Sodium hydride → (R)-2-[4-(4-Fluoro-phenoxy)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 1909675Notes

Reaction equation

HRID 1909675 reaction equation
[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30][O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 11760051(R)-tert-Butyl 2-((tosyloxy)methyl)pyrrolidine-1-carboxylateHCID 129406244-(4-Fluorophenoxy)phenol

Product 1

HCID 69004867(R)-2-[4-(4-Fluoro-phenoxy)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl esterYield 74%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
2.5 °C

Procedure

To a solution of 4-(4-Fluoro-phenoxy)-phenol (200 mg, 0.979 mmol) in DMF (3 mL) at 0-5° C. was added 60% NaH (70 mg, 1.76 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (348 mg, 0.979 mmol) in DMF (2 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to rt and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain title the product (280 mg, 74%).

Workup

  1. temperatureThe reaction mixture was warmed to rt
  2. temperatureheated at 90° C. for 15 h
  3. concentrationThe mixture was concentrated
  4. additiondiluted with saturated aq NaHCO3
  5. extractionextracted with ethyl acetate
  6. extractionThe aqueous layer was re-extracted with ethylacetate
  7. customThe combined organic layers were dried over anhy
  8. customMgSO4 and the solvent was removed in vacuo
  9. customto obtain the crude mixture, which
  10. customwas purified by silica gel flash chromatography

Sources & evidence

ORD record
ord-86bed635e7a04be78b7a7d7ac63af868
Source dataset
uspto-grants-2013_12
Patent number
US08598359B2

Reaction notes

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