Hydrochloric Acid → 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 hydrochloride

HRID 1925145Notes

Reaction equation

HRID 1925145 reaction equation
[F:1][C:2]([F:33])([C:18]1[N:22]2[CH:23]=[C:24]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[CH:25]=[CH:26][C:21]2=[N:20][N:19]=1)[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:11]=2)[N:8]=1.[ClH:34].CO.Cl.CO>C(Cl)Cl>[ClH:34].[F:33][C:2]([F:1])([C:18]1[N:22]2[CH:23]=[C:24]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[CH:25]=[CH:26][C:21]2=[N:20][N:19]=1)[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([NH:12][C:13]([CH:15]3[CH2:16][CH2:17]3)=[O:14])[N:11]=2)[N:8]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 887MethanolHCID 21893726Hydrochloride methanolHCID 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)cyclopropanecarboxamide

Product 1

HCID 66633890N-(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 hydrochloride

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Further, 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 hydrochloride was prepared by suspending crude 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 (2.2 g; 4.9 mmol) in 333 ml of DCM. 50 ml of 0.2 M HCl in MeOH (10 mmol) was added. The mixture was stirred vigorously for 60 minutes and Sili-Thiourea (commercially available from Silicycle; 1.12 g) was added. The mixture was stirred at room temperature for 14 hours, filtered through Celite and washed with 10% MeOH in DCM (40 ml) to provide a total volume of filtrate of about 420 ml. 15 ml of a 2M HCl MeOH solution was added. The solution was concentrated by rotavap at 225 mbar, 22° C. bath temperature to remove about 325 ml of solvent. The solution was checked for clarity to ensure that solid formation was minimized. 10 ml of a 2M HCl MeOH solution was added. The solution was seeded with 25 mg of 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 hydrochloride salt. The solution was allowed to continue to concentrate at 130 mbar to remove 65 ml solvent in the presence of seed crystal. After the solution turned cloudy, the solution was maintained at room temperature for 40 minutes. The mixture was cooled to 0° C., stirred for 2 hours, and the solids collected by filtration. The solids were dried in vacuum at 60° C. overnight to afford 1.75 g of a pale-yellow solid.

Workup

  1. addition1.12 g) was added
  2. stirringThe mixture was stirred at room temperature for 14 hours
  3. filtrationfiltered through Celite
  4. washwashed with 10% MeOH in DCM (40 ml)
  5. customto provide a total volume of filtrate of about 420 ml
  6. concentrationThe solution was concentrated by rotavap at 225 mbar, 22° C. bath temperature
  7. customto remove about 325 ml of solvent
  8. addition10 ml of a 2M HCl MeOH solution was added
  9. concentrationto concentrate at 130 mbar
  10. customto remove 65 ml solvent in the presence of seed crystal
  11. temperatureThe mixture was cooled to 0° C.
  12. stirringstirred for 2 hours
  13. filtrationthe solids collected by filtration
  14. customThe solids were dried in vacuum at 60° C. overnight

Sources & evidence

ORD record
ord-3ab7d4a71b9944fd85d16440f4d2eeec
Source dataset
uspto-grants-2012_05
Patent number
US08178534B2

Reaction notes

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