Potassium Carbonate → methyl 3-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-5-phenylmethoxy-benzoate

HRID 600536Notes

Reaction equation

HRID 600536 reaction equation
[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH:21]1[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:26][N:23]1[CH2:24][CH2:25][C@H:21]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[C:22]1=[O:27]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 7472028Methyl 3-(benzyloxy)-5-hydroxybenzoateHCID 111829543-Bromo-1-methylpyrrolidin-2-one2×

Product 1

HCID 59761161methyl 3-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-5-phenylmethoxy-benzoate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Methyl 3-hydroxy-5-phenylmethoxy-benzoate (CAS no. 54915-31-0) (10.3 g, 40 mmol) and 3-bromo-1-methyl-pyrrolidin-2-one (Intermediate 4) (8.54 g, 48 mmol) were dissolved in DMF, treated with potassium carbonate (12.1 g, 88 mmol) and stirred at room temperature for 16 hours and then at 50° C. for 3 hours. The DMF was evaporated under reduced pressure and the residue partitioned between ethyl acetate (100 mL) and water (30 mL). The organic layer was separated, washed with brine (30 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 0-100% ethyl acetate in hexane to give the racemic product (8.7 g). The desired product was separated from its enantiomer by chiral HPLC using Merck 50 mm 20 μm Chiralpak AS—No ASV00SC JG001 and ASV000SC BD004 columns in series, eluting with 30% ethylacetate in isohexane at a flow rate of 60 mL/min, using 9 separate injections of 70 mL of a 14 mg/ml solution of the racemate in ethanol (32 mL) and isohexane (38 mL) to afford the product (3.6 g, 41%) which eluted before its enantiomer. 1H NMR δ (300 MHz, CDCl3) 2.06-2.20 (m, 1H), 2.51-2.63 (m, 1H), 2.94 (s, 3H), 3.31-3.54 (m, 2H), 3.89 (s, 3H), 4.87 (t, 1H), 5.08 (s, 2H), 6.90 (t, 1H), 7.27-7.46 (m, 7H).

Workup

  1. waitat 50° C. for 3 hours
  2. customThe DMF was evaporated under reduced pressure
  3. customthe residue partitioned between ethyl acetate (100 mL) and water (30 mL)
  4. customThe organic layer was separated
  5. washwashed with brine (30 mL)
  6. dry with materialdried (MgSO4)
  7. customevaporated under reduced pressure
  8. customThe residue was purified by flash chromatography on silica eluting with 0-100% ethyl acetate in hexane

Sources & evidence

ORD record
ord-c48d3330aa6d451daebdf67dbbb2154c
Source dataset
uspto-grants-2011_03
Patent number
US07902200B2

Reaction notes

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