Hydrochloric Acid → tert-butyl (1S)-1-{(2S)-5-oxo-4-[4-(2-pyridinyl)benzyl]tetrahydro-2-furanyl}-2-phenylethylcarbamate

HRID 1174099Notes

Reaction equation

HRID 1174099 reaction equation
[O:1]1[CH2:3][C@H:2]1[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OCC)(=O)CC(OCC)=O.[O-:31][CH2:32][CH3:33].[Na+].Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)=[CH:39][CH:38]=1.Cl>C(O)C.O.C(OCC)(=O)CC(OCC)=O>[O:31]=[C:32]1[O:1][C@H:2]([C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH:33]1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)=[CH:41][CH:42]=1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 7761Diethyl MalonateHCID 2723922Sodium ethoxideHCID 9813904tert-Butyl {(1S)-1-[(2R)-oxiran-2-yl]-2-phenylethyl}carbamateHCID 98875912-(4-(Bromomethyl)phenyl)pyridine

Product 1

HCID 86598802tert-butyl (1S)-1-{(2S)-5-oxo-4-[4-(2-pyridinyl)benzyl]tetrahydro-2-furanyl}-2-phenylethylcarbamate

Reagents, catalysts & solvents 3

HCID 7761Diethyl MalonateCatalystHCID 702EthanolSolvent2×HCID 962WaterSolvent

Conditions

Temperature
25 °C

Procedure

A solution of tert-Butyl (1S)-1-[(2R)-oxiran-2-yl]-2-phenylethylcarbamate (10.0 g, 38.0 mmol) and diethyl malonate (5.8 ml, 38.2 mmol) in ethanol (30 mL) at 0° C. was treated with sodium ethoxide (17 mL, 21% in ethanol) over 10 minutes. The reaction was warmed to 25° C. and stirred for 2 hours, treated with additional diethyl malonate (0.58 mL, 3.4 mmol) and stirred for 1 hour. The reaction was cooled to 0° C., and solid 2-[4-(bromomethyl)phenyl]pyridine (9.43 g, 38.0 mmol) was added in four increments over 10 minutes. To this suspension was added ethanol (20 mL) and the mixture was stirred at 25° C. for 16 hours. The reaction mixture was treated with LiOH monohydrate (4.6 g, 109.6 mmol) solution in water (30 mL), stirred at 25° C. for 16 hours, cooled to 0° C., adjusted to pH 5 by addition of 4N HCl and partitioned between dichloromethane and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. A solution of the concentrate in toluene (100 mL) was heated at reflux for 16 hours, cooled to 25° C. and concentrated to afford the title compound (21.4 g).

Workup

  1. stirringstirred for 1 hour
  2. temperatureThe reaction was cooled to 0° C.
  3. stirringthe mixture was stirred at 25° C. for 16 hours
  4. stirringstirred at 25° C. for 16 hours
  5. temperaturecooled to 0° C.
  6. custompartitioned between dichloromethane and water
  7. washThe organic phase was washed with brine
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. concentrationA solution of the concentrate in toluene (100 mL)
  12. temperaturewas heated
  13. temperatureat reflux for 16 hours
  14. temperaturecooled to 25° C.
  15. concentrationconcentrated

Sources & evidence

ORD record
ord-5aa5a96ff3874b909819adf5bee742de
Source dataset
uspto-grants-2010_11
Patent number
US07834043B2

Reaction notes

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