Cesium carbonate → 7-(5-Methylisoxazol-3-yl)-2-(1-methyl-1H-[1,2,4]triazol-5-ylmethoxy)-3-thiophen-3-ylpyrazolo[1,5-d][1,2,4]triazine

HRID 276764Notes

Reaction equation

HRID 276764 reaction equation
Br[C:2]1[C:3]([O:17][CH2:18][C:19]2[N:23]([CH3:24])[N:22]=[CH:21][N:20]=2)=[N:4][N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2[C:11]1[CH:15]=[C:14]([CH3:16])[O:13][N:12]=1.[S:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>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]>[CH3:16][C:14]1[O:13][N:12]=[C:11]([C:6]2[N:5]3[N:4]=[C:3]([O:17][CH2:18][C:19]4[N:23]([CH3:24])[N:22]=[CH:21][N:20]=4)[C:2]([C:27]4[CH:28]=[CH:29][S:25][CH:26]=4)=[C:10]3[CH:9]=[N:8][N:7]=2)[CH:15]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonate2×HCID 83681Tris(1,1-dimethylethyl)phosphine2×HCID 581760Thiophene-3-boronic acid2×HCID 226291463-Bromo-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-[1,2, 4]triazol-5-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine

Product 1

HCID 226291417-(5-Methylisoxazol-3-yl)-2-(1-methyl-1H-[1,2,4]triazol-5-ylmethoxy)-3-thiophen-3-ylpyrazolo[1,5-d][1,2,4]triazineYield 37%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A stirred mixture of the bromide (Example 7) (100 mg, 0.26 mmol), thiophene-3-boronic acid (49 mg, 0.38 mmol) and cesium carbonate (167 mg, 0.51 mmol) in dioxan (20 mL) was degassed by evaporating under high vacuum until cold then refilled with N2 and allowed to thaw. This freeze/thaw procedure was repeated 3 times. Pd2(dba)3 (23 mg, 0.026 mmol) and tri-tert-butylphosphine (0.1M solution in dioxane) (0.6 mL, 0.06 mmol) were added and the degassing procedure repeated twice. The mixture was heated at 90° C. under a flow of nitrogen overnight. Further quantities of reagents were added at room temperature: thiophene-3-boronic acid (49 mg, 0.38 mmol), cesium carbonate (167 mg, 0.51 mmol), Pd2(dba)3 (23 mg, 0.026 mmol) and tri-tert-butylphosphine (0.6 mL, 0.06 mmol) followed by the degassing procedure 3 times. Heating was continued at 90° C. for a further 24 h. After cooling the mixture was filtered and the solid washed with EtOAc. The combined organic filtrates were washed with brine, dried (MgSO4) and evaporated. The residue was purified using silica plug chromatography eluting with 1% MeOH/DCM to give the title compound (35 mg, 37%) as a yellow solid. MS (ES+) 395 (M+1). 1H NMR (400 MHz, d6-DMSO) δ2.61 (3H, s), 3.96 (3H, s), 5.74, (2H, s), 7.15 (1H, s), 7.69-7.71 (1H, m), 7.74-7.78 (1H, m), 7.96 (1H, s), 8.03-8.05 (1H, m), 9.85 (1H, s).

Workup

  1. customwas degassed
  2. customby evaporating under high vacuum until cold
  3. additionthen refilled with N2
  4. additionFurther quantities of reagents were added at room temperature
  5. temperatureHeating
  6. temperatureAfter cooling the mixture
  7. filtrationwas filtered
  8. washthe solid washed with EtOAc
  9. washThe combined organic filtrates were washed with brine
  10. dry with materialdried (MgSO4)
  11. customevaporated
  12. customThe residue was purified
  13. washeluting with 1% MeOH/DCM

Sources & evidence

ORD record
ord-9db226d6ec07402da5e9a87dcc5f7f9e
Source dataset
uspto-grants-2002_03
Patent number
US06355638B1

Reaction notes

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