Dichloromethane → N-[3-(7-chloroimidazo[1,2-b]pyridazin-3-yl)phenyl]-N'-(2,2,2-trifluoroethyl)urea

HRID 407003Notes

Reaction equation

HRID 407003 reaction equation
[Cl:1][C:2]1[CH:7]=[N:6][N:5]2[C:8](I)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:23]=[CH:24][CH:25]=2)O1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[N:6][N:5]2[C:8]([C:24]3[CH:23]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:32])([F:33])[F:34])=[O:28])[CH:21]=[CH:20][CH:25]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 574976911-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-ureaHCID 679805887-Chloro-3-iodoimidazo[1,2-b]pyridazine

Product 1

HCID 67980172N-[3-(7-chloroimidazo[1,2-b]pyridazin-3-yl)phenyl]-N'-(2,2,2-trifluoroethyl)ureaYield 53.3%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of 7-chloro-3-iodoimidazo[1,2-b]pyridazine (1.40 g, 5.01 mmol), N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (1.76 g, 5.11 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (DCM) (1:1) (164 mg, 0.200 mmol), and potassium carbonate (2.08 g, 15.0 mmol) in 1,4-dioxane (15 mL) and water (5 mL) was degassed and recharged with nitrogen three times. The mixture was then heated and stirred at 60° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was treated with DCM (3 mL) and acetonitrile (3 mL). The precipitate was collected by filtration and washed with acetonitrile, dried under vacuum to afford the desired product (0.988 g). The filtrate (mother liquid) was concentrated. The residue was purified by flash chromatography on a silica gel column with methanol in DCM (0-10%) to afford the additional product 0.17 g. The total product is 1.158 g (62.5%). LCMS (M+H)+: m/z=370.0/372.0.

Workup

  1. customwas degassed
  2. temperatureThe mixture was then heated
  3. temperatureAfter cooling
  4. additionthe mixture was diluted with ethyl acetate
  5. washwashed with water and brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. additionThe residue was treated with DCM (3 mL) and acetonitrile (3 mL)
  10. filtrationThe precipitate was collected by filtration
  11. washwashed with acetonitrile
  12. customdried under vacuum

Sources & evidence

ORD record
ord-c9267db2019946508433822d1bedf61f
Source dataset
uspto-grants-2014_06
Patent number
US08754114B2

Reaction notes

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