Triphenylphosphine → 6-[4-[4-[2-(4-Acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine

HRID 2381104Notes

Reaction equation

HRID 2381104 reaction equation
[F:1][C:2]([F:26])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][N:52]([C:55](=[O:57])[CH3:56])[CH2:51][CH2:50]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl.CCCCCCC>[C:55]([N:52]1[CH2:53][CH2:54][N:49]([CH2:48][CH2:47][O:24][C:21]2[CH:22]=[CH:23][C:18]([CH:15]3[CH2:16][CH2:17][N:12]([C:9]4[CH:10]=[CH:11][C:6]5[N:7]([C:3]([C:2]([F:1])([F:25])[F:26])=[N:4][N:5]=5)[N:8]=4)[CH2:13][CH2:14]3)=[CH:19][CH:20]=2)[CH2:50][CH2:51]1)(=[O:57])[CH3:56]

Participants

7

Reactant 4

HCID 11776TriphenylphosphineHCID 75555Diisopropyl diazene-1,2-dicarboxylateHCID 47396291-Acetyl-4-(2-hydroxyethyl)piperazineHCID 367300784-(1-(3-(Trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenol

Product 1

HCID 591497636-[4-[4-[2-(4-Acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazineYield 85.9%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8900HeptaneSolvent

Conditions

Temperature
23.5 °C

Procedure

Dichloromethane (225.0 mL) and 4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (50.0 g, 138 m mol) were charged to a suitable round bottom flask at 22-25° C. Triphenylphosphine (72.2 g, 275 m mol) and 1-[4-(2-hydroxy-ethyl)piperazin-1-yl]ethanone [CAS: 83502-55-0] (47.4 g, 275 m mol) were added successively to the reaction mass and stirred for 10 min at 22-25° C. Di-isopropyl azodicarboxylate (55.65 g, 275 m mol) in dichloromethane (75.0 mL) was added to the reaction mass slowly drop wise at 25-30° C. over a period of 60-90 min. The resulting reaction mass was stirred for 1.0 h at 25-30° C. to complete the reaction. n-Heptane (600.0 mL) was introduced to the reaction mass by drop wise addition over a period of 15-30 min at 22-25° C. and stirred for 30 min at the same temperature. Thus precipitated solid was filtered and washed with n-heptane (150.0 mL). The material was then suck dried for 30 min under reduced pressure. The crude material was purified by slurry washing in methanol (325.0 mL) at 22-25° C. The solid was then collected by filtration and washed with methanol (50.0 mL). The material was dried under reduced pressure with nitrogen gas bleed at 50° C. to afford the desired product 6-[4-[4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (61.2 g, 84%) as a free flowing solid.

Workup

  1. waitslowly drop wise at 25-30° C. over a period of 60-90 min
  2. customThe resulting reaction mass
  3. stirringwas stirred for 1.0 h at 25-30° C.
  4. customthe reaction
  5. stirringstirred for 30 min at the same temperature
  6. filtrationThus precipitated solid was filtered
  7. washwashed with n-heptane (150.0 mL)
  8. customThe material was then suck dried for 30 min under reduced pressure
  9. customThe crude material was purified by slurry
  10. washwashing in methanol (325.0 mL) at 22-25° C
  11. filtrationThe solid was then collected by filtration
  12. washwashed with methanol (50.0 mL)
  13. customThe material was dried under reduced pressure with nitrogen gas
  14. custombleed at 50° C.

Sources & evidence

ORD record
ord-19408ee4b1424e939dd674a0301a9928
Source dataset
uspto-grants-2012_09
Patent number
US08258140B2

Reaction notes

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