Dichloromethane → N-(6-(Difluoro(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide

HRID 1925148Notes

Reaction equation

HRID 1925148 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:28])([F:27])[C:12]3[CH:13]=[CH:14][C:15]4[N:16]([CH:18]=[C:19]([NH:21][C:22]([CH:24]5[CH2:26][CH2:25]5)=[O:23])[N:20]=4)[N:17]=3)=[N:9][N:10]=2)[CH:7]=1.[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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]>[F:27][C:11]([F:28])([C:8]1[N:6]2[CH:7]=[C:2]([C:33]3[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([NH:21][C:22]([CH:24]3[CH2:26][CH2:25]3)=[O:23])[N:20]=2)[N:17]=1

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 59233213N-(6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide

Product 1

HCID 56593558N-(6-(Difluoro(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamideYield 71.1%

Reagents, catalysts & solvents 2

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

Procedure

A mixture of N-(6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (7.2 g, 16.06 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.01 g, 24.10 mmol) and PdCl2(dppf):CH2Cl2 (0.655 g, 0.803 mmol) in 1,4-Dioxane:1M Na2CO3 (Ratio: 2.1, Volume: 100 ml) was heated at 95° C. for 4 h. The reaction mixture cooled and concentrated to dryness via rotary evaporation, diluted with EtOAc and water. The resulting solid was collected by filtration, rinsed with H2O followed by EtOAc. The grey color solid dissolved in 20% MeOH in chloroform and treated with activated charcoal for overnight, filtered through a pad of celite and the celite pad rinsed with 20% MeOH in chloroform until no compound detected by HPLC. This solution passed through a silica gel column. The solvent evaporated and the resulting solid rinsed with EtOAc, MeOH, followed by EtOAc and then Et2O, dried under vacuum to provide N-(6-(difluoro(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (5.13 g, 11.41 mmol, 71.1% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 8.71 (s, 1H), 8.41 (s, 1H), 8.19-8.34 (m, 2H), 8.00-8.12 (m, 2H), 7.91 (dd, J=1.64, 9.47 Hz, 1H), 7.71 (d, J=9.35 Hz, 1H), 3.88 (s, 3H), 1.88-2.02 (m, 1H), 0.83 (d, J=6.32 Hz, 4H). ESI-MS:m/z 450.1 (M+H)+. MP: 274.9° C.

Workup

  1. temperatureThe reaction mixture cooled
  2. concentrationconcentrated to dryness via rotary evaporation
  3. additiondiluted with EtOAc and water
  4. filtrationThe resulting solid was collected by filtration
  5. washrinsed with H2O
  6. dissolutionThe grey color solid dissolved in 20% MeOH in chloroform
  7. additiontreated with activated charcoal for overnight
  8. filtrationfiltered through a pad of celite
  9. washthe celite pad rinsed with 20% MeOH in chloroform until no compound
  10. customThe solvent evaporated
  11. washthe resulting solid rinsed with EtOAc, MeOH
  12. dry with materialEt2O, dried under vacuum

Sources & evidence

ORD record
ord-317c70a53a4a48b6849d80177795450b
Source dataset
uspto-grants-2012_05
Patent number
US08178534B2

Reaction notes

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