Dichloromethane → 2-Chloro-6-{3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-benzonitrile

HRID 1752261Notes

Reaction equation

HRID 1752261 reaction equation
[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Br[CH2:24][C:25]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:26]=1[C:27]#[N:28].[H-].[Na+].ClCCl>O1CCCC1.CN(C)C=O.CO>[Cl:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:25]([CH2:24][N:17]2[CH2:18][CH2:19][CH:15]([N:12]3[CH2:13][CH2:14][CH:9]([C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=4)[CH2:10][CH2:11]3)[C:16]2=[O:20])[C:26]=1[C:27]#[N:28]

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 24758Sodium hydrideHCID 667339472-(Bromomethyl)-6-chlorobenzonitrileHCID 712122103-(4-(4-Methoxybenzoyl)piperidin-1-yl)pyrrolidin-2-one

Product 1

HCID 712123282-Chloro-6-{3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-benzonitrile

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 3-(4-(4-methoxybenzoyl)piperidin-1-yl)pyrrolidin-2-one (70 mg, 0.23 mmol) and 2-(bromomethyl)-6-chlorobenzonitrile (80 mg, 0.35 mmol) in tetrahydrofuran (1 mL) and dimethylformamide (0.1 mL) was added sodium hydride (46 mg, 1.2 mmol, 60% in mineral oil). The mixture was stirred at ambient temperature for 30 minutes. Dichloromethane and methanol were added slowly to quench the reaction. Then the mixture was filtered through a short pad of silical gel column, the solvent was removed in vacuo, and the residue was purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0) first and then (methanol: dichloromethane, 1:99 to 10:90) to give brown oil which is further purified by HPLC to give a colorless product. 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 2H), 7.45 (t, J=8.0 Hz, 1H), 7.35-7.41 (m, 1H), 7.30 (d, J=7.5 Hz, 1H), 6.87 (m, J=9.0 Hz, 2H), 4.62 (q, J=15.6 Hz, 2H), 3.80 (s, 3H), 3.50 (t, J=9.0 Hz, 1H), 3.11-3.37 (m, 3H), 2.94-3.11 (m, 1H), 2.75-2.94 (m, 2H), 2.28-2.54 (m, 1H), 2.09-2.28 (m, 1H), 1.90-2.09 (m, 1H), 1.66-1.90 (m, 4H). HRMS calculated for C25H26ClN3O3 452.1741. found (ESI, [M+H]+), 452.1760.

Workup

  1. customto quench
  2. customthe reaction
  3. filtrationThen the mixture was filtered through a short pad of silical gel column
  4. customthe solvent was removed in vacuo
  5. customthe residue was purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0) first
  6. custom(methanol: dichloromethane, 1:99 to 10:90) to give brown oil which
  7. customis further purified by HPLC
  8. customto give a colorless product

Sources & evidence

ORD record
ord-92cdd315ccef470e8e4ec62f2662300b
Source dataset
uspto-grants-2015_10
Patent number
US09163003B2

Reaction notes

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