Iodine → N'-(Desmethyl)azithromycin

HRID 2059558Notes

Reaction equation

HRID 2059558 reaction equation
[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41](C)[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][N:7]([CH3:48])[C@H:6]([CH3:49])[C@@H:5]([OH:50])[C@@:4]1([OH:52])[CH3:51].C([O-])(=O)C.[Na+].II.[OH-].[Na+].C(Cl)Cl.CO.[NH4+].[OH-].[NH4+].[OH-]>CO.O>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([NH:41][CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][N:7]([CH3:48])[C@H:6]([CH3:49])[C@@H:5]([OH:50])[C@@:4]1([OH:52])[CH3:51]

Participants

9

Reactant 6

HCID 807IodineHCID 14798Sodium HydroxideHCID 14923Ammonium HydroxideHCID 447043AzithromycinHCID 517045Sodium AcetateHCID 21896990Dichloromethane methanol ammonium hydroxide

Product 1

HCID 9987533N'-(Desmethyl)azithromycinYield 55%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
50 °C

Procedure

Azithromycin 1 (0.80 g, 1.02 mmol) and sodium acetate (NaOAc) (0.712 g, 8.06 mmol) were dissolved in 80% aqueous MeOH (25 mL). The solution was heated to 50° C. followed by addition of iodine (I2) (0.272 g, 1.07 mmol) in three batches within 3 minutes. The reaction was maintained at a pH between 8 and 9 by adding 1N sodium hydroxide (NaOH) (1 mL) at 10 min and 45 minute intervals. The solution turned colorless within 45 minutes. Stirring was continued for 2 hours. TLC(CH2Cl2/MeOH/NH4OH 10:1:0.05) after 2 hours showed a single major product (Rf=0.66). The reaction was cooled to room temperature, poured into H2O (75 mL) containing NH4OH (1.5 mL) and extracted with CHCl3 (3×30 mL). The combined organic layers were washed with H2O (30 mL) containing NH4OH (1.5 mL), dried over Na2SO4 and the solvent evaporated to give a white residue. The crude was purified on a silica gel column eluting with CH2Cl2/MeOH/NH4OH 18:1:0.05 to 10:1:0.05 to provide compound 2 (0.41 g, 55%).

Workup

  1. temperatureThe reaction was maintained at a pH between 8 and 9
  2. custom45 minute intervals
  3. waitwas continued for 2 hours
  4. temperatureThe reaction was cooled to room temperature
  5. extractionextracted with CHCl3 (3×30 mL)
  6. washThe combined organic layers were washed with H2O (30 mL)
  7. additioncontaining NH4OH (1.5 mL)
  8. dry with materialdried over Na2SO4
  9. customthe solvent evaporated
  10. customto give a white residue
  11. customThe crude was purified on a silica gel column
  12. washeluting with CH2Cl2/MeOH/NH4OH 18:1:0.05 to 10:1:0.05

Sources & evidence

ORD record
ord-6df9e0e532c44d98b2ca539593dea498
Source dataset
uspto-grants-2012_10
Patent number
US08278281B2

Reaction notes

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