Hydrochloric Acid → HCID 9937786, compound

HRID 1169159Notes

Reaction equation

HRID 1169159 reaction equation
[C:1]1([CH:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[C:26]([C:28]([CH3:35])([CH3:34])[C:29]([O:31]CC)=[O:30])[N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl.C(OCC)(=[O:47])C>O>[OH2:8].[OH2:47].[C:36]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[C:26]([C:28]([CH3:35])([CH3:34])[C:29]([OH:31])=[O:30])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1

Participants

6

Reactant 4

HCID 313Hydrochloric Acid2×HCID 8857Ethyl AcetateHCID 14798Sodium HydroxideHCID 9872422Ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate

Product 1

HCID 9937786HCID 9937786, compoundYield 80.1%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent2×

Conditions

Temperature
60 °C

Procedure

In 24 L of dimethyl sulfoxide were suspended 14.5 kg (44.68 mol) of 4-(diphenylmethoxy)-1-piperidinepropaneamine, 8.0 kg (29.88 mol) of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate, 6.3 kg (59.43 mol) of sodium carbonate and 300 g (2.92 mol) of sodium bromide, which were then heated to 145±5° C. under a nitrogen atmosphere and stirred for 7 hours. After cooling to room temperature, 80 L of ethyl acetate and 80 L of water were added, followed by separation into two layers. The organic layer was washed with 40 L of water twice and concentrated under reduced pressure. To the residue was added 60 L of ethanol and concentrated until the total volume became 40 L under reduced pressure to yield a solution of crude ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate in ethanol. To the ethanol solution was added 2.4 kg of sodium hydroxide dissolved in 8 L of water. The reaction mixture was heated to 60±5° C. and stirred for 1 hour. The reaction mixture was cooled to 30±5° C. and adjusted to pH 10 or lower by the addition of 13 L of 3N hydrochloric acid, followed by the addition of 56 L of ethyl acetate. The mixture was adjusted to pH 6-7 by the addition of 13 L of 3N hydrochloric acid and 6 L of water was added thereto. The crystals formed were collected by filtration, washed with 40 L of a mixed solvent of water:ethanol:ethyl acetate (1:1:1), and dried to yield 13.5 kg of the title compound. HPLC purity area percentage 98.0%, Yield 80.1%.

Workup

  1. temperatureThe reaction mixture was cooled to 30±5° C.
  2. additionwas added
  3. customThe crystals formed
  4. filtrationwere collected by filtration
  5. washwashed with 40 L of a mixed solvent of water:ethanol:ethyl acetate (1:1:1)
  6. customdried

Sources & evidence

ORD record
ord-91bf4a63d87d4279b8f6ec56e90de9d9
Source dataset
uspto-grants-2003_09
Patent number
US06627630B1

Reaction notes

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