Potassium Carbonate → 4-[(1-{2-[2-(2-Oxopiperidin-1-yl)phenyl]ethyl}azetidin-3-yl)oxy]benzonitrile oxalate

HRID 2178534Notes

Reaction equation

CS([O:5][CH:6]1[CH2:9][N:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=[O:24])[CH2:7]1)(=O)=O.[OH:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1.[C:34]([O-:37])([O-:36])=O.[K+].[K+]>C(#N)C.C(#N)C.C(Cl)Cl.CO.CN(C=O)C>[C:19]([OH:24])(=[O:25])[C:34]([OH:37])=[O:36].[O:24]=[C:19]1[CH2:20][CH2:21][CH2:22][CH2:23][N:18]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH2:10][N:8]1[CH2:9][CH:6]([O:5][C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[CH2:7]1

Participants

Conditions

Temperature: 100 °C

Procedure

To 1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}azetidin-3-yl methanesulfonate a11-2 (273 mg, 0.775 mmol, 1 eq) and 4-hydroxybenzonitrile (110.8 mg, 0.93 mmol, 1.2 eq) in acetonitrile (5 ml) is added, under stirring, K2CO3 (374.9 mg, 2.71 mmol, 3.5 eq). The reaction mixture is heated at 100° C. for 10 minutes under microwave conditions. The reaction mixture is cooled, diluted with a mixture of acetonitrile/CH2Cl2/MeOH/DMF (1/1/1/1) (approximately 10 ml) to ensure the solubilisation of the expected product. The suspension obtained is loaded on an ion exchange acidic resin cartridge (2 g) prewashed with methanol. The cartridge is washed with approximately 3 column volumes of methanol, then eluted with 3 column volumes of 1M ammonia in methanol. The eluate is evaporated to dryness and the crude material is purified by reverse phase chromatography (gradient: acetonitrile//H2O/NH4OH from 40/60/0.1 to 70/30/0.1 in 10 minutes). The residue obtained is dissolved in acetone (approximately 2 ml) and oxalic acid (4.4 mg, 0.05 mmole, 1 eq) in acetone (2 ml) is added. This solution is evaporated slowly and some crystals appear. Acetone (approximately 2 ml) then diethylether (approximately 10 ml) are added to give a white precipitate which is filtrated, extensively washed with diethylether and dried overnight at 40° C. under vacuum to afford 15.5 mg of 4-[(1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}azetidin-3-yl)oxy]benzonitrile oxalate 55.

Workup

temperatureThe reaction mixture is cooled

Sources & evidence

ORD record: ord-de5570e68ffc4cfc8537cdffa0495dc9
Source dataset: uspto-grants-2015_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09067930B2

Reaction notes

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