Bromine → HCID 86627071, compound

HRID 1427339Notes

Reaction equation

HRID 1427339 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][C@@H:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:35]Br.[Na].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>C(Cl)Cl.CO.O.C(=O)(O)[O-].[Na+]>[Br:35][C@H:10]1[C@H:11]2[C@H:12]([C:14](=[O:16])[O:15]2)[CH2:13][C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]

Participants

9

Reactant 4

HCID 24408Bromine2×HCID 2723671Tetrabutylammonium HydroxideHCID 7168126(1R,4R)-4-(tert-butoxycarbonylamino)cyclopent-2-enecarboxylic acidHCID 66586226sodium L-ascorbic acid

Product 1

HCID 86627071HCID 86627071, compoundYield 85%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent2×HCID 516892Sodium BicarbonateSolvent

Procedure

To (1R,4R)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylic acid (400.00 g, 1.7601 mol; prepared in a procedure analogous to that described in Examples 1 to 3 above) dissolved in methylene chloride (6 L) was added tetrabutylammonium hydroxide in methanol (1.0M, 1800 ml), and the mixture was stirred at ambient temperature for 60 minutes. The reaction mixture was then cooled to −25° C. under a blanket of Nitrogen. Bromine (181 ml, 3.52 mol) in methylene chloride (2 L) was then added slowly over 60 minutes, maintaining an internal temperature lower than −20° C. On completion of the bromine addition, the mixture was stirred at −25° C. for a further 30 minutes, and then warmed slowly to 0° C. over 30 minutes. The mixture was then allowed to stir at 0° C. for 1 hour. At 0° C., a mixture of L-ascorbic acid sodium salt (523.0 g, 2.640 mol) in water (3 L) and saturated sodium bicarbonate in water (3 L), was added slowly over 30 minutes maintaining an internal temperature lower than 10° C. The resulting bi-phasic mixture was stirred and allowed to warm to ambient temperature over 1 hr. The methylene chloride layer was separated and the aqueous layer was extracted with methylene chloride (2 L). The methylene chloride layers were combined and concentrated to a volume of about 4 L. Ethyl acetate (8 L) was added, and the mixture was concentrated to a volume of about 5 L. Ethyl acetate (5 L) was added, and the resulting mixture was washed 3 times with water (4 L). The organic layer was then washed with saturated sodium chloride in water (2 L) and concentrated to afford the title compound (460 g, 85%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 5.09 (d, 1H), 4.80 (m, 1H), 4.71 (m, 1H), 4.47 (m, 1H), 4.04 (m, 1H), 2.39 (m, 1H), 1.89 (m, 1H) and 1.46 (bs, 9H).

Workup

  1. customprepared in a procedure analogous to
  2. temperatureThe reaction mixture was then cooled to −25° C. under a blanket of Nitrogen
  3. temperaturemaintaining an internal temperature lower than −20° C
  4. stirringthe mixture was stirred at −25° C. for a further 30 minutes
  5. temperaturewarmed slowly to 0° C. over 30 minutes
  6. stirringto stir at 0° C. for 1 hour
  7. additionwas added slowly over 30 minutes
  8. temperaturemaintaining an internal temperature lower than 10° C
  9. stirringThe resulting bi-phasic mixture was stirred
  10. temperatureto warm to ambient temperature over 1 hr
  11. customThe methylene chloride layer was separated
  12. extractionthe aqueous layer was extracted with methylene chloride (2 L)
  13. concentrationconcentrated to a volume of about 4 L
  14. additionEthyl acetate (8 L) was added
  15. concentrationthe mixture was concentrated to a volume of about 5 L
  16. additionEthyl acetate (5 L) was added
  17. washthe resulting mixture was washed 3 times with water (4 L)
  18. washThe organic layer was then washed with saturated sodium chloride in water (2 L)
  19. concentrationconcentrated

Sources & evidence

ORD record
ord-22edf4881fe24e9a945ab9e7170de550
Source dataset
uspto-grants-2015_01
Patent number
US08933225B2

Reaction notes

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