Sodium Carbonate → (3R,4S)-tert-butyl 3-(benzyloxycarbonylamino)-4-(bis(4-methoxyphenyl)(phenyl)methoxy)pyrrolidine-1-carboxylate

HRID 338941Notes

Reaction equation

HRID 338941 reaction equation
[N:1]([C@H:4]1[C@@H:8]([O:9][C:10]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][N:6]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N[C@H]1[C@@H](OC(C2C=CC(OC)=CC=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)CN(C(OC(C)(C)C)=O)C1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:103]([O:105][CH2:106][C:107]1[CH:112]=[CH:111][CH:110]=[CH:109][CH:108]=1)=[O:104]>C1COCC1.O1CCOCC1.O>[CH2:106]([O:105][C:103]([NH:1][C@H:4]1[C@@H:8]([O:9][C:10]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][N:6]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:5]1)=[O:104])[C:107]1[CH:112]=[CH:111][CH:110]=[CH:109][CH:108]=1

Participants

8

Reactant 5

HCID 10340Sodium CarbonateHCID 10387Benzyl chloroformateHCID 11776TriphenylphosphineHCID 86707463(3R,4S)-tert-butyl 3-azido-4-(bis(4-methoxyphenyl)(phenyl)methoxy)pyrrolidine-1-carboxylateHCID 86707465(3R,4S)-tert-butyl 3-amino-4-(bis(4-methoxyphenyl)(phenyl)methoxy)pyrrolidine-1-carboxylate

Product 1

HCID 86707464(3R,4S)-tert-butyl 3-(benzyloxycarbonylamino)-4-(bis(4-methoxyphenyl)(phenyl)methoxy)pyrrolidine-1-carboxylateYield 60.4%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 218864351,4-Dioxane--water (1/1)Solvent

Procedure

To a solution of (3R,4S)-tert-butyl 3-azido-4-(bis(4-methoxyphenyl)(phenyl)methoxy)pyrrolidine-1-carboxylate (3.0 g, 5.65 mmol) in anhydrous THF (70 mL) was added triphenylphosphine (2.97 g, 11.3 mmol). The resulting mixture was stirred at ambient temperature for 18 hours. The mixture was concentrated under reduced pressure and to the residue were added methanol (35 mL) and a 0.5 N sodium hydroxide solution (35 mL). The mixture was stirred at ambient temperature 18 hours, and then partitioned between water (35 mL) and ethyl acetate (150 mL). The layers were separated and the aqueous layer was back extracted with ethyl acetate. The combined organic extracts washed with water and brine, dried (MgSO4), filtered and concentrated under reduce pressure. The residue was purified by column chromatography (Biotage 40M; 2.5% MeOH:dichloromethane). To a solution of (3R,4S)-tert-butyl 3-amino-4-(bis(4-methoxyphenyl)(phenyl)methoxy)pyrrolidine-1-carboxylate (2.85 g, 5.65 mmol) in a 50% mixture of 1,4-dioxane/water (20 mL) was added sodium carbonate (0.72 g, 6.78 mmol) and the mixture cooled to 0° C. in an ice bath. Benzyl chloroformate (1 mL, 6.78 mmol) was added dropwise and the mixture was stirred at 0° C. for 30 minutes and then at ambient temperature for 18 hours. The mixture was partitioned between water (20 mL) and diethyl ether (100 mL), and the layers were separated. The organic layer was washed sequentially with water, saturated sodium bicarbonate and brine, then dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 40M 25% ethyl acetate/hexanes) to afford (3R,4S)-tert-butyl 3-(benzyloxycarbonylamino)-4-(bis(4-methoxyphenyl)(phenyl)methoxy)pyrrolidine-1-carboxylate (2.18 g, 60%).

Workup

  1. concentrationThe mixture was concentrated under reduced pressure and to the residue
  2. additionwere added methanol (35 mL)
  3. stirringThe mixture was stirred at ambient temperature 18 hours
  4. custompartitioned between water (35 mL) and ethyl acetate (150 mL)
  5. customThe layers were separated
  6. extractionthe aqueous layer was back extracted with ethyl acetate
  7. washThe combined organic extracts washed with water and brine
  8. dry with materialdried (MgSO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe residue was purified by column chromatography (Biotage 40M; 2.5% MeOH:dichloromethane)
  12. temperaturethe mixture cooled to 0° C. in an ice bath
  13. stirringthe mixture was stirred at 0° C. for 30 minutes
  14. waitat ambient temperature for 18 hours
  15. customThe mixture was partitioned between water (20 mL) and diethyl ether (100 mL)
  16. customthe layers were separated
  17. washThe organic layer was washed sequentially with water, saturated sodium bicarbonate and brine
  18. dry with materialdried (MgSO4)
  19. filtrationfiltered
  20. concentrationconcentrated under reduced pressure
  21. customThe residue was purified by column chromatography (Biotage 40M 25% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-2352672a19d046409ddcb9b91ba33ea8
Source dataset
uspto-grants-2014_11
Patent number
US08889704B2

Reaction notes

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