Methyl benzenesulfonate → 1-(3-Chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one

HRID 17984Notes

Reaction equation

HRID 17984 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(S(OC)(=O)=O)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]=[CH:8][C:7]1=[O:12]

Participants

6

Reactant 3

HCID 6630Methyl benzenesulfonateHCID 2733832Lithium HexamethyldisilazideHCID 669976831-(3-Chloro-4-fluorobenzyl)piperidin-2-one

Product 1

HCID 594556041-(3-Chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-20 °C

Procedure

To a cold (−20° C.) solution of 1-(3-chloro-4-fluorobenzyl)piperidin-2-one (340 g, 1.41 mol) in anhydrous tetrahydrofuran (5 L) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide (3.09 L, 3.09 mol; 1M in TIE) was added over a period of 40 minutes with the temperature of the reaction maintained at −20° C. After the addition was complete, the reaction mixture was stirred at −20° C. for one hour. Methyl benzene sulfonate (231 mL, 1.69 mol) was added to the reaction mixture over a period of 30 minutes. The reaction mixture was stirred at −20° C. for 30 minutes. The product mixture was diluted with ethyl acetate (4 L) and washed with water (four times; 2 L each time). The organic extract was concentrated under vacuum. The residue was dissolved in toluene (4 L), treated with solid sodium carbonate (500 g), and heated at 100° C. for one hour. The product mixture was diluted with ethyl acetate (4 L) and washed with water (4 times; 2 L each). The organic extract was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a gradient of 0-60% EtOAc in heptane. Collection and concentration of appropriate fractions provide the title compound as oil.

Workup

  1. additionAfter the addition
  2. stirringThe reaction mixture was stirred at −20° C. for 30 minutes
  3. washwashed with water (four times; 2 L each time)
  4. extractionThe organic extract
  5. concentrationwas concentrated under vacuum
  6. dissolutionThe residue was dissolved in toluene (4 L)
  7. additiontreated with solid sodium carbonate (500 g)
  8. temperatureheated at 100° C. for one hour
  9. additionThe product mixture was diluted with ethyl acetate (4 L)
  10. washwashed with water (4 times; 2 L each)
  11. extractionThe organic extract
  12. concentrationwas concentrated under vacuum
  13. customCollection and concentration of appropriate fractions

Sources & evidence

ORD record
ord-00911e535774408c95edef86f439d8e1
Source dataset
uspto-grants-2010_06
Patent number
US07741315B2

Reaction notes

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