Sodium Chloride → (R)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester

HRID 858923Notes

Reaction equation

HRID 858923 reaction equation
[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[Na+].S([O-])([O-])(=O)=O.[Mg+2].[OH-].[Na+]>C1CCCCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH2:6]1)=[O:4]

Participants

7

Reactant 5

HCID 5234Sodium ChlorideHCID 14798Sodium HydroxideHCID 24083Sulfuric acid magnesium salt (1:1)HCID 62657Potassium Phosphate, TribasicHCID 2883518Methyl 1-(4-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylate

Product 1

HCID 785702(R)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl esterYield 44.8%

Reagents, catalysts & solvents 1

HCID 8078CyclohexaneSolvent

Procedure

213.5 mmol of (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (98% HPLC) was suspended in 500 ml cyclohexane under moderate stirring. 2.0 l of 3 mM potassium phosphate buffer pH 6.0, containing 0.1 M sodium chloride and 50 mM magnesium sulfate, was added, and the resulting emulsion/suspension was re-adjusted to pH 6.0, and the temperature set to 30° C. Hydrolysis was started by the addition of 201 mg of cholesterase from Candida cylindracea (Roche Applied Science, Industrial Products, Enzyme Projects, Sandhofer Str. 116, D-68305 Mannheim, Germany, order number 10129046103, hereinafter: Enzyme) and the pH kept constant at 6.0 by the controlled addition of 0.1 N NaOH solution (pH-stat) under moderate stirring. After a total consumption of 1016 ml of titrating agent (overnight; 48.6% conversion) the reaction mixture was extracted with 3.5 l and 2×2.5 l dichloromethane (turbid phases in the beginning), and subsequently with 3.5 l ethyl acetate (org. phase discarded). The combined dichloromethane phases were dried over sodium sulfate, evaporated and dried under HV to give 22.5 g (95.6 mmol; 44.8%) of (R)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as white crystals. Analytics: HPLC: >99%. Enantiomeric excess: 96.3% (Chiralpak AD, 250×4.6 mm; 70% hexane+10% 0.1% TFA in hexane+20% ethanol; 1 ml/min; DAD: sig=210.8 nm, ref=360.1 nm; sample application: 0.5 μl of 2 mg/ml 1% TFA in EtOH). [δ]D=−27.7° (c=1.02; EtOH). EI-MS: m/e=235.1 (M; 67), 122.0 (100). 1H-NMR (400 MHz; CDCl3): 2.89 (ddd, 2H, —CHaHb—), 3.37 (m, 1H, —CHCOO), 3.78 (s, 3H, COOCH3), 4.03 (ddd, 2H, C(O)NCHaHb), 6.08 (s, 1H, Ph-OH), 6.77, 7.30 (AA′XX′, 2×2H, C6H4).

Workup

  1. additionwas added
  2. customset to 30° C
  3. customHydrolysis
  4. additionwas started by the addition of 201 mg of cholesterase from Candida cylindracea (Roche Applied Science, Industrial Products, Enzyme Projects, Sandhofer Str
  5. customAfter a total consumption of 1016 ml of titrating agent (overnight; 48.6% conversion) the reaction mixture
  6. extractionwas extracted with 3.5 l and 2×2.5 l dichloromethane (turbid phases in the beginning), and subsequently with 3.5 l ethyl acetate (org. phase discarded)
  7. dry with materialThe combined dichloromethane phases were dried over sodium sulfate
  8. customevaporated
  9. customdried under HV

Sources & evidence

ORD record
ord-b2dc4bb5216c4beb9d2e0afcc5901bef
Source dataset
uspto-grants-2006_12
Patent number
US07148362B2

Reaction notes

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