4-(Diphenylmethoxy)piperidinepropanol → 2-[6-[3-[4-(Diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl]-2-methylpropionitrile Hydrochloride

HRID 397561Notes

Reaction equation

HRID 397561 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.CC(C)([O-])C.[Na+].[Cl:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([C:38]([C:41]([CH3:45])([CH3:44])[C:42]#[N:43])=[N:39][N:40]=2)[N:37]=1>O1CCCC1>[ClH:31].[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([C:41]([CH3:45])([CH3:44])[C:42]#[N:43])=[N:39][N:40]=4)[N:37]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1

Participants

5

Reactant 3

HCID 229892644-(Diphenylmethoxy)piperidinepropanolHCID 230002902-[6-Chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-2-methylpropionitrileHCID 23676156Sodium t-butoxide

Product 1

HCID 230003052-[6-[3-[4-(Diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl]-2-methylpropionitrile HydrochlorideYield 47.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

6.55 g of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 100 ml of tetrahydrofuran; 2.12 g of sodium tert-butoxide was added, followed by stirring at an external temperature of 60° C. for 40 minutes. After cooling, 4.86 g of 2-[6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-2-methylpropionitrile was added, followed by refluxing under heating for 5 hours. After cooling, 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; in 7.90 g of the residue was dissolved in 5 ml of pyridine; 5 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 extracted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; the residue (6.26 g) was dissolved in ethanol; 1.52 ml of a 4 N solution of hydrogen chloride in ethyl acetate was added, followed by concentration under reduced pressure. The residue was crystallized from methanol-ethanol (1:5), washed with ethanol-ethyl acetate (1:5), and dried, to yield 5.19 g of the title compound.

Workup

  1. temperatureAfter cooling
  2. temperatureby refluxing
  3. temperatureunder heating for 5 hours
  4. temperatureAfter cooling
  5. additionsaline was added
  6. extractionthe reaction mixture was extracted with ethyl acetate
  7. washwashed with saturated saline
  8. dry with materialdried over magnesium sulfate
  9. concentrationAfter concentration under reduced pressure
  10. washeluted with ethyl acetate-methanol-triethylamine (50:5:1)
  11. customThe desired fraction was collected
  12. concentrationconcentrated under reduced pressure
  13. dissolutionin 7.90 g of the residue was dissolved in 5 ml of pyridine
  14. addition5 ml of acetic anhydride was added
  15. stirringby stirring at room temperature for 15 hours
  16. additionAfter saline was added
  17. extractionthe reaction mixture was extracted with ethyl acetate
  18. washwashed with saturated saline
  19. dry with materialdried over magnesium sulfate
  20. concentrationAfter concentration under reduced pressure
  21. extractionextracted with ethyl acetate-methanol-triethylamine (50:5:1)
  22. customThe desired fraction was collected
  23. concentrationconcentrated under reduced pressure
  24. dissolutionthe residue (6.26 g) was dissolved in ethanol
  25. addition1.52 ml of a 4 N solution of hydrogen chloride in ethyl acetate was added
  26. concentrationfollowed by concentration under reduced pressure
  27. customThe residue was crystallized from methanol-ethanol (1:5)
  28. washwashed with ethanol-ethyl acetate (1:5)
  29. customdried

Sources & evidence

ORD record
ord-a13b76abe6994977bee8f92642041bf1
Source dataset
uspto-grants-2003_08
Patent number
US06610694B1

Reaction notes

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