Acetic Acid → 3-(1-{2-[2-(2-Oxopiperidin-1-yl)phenyl]ethyl}azetidin-3-yl)benzonitrile oxalate

HRID 2178521Notes

Reaction equation

HRID 2178521 reaction equation
[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH:15]=O.[NH:17]1[CH2:20][CH:19]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])[CH2:18]1.C(O)(=O)C.[BH3-]C#N.[Na+].[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39]>CO.CC(C)=O>[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:17]1[CH2:20][CH:19]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])[CH2:18]1

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 971Oxalic AcidHCID 5003444Sodium cyanoborohydrideHCID 552549933-(Azetidin-3-yl)benzonitrileHCID 89500863[2-(2-Oxopiperidin-1-yl)phenyl]acetaldehyde

Product 1

HCID 715234573-(1-{2-[2-(2-Oxopiperidin-1-yl)phenyl]ethyl}azetidin-3-yl)benzonitrile oxalateYield 31%

Reagents, catalysts & solvents 2

HCID 180AcetoneSolventHCID 887MethanolSolvent2×

Procedure

To [2-(2-oxopiperidin-1-yl)phenyl]acetaldehyde a3-1 (108.6 mg, 0.5 mmol, 1 eq) and 3-(azetidin-3-yl)benzonitrile a3-2 (97.33 mg, 0.5 mmole, 1 eq) in methanol (4 ml) are added acetic acid (42.9 μl, 0.75 mmol, 1.5 eq) then NaBH3CN (94.3 mg, 1.5 mmol, 3 eq). The reaction mixture is stirred overnight at room temperature. The crude reaction mixture is then loaded on an ion exchange acidic resin cartridge (2 g) prewashed with methanol. The cartridge is washed twice with approximately 3 column volumes of methanol, then eluted with 3 column volumes of 1M NH3 in methanol. This eluate is evaporated to dryness to give 141 mg of a crude material which is purified by reverse phase chromatography (basic mode; gradient: H2O/acetonitrile/NH4OH from 60/40/0.1 to 30/70/0.1 in 10 minutes). The residue obtained is redissolved in acetone (approximately 3 ml), and after addition of oxalic acid (22.7 mg, 0.25 mmol, 1 eq), a precipitate slowly appeared. This precipitate is filtered, washed with diethylether and dried overnight under vacuum at 40° C. to afford 69.6 mg of 3-(1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}azetidin-3-yl)benzonitrile oxalate 31.

Workup

  1. customThe crude reaction mixture
  2. washThe cartridge is washed twice with approximately 3 column volumes of methanol
  3. washeluted with 3 column volumes of 1M NH3 in methanol
  4. customThis eluate is evaporated to dryness
  5. customto give 141 mg of a crude material which
  6. customis purified by reverse phase chromatography (basic mode; gradient: H2O/acetonitrile/NH4OH from 60/40/0.1 to 30/70/0.1 in 10 minutes)
  7. customThe residue obtained
  8. filtrationThis precipitate is filtered
  9. washwashed with diethylether
  10. customdried overnight under vacuum at 40° C.

Sources & evidence

ORD record
ord-051dc52ed67b47a38c586ccdb9ab1ff3
Source dataset
uspto-grants-2015_06
Patent number
US09067930B2

Reaction notes

Loading…