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Diisopropylethylamine → 6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-4-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-quinoline

HRID 1890965
Notes
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Reaction equation

HRID 1890965 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](Br)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:64][C:65]1[CH:66]=[CH:67][C:68]2[N:69]([C:71]([SH:74])=[N:72][N:73]=2)[N:70]=1.ClC1C2C(=CC=C(SC3N4N=C(C)C=CC4=NN=3)C=2)N=CC=1.BrC1C=C2C(=CC=1)N=CC=C2SC1N2N=C(C)C=CC2=NN=1.[CH3:119][N:120]1[CH:124]=[N:123][N:122]=[C:121]1[SH:125]>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]>[CH3:64][C:65]1[CH:66]=[CH:67][C:68]2[N:69]([C:71]([S:74][C:9]3[CH:10]=[C:11]4[C:6](=[CH:7][CH:8]=3)[N:5]=[CH:4][CH:3]=[C:2]4[S:125][C:121]3[N:120]([CH3:119])[CH:124]=[N:123][N:122]=3)=[N:72][N:73]=2)[N:70]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

10

Reactant 7

HCID 81531DiisopropylethylamineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 51395376-Bromo-4-chloroquinolineHCID 689019394-Chloro-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinolineHCID 689763766-Bromo-4-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline
HCID 178423528
HCID 178423528, compound
HCID 178481306HCID 178481306, compound

Product 1

HCID 579110176-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-4-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-quinolineYield 39.4%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolvent2×

Conditions

Temperature
100 °C

Procedure

A solution of 4-chloro-6-bromoquinoline (1.6 g, 6.63 mmol), diisopropylethylamine (1.93 mL, 11.05 mmol) in DMF (20 mL) under nitrogen was degassed by bubbling in nitrogen for 30 min. Tris(dibenzylideneacetone)dipalladium (506 mg, 0.552 mmol), Xantphos (640 mg, 1.105 mmol), and 6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (1.0 g, 5.525 mmol) were added. The reaction mixture was stirred at 100° C. for 18 h. The reaction mixture was cooled to room temperature, and partitioned between 1 N aqueous NaOH and 10% methanol/di-chloromethane. The aqueous layer was extracted with 10% methanol/dichloromethane (3×) and the combined organic layers were adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-6% methanol/dichloromethane afforded 468 mg of a (1:1) mixture of 4-chloro-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline and 6-bromo-4-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline as a beige solid. The (1:1) mixture (70 mg) was dissolved in DMF (0.5 mL), and 4-methyl-4H-[1,2,4]triazole-3-thiol (12 mg, 0.1 mmol) was added. The reaction mixture was stirred at 60° C. for 21 h then at 80° C. for 25 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between 1 N aqueous NaOH and 10% methanol/dichloromethane. The aqueous layer was extracted with 10% methanol/dichloromethane (2×) and the combined organic layers were adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-10% methanol/dichloromethane afforded 16 mg of 6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-4-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-quinoline as a cream color solid (78% yield).

Workup

  1. customby bubbling in nitrogen for 30 min
  2. temperatureThe reaction mixture was cooled to room temperature
  3. custompartitioned between 1 N aqueous NaOH and 10% methanol/di-chloromethane
  4. extractionThe aqueous layer was extracted with 10% methanol/dichloromethane (3×)
  5. customPurification by flash chromatography on silica gel using a gradient of 0-6% methanol/dichloromethane
  6. customafforded
  7. stirringThe reaction mixture was stirred at 60° C. for 21 h
  8. waitat 80° C. for 25 h
  9. temperatureThe reaction mixture was cooled to room temperature
  10. concentrationconcentrated in vacuo
  11. customThe residue was partitioned between 1 N aqueous NaOH and 10% methanol/dichloromethane
  12. extractionThe aqueous layer was extracted with 10% methanol/dichloromethane (2×)
  13. customPurification by flash chromatography on silica gel using a gradient of 0-10% methanol/dichloromethane

Sources & evidence

ORD record
ord-7e9db9b9f5b84d13bb7337877252b527
Source dataset
uspto-grants-2013_08
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08507489B2

Reaction notes

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