Methanesulfonyl chloride → Benzyl 3-(aminomethyl)pyrrolidine-1-carboxylate

HRID 2268949Notes

Reaction equation

HRID 2268949 reaction equation
[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16]O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:21](C(C)C)CC)(C)C.CS(Cl)(=O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 18332648Benzyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate

Product 1

HCID 15550581Benzyl 3-(aminomethyl)pyrrolidine-1-carboxylateYield 78.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a 0° C. solution of 350 mg of 1-benzyloxycarbonyl-3-hydroxymethylpyrrolidine in 10 mL of CH2Cl2 was added 288 mg of diisopropylethylamine, then 204 mg of methanesulfonyl chloride. After 10 min, the cooling bath was removed and the mixture was stirred for 30 min at room temperature. The mixture was diluted with 25 mL of EtOAc and washed with 10 mL of saturated NaHCO3, 2×10 mL of 1 N HCl and 10 mL of brine. The organic phase was dried over MgSO4 and concentrated. The residue was dissolved in 10 mL of DMF and 145 mg of sodium azide was added. The mixture was heated to 100° C. and stirred overnight at this temperature, then cooled, diluted with 25 mL of EtOAc, and washed with 2×10 mL of water and 10 ml of brine. The organic phase was dried over MgSO4 and concentrated. The residue was dissolved in 10 mL of 9:1 THF-water and 586 mg of triphenylphosphine was added. The mixture was heated to 50° C. and stirred at this temperature for 3 h, then cooled, poured into 20 mL of 1 N HCl, and extracted with 2×10 mL of EtOAc. The aqueous phase was made very basic (pH>12) by addition of 5 N NaOH, then extracted with 4×10 mL of EtOAc. The combined organic extracts were washed with 10 mL of brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography, eluting with 20:1 CH2Cl2-2M NH3 in MeOH, to yield 273 mg of the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.28-7.40 (m, 5H), 5.13 (m, 2H), 3.47-3.67 (m, 2H), 3.38 (dt J=9.8, 16.7 Hz, 1H), 3.09 (ddd, J=7.6, 10.5, 15.1 Hz, 1H), 2.64-2.78 (m, 2H), 2.23 (dt, J=7.8, 15.3 Hz, 1H), 1.96-2.08 (m, 1H), 1.52-1.67 (m, 1H), 1.25 (br s, 2H).

Workup

  1. customthe cooling bath was removed
  2. additionThe mixture was diluted with 25 mL of EtOAc
  3. washwashed with 10 mL of saturated NaHCO3, 2×10 mL of 1 N HCl and 10 mL of brine
  4. dry with materialThe organic phase was dried over MgSO4
  5. concentrationconcentrated
  6. dissolutionThe residue was dissolved in 10 mL of DMF
  7. addition145 mg of sodium azide was added
  8. temperatureThe mixture was heated to 100° C.
  9. stirringstirred overnight at this temperature
  10. temperaturecooled
  11. additiondiluted with 25 mL of EtOAc
  12. washwashed with 2×10 mL of water and 10 ml of brine
  13. dry with materialThe organic phase was dried over MgSO4
  14. concentrationconcentrated
  15. dissolutionThe residue was dissolved in 10 mL of 9:1 THF-water
  16. addition586 mg of triphenylphosphine was added
  17. temperatureThe mixture was heated to 50° C.
  18. stirringstirred at this temperature for 3 h
  19. temperaturecooled
  20. additionpoured into 20 mL of 1 N HCl
  21. extractionextracted with 2×10 mL of EtOAc
  22. additionby addition of 5 N NaOH
  23. extractionextracted with 4×10 mL of EtOAc
  24. washThe combined organic extracts were washed with 10 mL of brine
  25. dry with materialdried over MgSO4
  26. concentrationconcentrated
  27. customThe residue was purified by flash chromatography
  28. washeluting with 20:1 CH2Cl2-2M NH3 in MeOH

Sources & evidence

ORD record
ord-02ba3ea4f5c64b3aaeeb78976d3fcf57
Source dataset
uspto-grants-2001_12
Patent number
US06329380B1

Reaction notes

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