Chloroacetyl chloride → (+/-)-(5S,7aR)-7-(2,5-Difluorophenyl)-2-cyclopropyl-5-phenyl-1,2,5,7a-tetrahydro-3H-pyrrolo[1,2-c]imidazol-3-one

HRID 32860Notes

Reaction equation

HRID 32860 reaction equation
[N:1]([CH2:4][CH:5]1[C:9]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])=[CH:8][CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:6]1[C:24]([O:26]C(C)(C)C)=O)=[N+]=[N-].C1(P([C:44]2[CH:49]=[CH:48]C=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCC(Cl)=O.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[F:17][C:11]1[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[C:9]1[C@H:5]2[N:6]([C:24](=[O:26])[N:1]([CH:48]3[CH2:49][CH2:44]3)[CH2:4]2)[C@H:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=1

Participants

7

Reactant 4

HCID 6577Chloroacetyl chlorideHCID 8471TriethylamineHCID 11776TriphenylphosphineHCID 71026191(+/-)-tert-Butyl 2-(azidomethyl)-3-(2,5-difluorophenyl)-5-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate

Product 1

HCID 11772541(+/-)-(5S,7aR)-7-(2,5-Difluorophenyl)-2-cyclopropyl-5-phenyl-1,2,5,7a-tetrahydro-3H-pyrrolo[1,2-c]imidazol-3-one

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

A solution of the azidocarbamate 2-1a (0.39 g, 0.95 mmol) in THF (10.0 mL) was treated with polystyrene bound triphenylphosphine and heated at 60° C. for 2 h. The reaction was quenched with water and heated at 60° C. for an additional hour. The reaction was diluted with EtOAc and filtered. The filtrate was washed with brine, dried over MgSO4, filtered and concentrated. A solution of this product (0.025 g, 0.07 mmol) in CH2Cl2 (3 mL) was treated with chloroacetyl chloride (0.007 g, 0.07 mmol) and triethylamine (0.007 g, 0.07 mmol) and stirred at rt for 2 h. The reaction was partitioned between dichloromethane and water. The organic solution was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was dissolved in 4M HCl/dioxane and stirred for 1 hr. The reaction was then made basic with 3N aq NaOH and stirred vigorously. After 2 h, the reaction mixture was extracted with EtOAc. The organic solution was washed with brine, dried over MgSO4, filtered and concentrated. The remaining oil was dissolved in CH3CN (0.5 mL) and purified on a Gilson automated system affixed with a YMC J'sphere H80 20×50 mm column (eluting with 5-95% CH3CN +0.1% TFA in water +0.11% TF A over 10 min) to afford pure 5-1.

Workup

  1. customThe reaction was quenched with water
  2. temperatureheated at 60° C. for an additional hour
  3. additionThe reaction was diluted with EtOAc
  4. filtrationfiltered
  5. washThe filtrate was washed with brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe reaction was partitioned between dichloromethane and water
  10. washThe organic solution was washed with brine
  11. dry with materialdried over MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated
  14. dissolutionThe residue was dissolved in 4M HCl/dioxane
  15. stirringstirred for 1 hr
  16. stirringstirred vigorously
  17. waitAfter 2 h
  18. extractionthe reaction mixture was extracted with EtOAc
  19. washThe organic solution was washed with brine
  20. dry with materialdried over MgSO4
  21. filtrationfiltered
  22. concentrationconcentrated
  23. dissolutionThe remaining oil was dissolved in CH3CN (0.5 mL)
  24. custompurified on a Gilson automated system
  25. washeluting with 5-95% CH3CN +0.1% TFA in water +0.11% TF A over 10 min)
  26. customto afford pure 5-1

Sources & evidence

ORD record
ord-6e726cd27f1b4e478389d13da4c6ea80
Source dataset
uspto-grants-2008_09
Patent number
US07427637B2

Reaction notes

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