Ethyl Acetate → Ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate

HRID 1169155Notes

Reaction equation

HRID 1169155 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][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CS(C)=O.O>[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][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:41])([CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 10340Sodium CarbonateHCID 109693934-(Diphenylmethoxy)-1-piperidinepropaneamineHCID 11043751Ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropanoate

Product 1

HCID 9872422Ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionateYield 141.1%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Conditions

Temperature
160 °C

Procedure

In 300 mL of dimethyl sulfoxide were suspended 181.8 g (560 mmol) of 4-(diphenylmethoxy)-1-piperidinepropaneamine, 100.0 g (374 mmol) of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate and 79.18 g (747 mmol) of sodium carbonate, which were then heated to 160° C. under a nitrogen atmosphere and stirred for 2 hours. After cooling to room temperature, 1000 mL of ethyl acetate and 1000 mL of water were added, followed by separation into two layers. The organic layer was washed with 500 mL of water twice and concentrated under reduced pressure. To the residue was added 500 mL of ethanol and concentrated under reduced pressure to yield 293.3 g of crude ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate as an oily material (HPLC purity area percentage 58.3%). This oily material was dissolved in 700 mL of ethanol, and 29.88 g of sodium hydroxide dissolved in 300 mL of water was added thereto. The reaction solution was heated to 60° C. and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue were added 1000 mL of water and 1000 mL of ethyl acetate, followed by separation into two layers. The aqueous layer was washed with 500 mL of ethyl acetate twice, and 1000 mL of ethanol was added to the aqueous layer. After the aqueous layer was adjusted to about pH 6 by the addition of 500 mL of 1N hydrochloric acid, the crystals formed were collected by filtration, washed with 400 mL of water and 400 mL of ethanol:water (1:1), and dried to yield 137.8 g of the title compound. HPLC purity area percentage 92.5%, Yield 60.6%.

Workup

  1. temperatureAfter cooling to room temperature
  2. customfollowed by separation into two layers
  3. washThe organic layer was washed with 500 mL of water twice
  4. concentrationconcentrated under reduced pressure
  5. additionTo the residue was added 500 mL of ethanol
  6. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-8084dd1d97c8456c90902fe1dc8d4fca
Source dataset
uspto-grants-2003_09
Patent number
US06627630B1

Reaction notes

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