4-Methylmorpholine → (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid amide

HRID 1516625Notes

Reaction equation

HRID 1516625 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@H:15]([C:19](O)=[O:20])[CH2:14]2)=[CH:9][CH:8]=1.C[N:26]1CCOCC1.ClC(OCC)=O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@H:15]([C:19]([NH2:26])=[O:20])[CH2:14]2)=[CH:9][CH:8]=1

Participants

5

Reactant 3

HCID 79724-MethylmorpholineHCID 10928Ethyl chloroformateHCID 67409315(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid

Product 1

HCID 44128415(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid amideYield 88%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (2.0 g, 6.07 mmol; enantiomeric purity (S):(R)>99.9:0.1) in tetrahydrofuran (40 mL), N-methylmorpholine (676 mg, 6.68 mmol) was added at 0° C. After stirring for 20 min, a solution of ethyl chloroformate (725 mg, 6.68 mmol) was added dropwise over 10 min, and stirring at 0° C. was continued for another 20 min. Ammonia (excess) was then bubbled for 15 min through the resulting suspension. The reaction mixture was warmed up to room temperature and stirred for 15 min. Water (50 mL) was added, and the tetrahydrofuran was evaporated in vacuo. The product, which precipitated, was collected by filtration, washed with water and tert-butyl methyl ether and dried at 45° C. in vacuo to afford (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid amide (1.75 g, 88%). The purity of the product by HPLC was 98.9% (area) and the enantiomeric ratio (S):(R) was determined as 99.8:0.2.

Workup

  1. stirringstirring at 0° C.
  2. waitwas continued for another 20 min
  3. customAmmonia (excess) was then bubbled for 15 min through the resulting suspension
  4. stirringstirred for 15 min
  5. additionWater (50 mL) was added
  6. customthe tetrahydrofuran was evaporated in vacuo
  7. customThe product, which precipitated
  8. filtrationwas collected by filtration
  9. washwashed with water and tert-butyl methyl ether
  10. customdried at 45° C. in vacuo

Sources & evidence

ORD record
ord-2f0d2b3ee6e84d66a5e9c7f44a515ec7
Source dataset
uspto-grants-2012_07
Patent number
US08227505B2

Reaction notes

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