1-Ethynyl-2,4-difluorobenzene → 6-((2,4-Difluorophenyl)ethynyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine

HRID 1929983Notes

Reaction equation

HRID 1929983 reaction equation
Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23])#[CH:15]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C:14]#[C:15][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1

Participants

6

Reactant 2

HCID 50638201-Ethynyl-2,4-difluorobenzeneHCID 397324056-Chloro-3-(propan-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine

Product 1

HCID 579299326-((2,4-Difluorophenyl)ethynyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazineYield 64.1%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

A solution of 6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (20.0 g, 102 mmol, Preparation #G.1) in DMF (300 mL) was evacuated and purged with nitrogen 3 times. To the reaction mixture was added 1-ethynyl-2,4-difluorobenzene (21.1 g, 153 mmol), CuI (0.969 g, 5.09 mmol), TEA (42.5 mL, 305 mmol) and bis(triphenylphosphine)palladium(II) chloride (3.57 g, 5.09 mmol). The reaction mixture was evacuated and purged with nitrogen 3 times. The reaction mixture was heated to about 60° C. for about 6 h, cooled to ambient temperature, and diluted with EtOAc (500 mL). The organic solution was washed with water (3×500 mL), brine (500 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was dissolved in a minimal amount of hot DCM and allowed to cool to ambient temperature. The solid 1,2-bis(2,4-difluorophenyl)ethyne (6.7 g, 26.3%) was filtered off and the filtrate was purified by silica gel chromatography using heptane/EtOAc (gradient, 1:1 to 0:1) to give product. The product was then precipitated by dissolving in EtOAc (500 mL) and adding heptane (100 mL portions) while concentrating in vacuo. The solid was collected by vacuum filtration and dried under vacuum to give the title compound (19.5 g, 64%) as an off white solid. LC/MS (Table 1, Method a) Rt=2.72 min; MS m/z: 299.1 (M+H)+.

Workup

  1. custompurged with nitrogen 3 times
  2. customThe reaction mixture was evacuated
  3. custompurged with nitrogen 3 times
  4. temperaturecooled to ambient temperature
  5. additiondiluted with EtOAc (500 mL)
  6. washThe organic solution was washed with water (3×500 mL), brine (500 mL)
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. dissolutionThe crude material was dissolved in a minimal amount of hot DCM
  11. temperatureto cool to ambient temperature
  12. filtrationThe solid 1,2-bis(2,4-difluorophenyl)ethyne (6.7 g, 26.3%) was filtered off
  13. customthe filtrate was purified by silica gel chromatography
  14. customto give product
  15. customThe product was then precipitated
  16. dissolutionby dissolving in EtOAc (500 mL)
  17. additionadding heptane (100 mL portions)
  18. concentrationwhile concentrating in vacuo
  19. filtrationThe solid was collected by vacuum filtration
  20. customdried under vacuum

Sources & evidence

ORD record
ord-a18fe073eb964d099603238ef5634827
Source dataset
uspto-grants-2012_05
Patent number
US08188083B2

Reaction notes

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