Acetic Acid → 1-[2-[2-(3-Hydroxy-1-azetidinyl)ethyl]phenyl]-2-piperidinone

HRID 2178532Notes

Reaction equation

HRID 2178532 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.Cl.[NH:18]1[CH2:21][CH:20]([OH:22])[CH2:19]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.[Cl-].[Na+].O.ClCCl.O>[OH:22][CH:20]1[CH2:21][N:18]([CH2:15][CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]2=[O:1])[CH2:19]1

Participants

9

Reactant 4

HCID 176Acetic AcidHCID 27592903-Hydroxyazetidine hydrochlorideHCID 5003444Sodium cyanoborohydrideHCID 89500863[2-(2-Oxopiperidin-1-yl)phenyl]acetaldehyde

Product 1

HCID 895006261-[2-[2-(3-Hydroxy-1-azetidinyl)ethyl]phenyl]-2-piperidinoneYield 12.7%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

To [2-(2-oxopiperidin-1-yl)phenyl]acetaldehyde a3-1 (1.32 g, 6.09 mmol, 1 eq) in methanol (50 ml) is added azetidin-3-ol hydrochloride al 1-0 (0.76 g, 6.96 mmol, 1.14 eq). After stirring at room temperature for approximately 30 minutes, acetic acid (522 μl, 9.13 mmol, 1.5 eq), then NaBH3CN (1.15 g, 18.26 mmol, 3 eq) are added. The reaction mixture is stirred overnight at room temperature, then filtered and loaded on an ion exchange acidic resin cartridge prewashed with methanol. The cartridge is then washed with approximately 3 column volumes of methanol, then eluted with 3 column volumes of 1M ammonia in methanol. This eluate is evaporated to dryness. To the residue obtained is added water (50 ml) and dichloromethane (50 ml). After vigorous shaking and addition of brine, the 2 phases are separated. The organic phase is washed with water (50 ml). The aqueous phases are pooled and washed 3 times with iPrOH/CH2Cl2 (25 ml/50 ml). The organic phases are combined, evaporated to dryness to give 212.6 mg of 1-{2-[2-(3-hydroxyazetidin-1-yl)ethyl]phenyl}piperidin-2-one a11-1 (212.6 mg, 0.775 mmole if assumed pure, 12.7% yield), which is used in next step without any further purification.

Workup

  1. stirringThe reaction mixture is stirred overnight at room temperature
  2. filtrationfiltered
  3. washThe cartridge is then washed with approximately 3 column volumes of methanol
  4. washeluted with 3 column volumes of 1M ammonia in methanol
  5. customThis eluate is evaporated to dryness
  6. customTo the residue obtained
  7. stirringAfter vigorous shaking
  8. customthe 2 phases are separated
  9. washThe organic phase is washed with water (50 ml)
  10. washwashed 3 times with iPrOH/CH2Cl2 (25 ml/50 ml)
  11. customevaporated to dryness

Sources & evidence

ORD record
ord-c1829c794e97424aae433a7868832205
Source dataset
uspto-grants-2015_06
Patent number
US09067930B2

Reaction notes

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