Dichloromethane → 1-(4-Isopropoxy-3-methoxy-benzoyl)piperidin-4-one

HRID 1478426Notes

Reaction equation

HRID 1478426 reaction equation
O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[OH-].[Na+].[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])([CH3:14])[CH3:13].C(Cl)Cl>C1(C)C=CC=CC=1.O>[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])([CH3:14])[CH3:13]

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 14798Sodium Hydroxide2×HCID 2723901PiperonylamineHCID 467796443-Methoxy-4-(1-methylethoxy)benzoyl chloride

Product 1

HCID 897046151-(4-Isopropoxy-3-methoxy-benzoyl)piperidin-4-oneYield 29.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent

Procedure

Piperidin-4-one hydrochloride hydrate (29.2 g, 190 mmol) was dissolved in an aqueous solution of sodium hydroxide (95 mL of 2.0 M, 190 mmol). The resulting clear solution was then stirred under nitrogen in an ice water bath. 4-isopropoxy-3-methoxy-benzoyl chloride (43.5 g, 190 mmol) was dissolved in toluene (90 mL) to provide a final volume of 100 mL. This solution was added dropwise in 2 mL portions followed by addition of 1 mL of an aqueous sodium hydroxide (48 mL of 4.0 M, 192 mmol) solution. This process was repeated until both reagents were completely added. When complete, the reaction mixture was allowed to stir at 0° C. for an additional 30 minutes. To the mixture was added CH2Cl2 (250 mL) followed by water (200 mL). The mixture was mixed well in a separatory funnel, and the aqueous layer was further extracted with CH2Cl2 (2×100 mL). Organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide a dark brown oil. Purification was performed by column chromatography to provide 1-(4-isopropoxy-3-methoxy-benzoyl)piperidin-4-one (16.56 g) as a clear light brown oil that crystallized to a slightly tan white solid upon standing. 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J=1.9 Hz, 1H), 7.02 (dd, J=8.2, 2.0 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 4.59 (dt, J=12.2, 6.1 Hz, 1H), 3.90-3.88 (br s, 4H), 3.88 (s, 3H), 2.51 (s, 4H), 1.40 (d, J=6.1 Hz, 6H). ESI-MS m/z calc. 291.15, found 292.0 (M+1)+; Retention time: 0.94 minutes (3 minute run).

Workup

  1. customto provide a final volume of 100 mL
  2. additionThis solution was added dropwise in 2 mL portions
  3. additionwere completely added
  4. stirringto stir at 0° C. for an additional 30 minutes
  5. additionThe mixture was mixed well in a separatory funnel
  6. extractionthe aqueous layer was further extracted with CH2Cl2 (2×100 mL)
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customto provide a dark brown oil
  11. customPurification

Sources & evidence

ORD record
ord-a4ca4cc2a7c94d29b907cac8411062e8
Source dataset
uspto-grants-2016_08
Patent number
US09403839B2

Reaction notes

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