Trifluoroacetic acid → 6-(6-Methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-3-(1h-pyrazol-4-yl)-quinoline

HRID 1890968Notes

Reaction equation

HRID 1890968 reaction equation
Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12][C:13]1[N:17]3[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=1)=[CH:7][CH:6]=2.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][N:34](COCC[Si](C)(C)C)[CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C(F)(F)F)=O>O1CCOCC1>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([S:12][C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]=[CH:3][C:2]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[CH:11]4)=[N:14][N:15]=2)[N:18]=1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 10340Sodium CarbonateHCID 249009763-Bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinolineHCID 574776664-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

Product 1

HCID 249011206-(6-Methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-3-(1h-pyrazol-4-yl)-quinolineYield 44.5%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

A microwave vessel was charged with 3-bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline (970 mg, 2.606 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole (930 mg, 2.866 mmol), and dichlorobis(triphenylphosphine) palladium(0) (92 mg, 0.13 mmol). 1,4-Dioxane (10 mL) and a 2 M aqueous solution of sodium carbonate (5 mL) were added. The vessel was capped and microwaved at 130° C. for 30 min. The reaction mixture was partitioned between water and 10% methanol/dichloromethane. The aqueous layer was extracted with 10% methanol/dichloromethane, and the combined organics were adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-8% methanol/dichloromethane afforded 1.073 g of the crude coupling product as a light brown oil. The oil was treated with TFA (10 mL). The reaction mixture was stirred at room temperature for 2 h, before concentrating in vacuo. The residue was treated with 1 N aqueous NaOH, and the precipitate was filtered, washed sequentially with water and ethyl acetate. The resulting yellow solid was dissolved in 10% methanol/dichloromethane and adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-10% methanol/dichloromethane afforded 417 mg of impure 6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-3-(1H-pyrazol-4-yl)-quinoline. Purification of 30 mg of material by mass-triggered HPLC (5-95% CH3CN/H2O, 0.1% HCOOH modifier) provided 12 mg of pure 6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-3-(1H-pyrazol-4-yl)-quinoline.

Workup

  1. customThe vessel was capped
  2. custommicrowaved at 130° C. for 30 min
  3. customThe reaction mixture was partitioned between water and 10% methanol/dichloromethane
  4. extractionThe aqueous layer was extracted with 10% methanol/dichloromethane
  5. customPurification by flash chromatography on silica gel using a gradient of 0-8% methanol/dichloromethane
  6. customafforded 1.073 g of the crude coupling product as a light brown oil
  7. concentrationbefore concentrating in vacuo
  8. additionThe residue was treated with 1 N aqueous NaOH
  9. filtrationthe precipitate was filtered
  10. washwashed sequentially with water and ethyl acetate
  11. dissolutionThe resulting yellow solid was dissolved in 10% methanol/dichloromethane
  12. customPurification by flash chromatography on silica gel using a gradient of 0-10% methanol/dichloromethane

Sources & evidence

ORD record
ord-0840abe58dc14f2f88e55dc2f6ad7dec
Source dataset
uspto-grants-2013_08
Patent number
US08507489B2

Reaction notes

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