5-Bromo-3-methylisothiazole → 6-(1-(6-(3-Methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline

HRID 1513828Notes

Reaction equation

HRID 1513828 reaction equation
Br[C:2]1[S:6][N:5]=[C:4]([CH3:7])[CH:3]=1.CC#N.C(=O)=O.Cl[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([CH:24]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[CH:31][CH:30]=[CH:29]4)[CH3:25])=[N:22][N:23]=2)[N:20]=1>C1COCC1.CN(C)C(=O)C.[Cl-].[Zn+2].[Cl-].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].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[CH3:7][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([CH:24]([C:26]4[CH:27]=[C:28]5[C:33](=[CH:34][CH:35]=4)[N:32]=[CH:31][CH:30]=[CH:29]5)[CH3:25])=[N:22][N:23]=3)[N:20]=2)[S:6][N:5]=1

Participants

9

Reactant 3

HCID 6009595-Bromo-3-methylisothiazoleHCID 249687116-(1-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinolineHCID 86587134Acetonitrile dry ice

Product 1

HCID 441805966-(1-(6-(3-Methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline

Reagents, catalysts & solvents 5

HCID 3007855ZincchlorideCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 129828017Ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane;iron(2+);(2,3,4,5-tetraphenylcyclopenta-1,4-dien-1-yl)benzeneCatalystHCID 8028TetrahydrofuranSolvent2×HCID 31374DimethylacetamideSolvent

Conditions

Temperature
-45 °C

Procedure

To a solution of 5-bromo-3-methylisothiazole (1.00 g, 5.6 mmol) in 10 mL of THF at −45° C. (CH3CN/dry ice) was added isopropylmagnesium chloride LiCl complex (7.9 ml, 7.9 mmol) (LiCl complex, 1 M in THF). The mixture was stirred at −45° C. for 20 minutes and to this was added zinc chloride, 0.5 M in THF (17 ml, 8.4 mmol) slowly via a syringe. The mixture was then warmed up to rt and continued to stir for additional 30 minutes. 6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (0.5787 g, 1.9 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.51 g, 0.56 mmol) and Q-Phos (0.65 g) in 15 mL of N,N-dimethyl acetamide was added to the reaction mixture. The reaction was warmed up to 50° C. for 6 hours and was quenched with 50 mL of satd. NH4Cl aq. solution. The mixture was extracted with 150 mL of EtOAc and the organic phase was washed with 60 mL of brine. The aqueous phases were further extracted with 100 mL EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH in EtOAc) to give afford a red solid. MS (ESI pos. ion) m/z: 373 (MH+). Calc'd exact mass for C20H16N6S: 372.

Workup

  1. temperatureThe mixture was then warmed up to rt
  2. stirringto stir for additional 30 minutes
  3. temperatureThe reaction was warmed up to 50° C. for 6 hours
  4. customwas quenched with 50 mL of satd
  5. extractionThe mixture was extracted with 150 mL of EtOAc
  6. washthe organic phase was washed with 60 mL of brine
  7. extractionThe aqueous phases were further extracted with 100 mL EtOAc
  8. dry with materialThe combined organics were dried over Na2SO4
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH in EtOAc)
  11. customto give
  12. customafford a red solid

Sources & evidence

ORD record
ord-90009d4fdec44538b088b50d630024da
Source dataset
uspto-grants-2012_07
Patent number
US08217177B2

Reaction notes

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