Dimethylformamide → N-[6-[3-[4-(Diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl]-2,2-dimethylglycine ethyl ester difumarate

HRID 397568Notes

Reaction equation

HRID 397568 reaction equation
[C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:27]([O:29][C:30](=[O:47])[C:31]([CH3:46])([CH3:45])[NH:32][C:33]([C:35]1[N:39]2[N:40]=[C:41](Cl)[CH:42]=[CH:43][C:38]2=[N:37][N:36]=1)=[O:34])[CH3:28].CN(C)[CH:50]=[O:51]>>[C:30]([OH:29])(=[O:47])/[CH:31]=[CH:46]/[C:17]([OH:18])=[O:51].[C:50]([OH:51])(=[O:8])/[CH:45]=[CH:31]/[C:30]([OH:47])=[O:29].[CH2:27]([O:29][C:30](=[O:47])[C:31]([CH3:46])([CH3:45])[NH:32][C:33]([C:35]1[N:39]2[N:40]=[C:41]([O:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)[CH:42]=[CH:43][C:38]2=[N:37][N:36]=1)=[O:34])[CH3:28]

Participants

5

Reactant 4

HCID 6228DimethylformamideHCID 24758Sodium hydrideHCID 229892644-(Diphenylmethoxy)piperidinepropanolHCID 23000300HCID 23000300, compound

Product 1

HCID 70028796N-[6-[3-[4-(Diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl]-2,2-dimethylglycine ethyl ester difumarate

Procedure

1.04 g of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 14 ml of N,N-dimethylformamide; 141 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature under reduced pressure for 50 minutes. Under ice cooling, 1.00 g of N-(6-chloro[1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl)-2,2-dimethylglycine ethyl ester was added, followed by stirring at ice temperature for 1 hour, then at room temperature for 2 hours. After saline was added, the reaction mixture was extracted with ethyl acetate-tetrahydrofuran (1:1) and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; 1.62 g of the residue was dissolved in 2 ml of pyridine; 1 ml of acetic anhydride was added, followed by stirring at room temperature for 15 hours. After saline was added, the reaction mixture was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; 1.32 g of the residue was dissolved in ethanol; a solution of 511 mg of fumaric acid in ethanol was added, followed by concentration under reduced pressure. The residue was powdered from diethyl ether and dried to yield 1.53 g of the title compound.

Workup

  1. stirringby stirring at ice temperature for 1 hour
  2. waitat room temperature for 2 hours
  3. additionAfter saline was added
  4. extractionthe reaction mixture was extracted with ethyl acetate-tetrahydrofuran (1:1)
  5. dry with materialdried over magnesium sulfate
  6. concentrationAfter concentration under reduced pressure
  7. washeluted with ethyl acetate-methanol-triethylamine (50:5:1)
  8. customThe desired fraction was collected
  9. concentrationconcentrated under reduced pressure
  10. dissolution1.62 g of the residue was dissolved in 2 ml of pyridine
  11. addition1 ml of acetic anhydride was added
  12. stirringby stirring at room temperature for 15 hours
  13. additionAfter saline was added
  14. extractionthe reaction mixture was extracted with ethyl acetate
  15. washwashed with saturated saline
  16. dry with materialdried over magnesium sulfate
  17. concentrationAfter concentration under reduced pressure
  18. washeluted with ethyl acetate-methanol-triethylamine (50:5:1)
  19. customThe desired fraction was collected
  20. concentrationconcentrated under reduced pressure
  21. dissolution1.32 g of the residue was dissolved in ethanol
  22. additiona solution of 511 mg of fumaric acid in ethanol was added
  23. concentrationfollowed by concentration under reduced pressure
  24. customdried

Sources & evidence

ORD record
ord-feff6fd073284842aa103eeb97c47295
Source dataset
uspto-grants-2003_08
Patent number
US06610694B1

Reaction notes

Loading…