Cesium carbonate → 4-(5-(2-methyl-1H-benzo[d]imidazol-1-yl)-2-((3-(tetrahydro-2H-pyran-4-yl)azetidin-1-yl)methyl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine

HRID 1923177Notes

Reaction equation

HRID 1923177 reaction equation
Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:15][CH:14](N4CCOCC4)[CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH3:28][C:29]1[NH:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1.[CH3:38][CH:39]([C:41]1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=[C:43](C(C)C)[CH:42]=1)C.C([O-])([O-])=[O:73].[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]>[CH3:28][C:29]1[N:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:5]3[N:10]=[C:9]([CH2:11][N:12]4[CH2:13][CH:14]([CH:41]5[CH2:42][CH2:43][O:73][CH2:38][CH2:39]5)[CH2:15]4)[S:8][C:6]=3[N:7]=2)[C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=2[N:30]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 119842-MethylbenzimidazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 596034604-(5-Chloro-2-((3-morpholinoazetidin-1-yl)methyl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine

Product 1

HCID 596061024-(5-(2-methyl-1H-benzo[d]imidazol-1-yl)-2-((3-(tetrahydro-2H-pyran-4-yl)azetidin-1-yl)methyl)thiazolo[5,4-d]pyrimidin-7-yl)morpholineYield 464.8%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
145 °C

Procedure

A mixture of 5-chloro-7-morpholin-4-yl-2-(3-morpholin-4-yl-azetidin-1-ylmethyl)-thiazolo[5,4-d]pyrimidine (100 mg, 0.24 mmol), 2-methylbenzimidazole (32 mg, 0.24 mmol), tris(dibenzylideneacetone)dipalladium (11 mg, 0.01 mmol), Xphos (12 mg, 0.02 mmol) and Cs2CO3 (159 mg, 0.48 mmol) in DMF (2 mL) was purged with argon then heated at 145° C. for 30 min in a microwave reactor. The reaction mixture was dissolved in EtOAc and washed with H2O (×6), then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-5%) to afford 482 as an orange solid (47 mg, 39%). LCMS (Method I): RT 2.59 min, [M+H]+ 507.2. 1H NMR (CDCl3, 400 MHz): δ 8.09-8.04 (m, 1 H); 7.73-7.68 (m, 1 H); 7.29-7.24 (m, 2 H); 4.41 (m, 4 H); 4.02 (s, 2 H); 3.88 (t, J=4.7 Hz, 4 H); 3.71 (m, 6 H); 3.17 (m, 3 H); 2.92 (s, 3 H) and 2.37 (m, 4 H)

Workup

  1. customwas purged with argon
  2. dissolutionThe reaction mixture was dissolved in EtOAc
  3. washwashed with H2O (×6)
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated in vacuo
  6. customThe resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-5%)

Sources & evidence

ORD record
ord-aa18d9e8e6f04f6c8a70bb382351e59f
Source dataset
uspto-grants-2012_05
Patent number
US08173650B2

Reaction notes

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