Diethyl chlorophosphate → Benzyl 7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate

HRID 408140Notes

Reaction equation

HRID 408140 reaction equation
[BH4-].[Na+].[N:3]([C@@H:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][C@H:7]1OS(C1C=CC(C)=CC=1)(=O)=O)=[N+]=[N-].N([C@H]1[C@H](OS(C2C=CC(C)=CC=2)(=O)=O)CCN(C(OCC2C=CC=CC=2)=O)C1)=[N+]=[N-].[P:63](Cl)(=[O:70])([O:67][CH2:68][CH3:69])[O:64][CH2:65][CH3:66]>CO.C(Cl)Cl.O>[CH2:65]([O:64][P:63]([N:3]1[CH:7]2[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH2:8]2)([O:67][CH2:68][CH3:69])=[O:70])[CH3:66]

Participants

8

Reactant 4

HCID 13139Diethyl chlorophosphateHCID 4311764Sodium borohydride2×HCID 59201561HCID 59201561, compoundHCID 59201713HCID 59201713, compound

Product 1

HCID 59455678Benzyl 7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylateYield 55%

Reagents, catalysts & solvents 3

HCID 887MethanolSolvent2×HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

NaBH4 (3.41 g, 90.3 mmol) was added portion wise to a solution of CuSO4.5H2O (10.73 g, 42.98 mmol) in methanol (200 mL) at 0° C. After 5 minutes, a solution of trans-benzyl 4-azido-3-(tosyloxy)piperidine-1-carboxylate and trans-benzyl 3-azido-4-(tosyloxy)piperidine-1-carboxylate (37 g, 85.95 mmol; mixed product from last step) in methanol (100 mL) was added at 0° C. After addition, additional NaBH4 (10.2 g, 270.6 mmol) was added in four portions over the course of 1 hour. After one hour at 0° C., the reaction mixture was filtered through a pad of celite and concentrated in vacuo. The residue obtained was dissolved in DCM (800 mL), washed with water (200 mL), saturated NH4Cl solution (200 mL), brine (200 mL), dried (sodium sulfate) and concentrated in vacuo. The residue obtained was dissolved in DCM (200 mL) and TEA (24.0 mL, 171.9 mmol) and diethyl phosphorochloridate (12.4 mL, 85.95 mmol) was added at 0° C. The reaction mixture was warmed to room temperature and stirred at room temperature for 30 minutes. Water (50 mL) was added. The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (ethyl acetate) to give benzyl 7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate (17.5 g, 55%) as an oil.

Workup

  1. additionwas added in four portions over the course of 1 hour
  2. waitAfter one hour at 0° C.
  3. filtrationthe reaction mixture was filtered through a pad of celite
  4. concentrationconcentrated in vacuo
  5. customThe residue obtained
  6. washwashed with water (200 mL), saturated NH4Cl solution (200 mL), brine (200 mL)
  7. dry with materialdried (sodium sulfate)
  8. concentrationconcentrated in vacuo
  9. customThe residue obtained
  10. customThe organic layer was separated
  11. washwashed with brine
  12. dry with materialdried (sodium sulfate)
  13. concentrationconcentrated in vacuo
  14. customThe residue obtained
  15. customwas purified by flash chromatography on silica gel (ethyl acetate)

Sources & evidence

ORD record
ord-9a09351784b946e98d80ee60de56d7c2
Source dataset
uspto-grants-2014_06
Patent number
US08758830B2

Reaction notes

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