Methanol → (2S)-1-((benzyloxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid

HRID 340812Notes

Reaction equation

HRID 340812 reaction equation
[OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.CO.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].[OH-].[Na+]>O.C1(C)C=CC=CC=1.ClCCl>[C:13]([N:5]1[CH2:6][CH:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]

Participants

8

Reactant 4

HCID 887MethanolHCID 5810L-HydroxyprolineHCID 10387Benzyl chloroformateHCID 14798Sodium Hydroxide2×

Product 1

HCID 12731799(2S)-1-((benzyloxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

trans-4-Hydroxyproline (27.5 g, 209.7 mmol) 7 was dissolved into 200 mL of 50% MeOH in water. This was then chilled on ice bath to 0° C. To this mixture was added 85.9 mL of benzyl chloroformate (0.252 mmol; 1.2 eq; 50% vol. in toluene) dropwise. Pellets of NaOH were added to maintain the pH at approximately 9-10 (monitored by litmus paper). The mixture was then allowed to warm to room temperature (22° C.). The mixture was allowed to stir over night at room temperature and the pH closely monitored and maintained at pH=10 by addition of NaOH pellets. The mixture was then diluted by addition of 200 mL water and then extracted with 3×200 mL toluene (to remove remaining benzyl chloroformate). The aqueous layer was then salted with NaCl until saturated and the pH was adjusted to approximately 2 by addition of HCl conc. This was then extracted with 4×200 mL of ethyl acetate. The ethyl acetate washes were then combined and concentrated via rotovap, leaving an oil residue. Dichloromethane (50 mL) was added 4 times to remaining oil and then removed by vacuum. Hexanes (50 mL) was then added to the oil and again removed by vacuum, leaving a sticky foam N-Cbz-4-hydroxyproline crude (quantitative yield) which was then used without any further purification. This residue can also be recrystallized in 10:1, hexanes:CH2Cl2. 1H and 13C NMR spectra were in agreement with 1H and 13C NMR spectra previously reported [Robinson. et al 1998].

Workup

  1. temperatureto maintain the pH at approximately 9-10 (monitored by litmus paper)
  2. temperatureto warm to room temperature (22° C.)
  3. extractionextracted with 3×200 mL toluene (to remove remaining benzyl chloroformate)
  4. additionwas adjusted to approximately 2 by addition of HCl conc.
  5. extractionThis was then extracted with 4×200 mL of ethyl acetate
  6. concentrationconcentrated via rotovap
  7. customleaving an oil residue
  8. customremoved by vacuum
  9. additionHexanes (50 mL) was then added to the oil
  10. customagain removed by vacuum

Sources & evidence

ORD record
ord-9ea4d934b44245b198bb767d70b6d6d2
Source dataset
uspto-grants-2014_11
Patent number
US08895607B2

Reaction notes

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