9-Fluorenylmethyl chloroformate → 1-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-4,4-difluoro-L-proline

HRID 2363368Notes

Reaction equation

HRID 2363368 reaction equation
[C:1]([N:8]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])(C)C)=[O:2].C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)(OCC1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=O>O1CCOCC1.O>[C:1]([N:8]1[CH2:15][C:14]([F:16])([F:17])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][CH2:4][CH:7]1[C:37]2[C:38](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:39]2[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:2]

Participants

6

Reactant 3

HCID 343679-Fluorenylmethyl chloroformateHCID 21863450Trifluoroacetic acid methylene chlorideHCID 22977458(2S)-1-[(tert-butoxy)carbonyl]-4,4-difluoropyrrolidine-2-carboxylic acid

Product 1

HCID 110469731-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-4,4-difluoro-L-prolineYield 113.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

A solution of 652 mg (2 mmol) of N-Boc-4,4-difluoroproline in 10 mL of 1; 1 TFA/CH2Cl2 was stirred at 0° C. for 45 min, and concentrated in vacuo. The residue was taken up in 3 mL of dioxane, and 5 mL of 10% aqueous sodium carbonate was added, followed by a solution of 675 mg (1 eq) of Fmoc-Cl in 5 mL of dioxane. The mixture was stirred at room temperature for 16 h, diluted with 20 mL of water, extracted with 2 20-mL portions of diethyl ether, acidified to pH 2, and extracted with three 30-mL portions of ethyl acetate. The combined organic extracts were washed with 50 mL of brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography over silica gel (eluted with CH2Cl2/CH3OH 10:1), to afford 850 mg (88%) of N-Fmoc-4,4-difluoroproline as a brownish solid. 1H NMR (500 MHz, CDCl3) δ 2.55 (m, 1H), 2.95 (m, 1H), 3.80 (m, 2H), 4.20 (m, 1H), 4.30 (m, 2H), 4.55 (m, 1H), 7.32 (m, 2H), 7.45 (m, 2H), 7.70 (m, 2H), 7.90 (m, 2H). Exact mass calculated for C20H17F2NO4 m/e 373.11. found m/e 374.4.

Workup

  1. concentrationconcentrated in vacuo
  2. addition5 mL of 10% aqueous sodium carbonate was added
  3. extractionextracted with 2 20-mL portions of diethyl ether
  4. extractionextracted with three 30-mL portions of ethyl acetate
  5. washThe combined organic extracts were washed with 50 mL of brine
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by column chromatography over silica gel (eluted with CH2Cl2/CH3OH 10:1)

Sources & evidence

ORD record
ord-647caa2d96d844cab452a81c7a78c1bc
Source dataset
uspto-grants-2014_04
Patent number
US08691848B2

Reaction notes

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