Hydrochloric Acid → (R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester

HRID 885616Notes

Reaction equation

HRID 885616 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[H-].[Na+].[Cl:28][C:29]1[CH:30]=[C:31](F)[CH:32]=[C:33]([Cl:35])[CH:34]=1.Cl>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]([O:20][C:31]2[CH:30]=[C:29]([Cl:28])[CH:34]=[C:33]([Cl:35])[CH:32]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 6228DimethylformamideHCID 24758Sodium hydrideHCID 1370021,3-Dichloro-5-fluorobenzeneHCID 58507559(r)-3-((s)-Hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester

Product 1

HCID 66924546(R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

(R)-3-((S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10.0 g, 36.0 mmol) was dissolved in anhydrous DMF (65 mL, 840 mmol). Washed and dried sodium hydride (1.0 g, 43 mmol) was added, and the mixture stirred at room temperature for 15 minutes. 3,5-Dichlorofluorobenzene (10 mL, 80 mmol) was then added, and the mixture stirred at 70° C. for 3 hours. The mixture was cooled to room temperature. EtOAc (200 mL) and 1M HCl (200 mL) was added, mixed, and the phases separated. The organic layer was washed with 2×200 mL of diluted aqueous NaCl, dried over Na2SO4, and concentrated to dryness to yield 19 g of crude product. The crude product was purified on a 300 g SiG column to yield (R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester as a white sticky foam (14.1 g, 91.67% purity).

Workup

  1. washWashed
  2. stirringthe mixture stirred at 70° C. for 3 hours
  3. temperatureThe mixture was cooled to room temperature
  4. additionmixed
  5. customthe phases separated
  6. washThe organic layer was washed with 2×200 mL of diluted aqueous NaCl
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated to dryness
  9. customto yield 19 g of crude product
  10. customThe crude product was purified on a 300 g SiG column

Sources & evidence

ORD record
ord-71b878a129a747fbbaca2ba6e85327cf
Source dataset
uspto-grants-2012_08
Patent number
US08242164B2

Reaction notes

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