Water → 3-(5-bromo-1-benzothien-2-yl)-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

HRID 1253531Notes

Reaction equation

HRID 1253531 reaction equation
I[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH3:18])[C:6]=12.[Br:19][C:20]1[CH:31]=[CH:30][C:23]2[S:24][C:25](B(O)O)=[CH:26][C:22]=2[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].O>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]>[Br:19][C:20]1[CH:31]=[CH:30][C:23]2[S:24][C:25]([C:2]3[CH:3]=[N:4][N:5]4[CH:10]=[C:9]([C:11]5[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=5)[CH:8]=[C:7]([O:17][CH3:18])[C:6]=34)=[CH:26][C:22]=2[CH:21]=1

Participants

7

Reactant 4

HCID 962WaterHCID 10340Sodium CarbonateHCID 230053555-Bromobenzo(b)thiophene-2-boronic acidHCID 448167683-iodo-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

Product 1

HCID 584048713-(5-bromo-1-benzothien-2-yl)-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

Reagents, catalysts & solvents 2

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

Conditions

Temperature
90 °C

Procedure

3-iodo-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (25.0 mg, 0.071 mmol), 5-bromobenzeno[B]thiophene-2-boronic acid (19.0 mg, 0.074 mmol), tetrakis(triphenylphosphine)palladium (0) (8.2 mg, 7.1 μmol), and sodium carbonate (15.0 mg, 0.141 mmol) were suspended in Dioxane (900 μl)/Water (100 μl). The mixture was sparged with argon for 10 minutes, heated to 90° C. and stirred overnight. The reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) to afford a tan solid that contained unidentified impurities. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to afford 3-(5-bromo-1-benzothien-2-yl)-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine. 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H); 8.33 (s, 1H); 8.27 (s, 1H); 8.06 (s, 1H); 8.03 (d, 1H); 7.88 (d, 1H); 7.64 (s, 1H); 7.41 (dd, 1H); 7.03 (s, 1H); 4.05 (s, 3H); 3.88 (s, 3H). LRMS (ESI) calculated for C20H1679BrN4OS [M+H]+, 439.0; found 438.9.

Workup

  1. customThe mixture was sparged with argon for 10 minutes
  2. additionThe reaction mixture was diluted in ethyl acetate
  3. washwashed with saturated aqueous sodium hydrogen carbonate and brine
  4. dry with materialthen dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient)
  8. customto afford a tan solid
  9. customThe residue was purified by preparative HPLC Reverse phase (C-18)
  10. washeluting with Acetonitrile/Water+0.05% TFA
  11. additionThe fractions containing product
  12. additiondiluted in ethyl acetate
  13. washwashed with aqueous sodium bicarbonate
  14. dry with materialdried over sodium sulfate
  15. filtrationThe solution was filtered
  16. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-1047300f5aa141e3a70525f319f84950
Source dataset
uspto-grants-2013_06
Patent number
US08455477B2

Reaction notes

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