Benzoic Acid → (2S,3R)-N-tert-Butoxycarbonyl-3-benzoyloxy-2-pyrrolidinecarboxylic acid methyl ester

HRID 751026Notes

Reaction equation

HRID 751026 reaction equation
[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:37](O)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOC(C)=O.CCCCCC>[CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([O:10][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]

Participants

7

Reactant 4

HCID 243Benzoic AcidHCID 11776TriphenylphosphineHCID 5462977Diethyl azodicarboxylateHCID 147292531-tert-butyl 2-methyl (2S,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate

Product 1

HCID 58583618(2S,3R)-N-tert-Butoxycarbonyl-3-benzoyloxy-2-pyrrolidinecarboxylic acid methyl esterYield 89.7%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 21226206Ethyl acetate hexaneSolvent

Procedure

To a stirred solution of compound 1B (69.1 g, 0.282 mol), Ph3P (88.7 g, 0.338 mol) and benzoic acid (41.32 g, 0.338 mol) in anhydrous THF (1.35 L) cooled to 0° C. was added a solution of DEAD (62 mL, 0.33 mol) in anhydrous THF (50 mL) dropwise over 1 h through an addition funnel. After the addition, the resulting light yellow solution was stirred at rt until the reaction was complete (˜8 h). The reaction mixture was then partitioned between EtOAc and aqueous NaHCO3. The organic layer was washed with saturated aqueous NaHCO3, water (2×), brine, dried (Na2SO4) and concentrated under reduced pressure to yield a crude product as a semi-solid. The crude product was suspended in 25% EtOAc/hexane and stirred vigorously for 3 h. The resulting suspension was filtered and the collected white solid (triphenylphosphine oxide) rinsed with 20% EtOAc/hexane (2×). The combined filtrate was concentrated under reduced pressure to yield an oily residue, which was triturated twice with 20% EtOAc/hexane as described above to yield approximately 150 g of the partially purified product as a yellow oil, which was further purified by flash chromatography (silica gel) eluting with 10-20% EtOAc/hexane to furnish pure compound 1C (88.4 g) as a light yellow viscous oil.

Workup

  1. additionAfter the addition
  2. custom(˜8 h)
  3. customThe reaction mixture was then partitioned between EtOAc and aqueous NaHCO3
  4. washThe organic layer was washed with saturated aqueous NaHCO3, water (2×), brine
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated under reduced pressure
  7. customto yield a crude product as a semi-solid
  8. stirringstirred vigorously for 3 h
  9. filtrationThe resulting suspension was filtered
  10. washthe collected white solid (triphenylphosphine oxide) rinsed with 20% EtOAc/hexane (2×)
  11. concentrationThe combined filtrate was concentrated under reduced pressure
  12. customto yield an oily residue, which
  13. customwas triturated twice with 20% EtOAc/hexane
  14. customto yield approximately 150 g of the partially purified product as a yellow oil, which
  15. customwas further purified by flash chromatography (silica gel)
  16. washeluting with 10-20% EtOAc/hexane

Sources & evidence

ORD record
ord-27def6d780314eb49c84657366a56ea3
Source dataset
uspto-grants-2008_07
Patent number
US07405234B2

Reaction notes

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