Benzyl chloroformate → tert-butyl (3R,4R)-3-(benzyloxycarbonylamino)-4-fluoro-pyrrolidine-1-carboxylate

HRID 928196Notes

Reaction equation

HRID 928196 reaction equation
C1([C@H](CC(O)=O)C(O)=O)C=CC=CC=1.[NH2:15][C@H:16]1[C@H:20]([F:21])[CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1.CCN(C(C)C)C(C)C.[C:38](Cl)([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>C(Cl)Cl>[CH2:41]([O:40][C:38]([NH:15][C@H:16]1[C@H:20]([F:21])[CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1)=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1

Participants

5

Reactant 3

HCID 10387Benzyl chloroformateHCID 81531DiisopropylethylamineHCID 131735056(2S)-2-phenylbutanedioic acid tert-butyl (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate

Product 1

HCID 118084914tert-butyl (3R,4R)-3-(benzyloxycarbonylamino)-4-fluoro-pyrrolidine-1-carboxylateYield 95.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A solution of (2S)-2-phenylbutanedioic acid-tert-butyl (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (1:1) (500 mg, 1.2 mmol) in DCM (20 mL) was cooled in an ice/water bath. DIPEA (0.69 mL, 4 mmol, 3.3 mol eq) was added, followed by CBZ-Cl (185 μL, 1.26 mmol, 1.05 mol eq). The resulting reaction solution was capped, stirred in the cold bath and allowed to warm to rt and stirred for 2 hr. The reaction was diluted with DCM (30 mL) and washed with sat. aq. NaHCO3 (10 mL). The organic layer was separated, dried over Na2SO4, and evaporated to give a colorless residue that was purified via flash chromatography (eluting with a gradient of 100% heptane to 50 ethyl acetate-50% heptane) to give the title compound as a colorless oil (388 mg, 96 yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.30-7.42 (m, 5 H) 5.12 (br. s., 2 H) 4.74-5.04 (m, 1 H) 4.28 (br. s., 1 H) 3.28-3.80 (m, 4 H) 1.47 (s, 9 H). 19F NMR (376 MHz, chloroform-d) δ ppm −180.76-−178.52 (m, 1 F). m/z (APCI+) for C17H23FN2O4 239.2 (M+H)+. Chiral purity was determined as below (using the racemic material to compare):

Workup

  1. customThe resulting reaction solution
  2. customwas capped
  3. stirringstirred for 2 hr
  4. washwashed with sat. aq. NaHCO3 (10 mL)
  5. customThe organic layer was separated
  6. dry with materialdried over Na2SO4
  7. customevaporated
  8. customto give a colorless residue that
  9. customwas purified via flash chromatography (
  10. washeluting with a gradient of 100% heptane to 50 ethyl acetate-50% heptane)

Sources & evidence

ORD record
ord-59f95f3d411343c9afb2cf2733c2c47a
Source dataset
uspto-grants-2016_03
Patent number
US09290496B2

Reaction notes

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