Ethyl bromoacetate → 2-(3-(4-Fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid

HRID 1667252Notes

Reaction equation

HRID 1667252 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].Br[CH2:21][C:22]([O:24]CC)=[O:23].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:21][C:22]([OH:24])=[O:23])[C:9]2=[O:13])=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 7748Ethyl bromoacetateHCID 14798Sodium HydroxideHCID 23665647Potassium tert-butoxideHCID 673577243-(4-Fluorophenyl)pyrrolidin-2-one

Product 1

HCID 673576422-(3-(4-Fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

To a suspension of 3-(4-fluorophenyl)pyrrolidin-2-one (Example 189B, 1.36 g, 7.59 mmol) in tetrahydrofuran was added potassium 2-methylpropan-2-olate (8.35 ml, 8.35 mmol). The reaction was allowed to stir for 30 minutes, during which time a yellow solution resulted. To the reaction was added ethyl 2-bromoacetate (0.92 ml, 8.35 mmol) and stirring was continued at room temperature. After stirring for 3 hours, the reaction was poured into a 1:1 mixture of ethyl acetate/1 N HCl (300 mL). The organic layer was separated, washed with brine (100 mL), dried over magnesium sulfate and concentrated. The residue was dissolved in minimal dichloromethane and loaded onto a GraceResolv 40 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=40 mL/minute) over 40 minutes. The resulting ethyl ester intermediate was dissolved in methanol (10 mL) and treated with sodium hydroxide (7.59 mL, 15.18 mmol). After stirring for 1 hour, the reaction was poured into a 1:1 mixture of ethyl acetate/1 N HCl (300 mL). The organic layer was washed with brine (100 mL), dried over magnesium sulfate and concentrated to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 12.87 (s, 1H), 7.34-7.26 (m, 2H), 7.20-7.10 (m, 2H), 4.00 (s, 2H), 3.71 (t, J=9.0, 1H), 3.52-3.43 (m, 2H), 2.59-2.35 (m, 1H), 2.07-1.91 (m, 1H).

Workup

  1. customresulted
  2. stirringstirring
  3. customwas continued at room temperature
  4. stirringAfter stirring for 3 hours
  5. customThe organic layer was separated
  6. washwashed with brine (100 mL)
  7. dry with materialdried over magnesium sulfate
  8. concentrationconcentrated
  9. dissolutionThe residue was dissolved in minimal dichloromethane
  10. washthe product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=40 mL/minute) over 40 minutes
  11. dissolutionThe resulting ethyl ester intermediate was dissolved in methanol (10 mL)
  12. stirringAfter stirring for 1 hour
  13. washThe organic layer was washed with brine (100 mL)
  14. dry with materialdried over magnesium sulfate
  15. concentrationconcentrated

Sources & evidence

ORD record
ord-7975c213b56b4ff5b9e4ca4a463028af
Source dataset
uspto-grants-2011_10
Patent number
US08044069B2

Reaction notes

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