Borane;tetrahydrofuran → tert-Butyl (2S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate

HRID 1754399Notes

Reaction equation

HRID 1754399 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][C@H:9]1[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[F:14][C:11]1([F:13])[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@H:9]([CH2:15][OH:16])[CH2:10]1

Participants

4

Reactant 2

HCID 2723981Borane;tetrahydrofuranHCID 22977458(2S)-1-[(tert-butoxy)carbonyl]-4,4-difluoropyrrolidine-2-carboxylic acid

Product 1

HCID 20648576tert-Butyl (2S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylateYield 74%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a THF (30 ml) solution of (S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (3.77 g, 15 mmol) at 0° C., BH3.THF solution (1.0 M in THF, 45 ml) was added dropwise over 20 minutes. The reaction mixture was allowed to warm to room temperature and stirring was continued for a total of 16 hours. Reaction went to completion as monitored by LC-MS. The reaction mixture was quenched by the addition of saturated aqueous solution of NaHCO3 (60 ml) at room temperature and the stirring was continued at room temperature for 4 hours. Most THF was removed in vacuo and the mixture was extracted with EtOAc (˜60 ml), two layers were separated, organic layer was washed with brine (˜50 ml), repeat the extraction/wash cycle one more time. Organic layers were combined, dried (Na2SO4), filtered, solvent was removed in vacuo. Crude product was purified by silica gel chromatography (Hexane/EtOAc, gradient from 100:0 to 50:50). Compound (S)-tert-butyl 4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate was obtained as a colorless oil: 2.6473 g (74% yield).

Workup

  1. customwas continued for a total of 16 hours
  2. customReaction
  3. customThe reaction mixture was quenched by the addition of saturated aqueous solution of NaHCO3 (60 ml) at room temperature
  4. customMost THF was removed in vacuo
  5. extractionthe mixture was extracted with EtOAc (˜60 ml), two layers
  6. customwere separated
  7. washorganic layer was washed with brine (˜50 ml)
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. customsolvent was removed in vacuo
  11. customCrude product was purified by silica gel chromatography (Hexane/EtOAc, gradient from 100:0 to 50:50)

Sources & evidence

ORD record
ord-440fa8693c30449797edd0da12656e25
Source dataset
uspto-grants-2015_10
Patent number
US09169249B2

Reaction notes

Loading…