Sodium Bicarbonate → 2-[6-[4-[4-(Diphenylmethoxy)piperidino]butylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionic Acid
Reaction equation
[C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([C:36]([CH3:43])([CH3:42])[C:37]([O:39]CC)=[O:38])[N:35]=2)[N:32]=1.C(=O)(O)[O-].[Na+]>>[C:20]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][CH2:18][NH:19][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[C:34]([C:36]([CH3:43])([CH3:42])[C:37]([OH:39])=[O:38])[N:35]=4)[N:32]=3)[CH2:11][CH2:10]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1Participants
Reactant 3
Product 1
Procedure
1.56 g of 4-(diphenylmethoxy)-1-piperidinebutanamine and 617 mg of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were stirred at 185° C. for 3 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated 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, concentrated under reduced pressure and dissolved in 5 ml of ethyl acetate; 0.52 ml of a 4 N hydrogen chloride solution in ethyl acetate was added, followed by concentration. The residue was dissolved in 4 ml of ethanol; 4 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 4 hours; 1 ml of a 2 N aqueous solution of sodium hydroxide was added, followed by stirring at 50° C. for 16 hours. The mixture was concentrated under reduced pressure. The residue was diluted with water and washed with ethyl acetate; the water layer was adjusted to pH 4.5 by the addition of 4 N hydrochloric acid and extracted with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was powdered by the addition of ethyl acetate, collected by filtration and dried to yield 271 mg of the title compound.
Workup
- temperatureAfter cooling
- extractionfollowed by extraction with ethyl acetate
- washthe extract was washed with saturated saline
- dry with materialdried over magnesium sulfate
- concentrationconcentrated under reduced pressure
- washeluted with ethyl acetate:methanol:triethylamine (50:5:1)
- customThe desired fraction was collected
- concentrationconcentrated under reduced pressure
- dissolutiondissolved in 5 ml of ethyl acetate
- addition0.52 ml of a 4 N hydrogen chloride solution in ethyl acetate was added
- concentrationfollowed by concentration
- dissolutionThe residue was dissolved in 4 ml of ethanol
- addition4 ml of a 1 N aqueous solution of sodium hydroxide was added
- addition1 ml of a 2 N aqueous solution of sodium hydroxide was added
- stirringby stirring at 50° C. for 16 hours
- concentrationThe mixture was concentrated under reduced pressure
- additionThe residue was diluted with water
- washwashed with ethyl acetate
- additionthe water layer was adjusted to pH 4.5 by the addition of 4 N hydrochloric acid
- extractionextracted with ethyl acetate-tetrahydrofuran (1:1)
- washthe extract was washed with saturated saline
- dry with materialdried over magnesium sulfate
- concentrationconcentrated under reduced pressure
- additionThe residue was powdered by the addition of ethyl acetate
- filtrationcollected by filtration
- customdried
Sources & evidence
- ORD record
- ord-1598175b8fc54b56b2d28f3f566fb7b4
- Source dataset
- uspto-grants-2003_09
- Patent number
- US06627630B1
Reaction notes
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