) followed by triturating with EtOAc affording 793 (22 mg, 13%). LCMS (method I): RT 3.79 min [M+H]+ 563.3. 1H NMR (CDCl3, 400 MHz): δ 8.07-8.03 (1 H, m), 7.76-7.75 (1 H, m), 7.30-7.29 (2 H, m), 4.72 (2 H, t, J=6.51 Hz), 4.62 (2 H, t, J=6.07 Hz), 4.40 (4 H, brd s), 4.07-4.06 (2 H, m), 3.89 (4 H, t, J=4.72 Hz), 3.53-3.52 (1 H, m), 3.36 (2 H, q, J=7.46 Hz), 2.47 (2 H, t, J=5.08 Hz), 2.25 (2 H, s), 1.56 (6 H, s), 1.44 (3 H, t, J=7.45 Hz)

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, 1-2%)
  5. customby triturating with EtOAc affording 793 (22 mg, 13%)
  6. customRT 3.79 min [M+H]+ 563.3

Sources & evidence

ORD record
ord-4fb3a4317efd43ae8e97ca17efd8ee20
Source dataset
uspto-grants-2012_05
Patent number
US08173650B2

Reaction notes

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