Water → HCID 15454934, compound

HRID 2287506Notes

Reaction equation

HRID 2287506 reaction equation
[CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([CH2:15][OH:16])[NH:13][C@@H:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11]1[C:23]([O:25][CH3:26])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].O>COCCOC.CCOC(C)=O>[CH2:33]([O:32][C:30]([N:13]1[C@H:14]([CH2:15][OH:16])[C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:11]([C:23]([O:25][CH3:26])=[O:24])[C@@H:12]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1

Participants

7

Reactant 4

HCID 962WaterHCID 10387Benzyl chloroformate2×HCID 14798Sodium HydroxideHCID 15454933HCID 15454933, compound

Product 1

HCID 15454934HCID 15454934, compoundYield 112%

Reagents, catalysts & solvents 2

HCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a stirred and ice-cooled suspension of (2R*,3S*,4S*,5S*)-4-benzyloxymethyl-5-hydroxymethyl-3-methoxycarbonyl-2-phenylpyrrolidine semifumarate (12.0 g, 29.0 mmol) in 1M NaOH aqueous solution (70.0 ml, 70.0 mmol) and DME (40 ml) was added benzyl chloroformate (Cbz-Cl, 4.97 ml, d1.195, 34.8 mmol) rapidly. After the heterogeneous white reaction mixture was stirred with ice-cooling for an hour, H2O (40 ml) and AcOEt(40 ml) was added to dissolve the white solids, and then a further amount of Cbz-Cl (1.0 ml, d1.195, 7.0 mmol) was added to the mixture at room temperature; on the addition, the reaction mixture became neutral. After stirring at room temperature for 30 minutes, the reaction went to almost completion. The stirring was continued at room temperature overnight, and then the layers were separated. The aqueous layer was extracted with AcOEt (50 ml×4). The combined organic layer and AcOEt extracts were washed with 0.5M NaOH aq. solution (×2), half sat. NaCl aq. solution (×1), 0.5M HCl aq. solution (×1), sat. NaCl aq. solution (×1), sat. NaHCO3 aq. solution (×1) and sat. NaCl aq. solution (×1), dried (MgSO4), and concentrated in vacuo to give crude title compound (15.9 g, quant.) as an almost colorless viscous oil: IRmax (film): 3420(s), 1738(vs), 1698(vs), 1680(vs), 1605(w), 1595(w), 1492(s), 1280(s), 1210(s), 1075(s), 758(s), 699(vs) cm-1 ; 1H-NMR δ: 7.53-7.10(m, 14H), 6.94(br.s, 1H), 5.30(d, J=9.5 Hz, 1H), 5.02(br.s, 2H), 4.53(d, J=12.1 Hz, 1H), 4.47(d, J=12.1 Hz, 1H), 4.13-3.90(m, 3H), 3.62(dd, J=9.7, 3.5 Hz, 1H), 3.58-3.41(m, 1H), 3.53(dd, J=9.7, 4.6 Hz, 1H), 3.29(s, 3H), 2.73(br.s, 1H), 1.61(br.s, OH, 1H) ppm. This was employed in the next step without further purification.

Workup

  1. temperatureice-cooled
  2. stirringAfter the heterogeneous white reaction mixture was stirred with ice-
  3. temperaturecooling for an hour
  4. dissolutionto dissolve the white solids
  5. additionon the addition
  6. stirringAfter stirring at room temperature for 30 minutes
  7. customthe layers were separated
  8. extractionThe aqueous layer was extracted with AcOEt (50 ml×4)
  9. washThe combined organic layer and AcOEt extracts were washed with 0.5M NaOH aq. solution (×2), half sat. NaCl aq. solution (×1), 0.5M HCl aq. solution (×1), sat. NaCl aq. solution (×1), sat. NaHCO3 aq. solution (×1) and sat. NaCl aq. solution (×1)
  10. dry with materialdried (MgSO4)
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-030c6f48d39c459d8971fb196c0c626b
Source dataset
uspto-grants-2000_07
Patent number
US06083943

Reaction notes

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