1,4-Dioxane → HCID 46175032, compound

HRID 1925121Notes

Reaction equation

HRID 1925121 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]4[N:15]([CH:17]=[C:18]([N:20](C(C5CC5)=O)[C:21]([CH:23]5[CH2:25][CH2:24]5)=[O:22])[N:19]=4)[N:16]=3)[C:6]=2[CH:31]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.O1CCOCC1>C([O-])([O-])=O.[Na+].[Na+].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].C(Cl)Cl>[CH3:32][N:33]1[CH:37]=[C:36]([C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[N:8][N:7]([CH2:10][C:11]4[CH:12]=[CH:13][C:14]5[N:15]([CH:17]=[C:18]([NH:20][C:21]([CH:23]6[CH2:24][CH2:25]6)=[O:22])[N:19]=5)[N:16]=4)[C:6]=3[CH:31]=2)[CH:35]=[N:34]1

Participants

6

Reactant 3

HCID 312751,4-DioxaneHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 59232987HCID 59232987, compound

Product 1

HCID 46175032HCID 46175032, compoundYield 135.9%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 10340Sodium CarbonateSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of N-(6-((6-bromo-1H-benzo[d][1,2,3]triazol-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)-N-(cyclopropanecarbonyl)cyclopropanecarboxamide 13E (0.7 g, 1.457 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.303 g, 1.457 mmol) and PdCl2(dppf)-CH2Cl2 (0.06 g, 0.075 mmol) in Na2CO3 (2N, 6 mL)/dioxane (12 mL) was heated in a microwave at 110° C. for 45 min. The reaction was filtered and rinsed with EtOAc. This reaction was repeated twice. The organic solutions were combined and washed with 5% citric acid followed by NaHCO3, dried with MgSO4, and filtered. MeOH was added to the EtOAc solution to give 5% MeOH (v/v), and the resulting solution was filtered through a short silica column and rinsed thoroughly with 5% MeOH/EtOAc. Activated charcoal (1 g) was added to the eluent and stirred at ambient temperature for 1 hr. The solution was filtered through Celite and concentrated to dryness via rotary evaporation. The resulting material was suspended in EtOAc (50 mL) and sonicated. The resulting solid was collected by filtration and rinsed with EtOAc to provide the title compound, N-(6-((6-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d][1,2,3]triazol-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide 13 (820 mg, 1.98 mmol, 45%). The filtrate was concentrated and reconstituted in 10% MeOH/EtOAc, loaded on a short silica column and eluted with 10% MeOH/EA to give provide additional product (190 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.76-0.86 (m, 4 H) 1.88-1.97 (m, 1 H) 3.88 (s, 3H) 6.15 (s, 2 H) 7.12 (d, J=9.35 Hz, 1 H) 7.66 (dd, J=8.72, 1.39 Hz, 1 H) 7.93-8.01 (m, 2 H) 8.04 (d, J=8.84 Hz, 1 H) 8.10 (s, 1 H) 8.17 (s, 1 H) 8.26 (s, 1 H) 11.18 (s, 1 H). MS:m/z 414.2 (M+H)+. MP 250.2-251.6° C.

Workup

  1. filtrationThe reaction was filtered
  2. washrinsed with EtOAc
  3. washwashed with 5% citric acid
  4. dry with materialdried with MgSO4
  5. filtrationfiltered
  6. additionMeOH was added to the EtOAc solution
  7. customto give 5% MeOH (v/v)
  8. filtrationthe resulting solution was filtered through a short silica column
  9. washrinsed thoroughly with 5% MeOH/EtOAc
  10. additionActivated charcoal (1 g) was added to the eluent
  11. filtrationThe solution was filtered through Celite
  12. concentrationconcentrated to dryness via rotary evaporation
  13. customsonicated
  14. filtrationThe resulting solid was collected by filtration
  15. washrinsed with EtOAc

Sources & evidence

ORD record
ord-77221d5307784bdfae90c5f2a8752a77
Source dataset
uspto-grants-2012_05
Patent number
US08178534B2

Reaction notes

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