Acetonitrile → Emtricitabine

HRID 1952783Notes

Reaction equation

HRID 1952783 reaction equation
[CH2:1]1[S:5][C@@H:4]([CH2:6][OH:7])[O:3][C@H:2]1[N:8]1[C:13](=[O:14])[N:12]=[C:11]([NH2:15])[C:10]([F:16])=[CH:9]1.CC#N.C([O-])(=O)CCC.C[O-].[Na+]>CO>[CH2:1]1[S:5][C@H:4]([CH2:6][OH:7])[O:3][C@@H:2]1[N:8]1[C:13](=[O:14])[N:12]=[C:11]([NH2:15])[C:10]([F:16])=[CH:9]1

Participants

6

Reactant 4

HCID 6342AcetonitrileHCID 104775Butyrate2×HCID 454858(+)-2′-Deoxy-3′-thia-5-fluorocytidineHCID 10942334Sodium Methoxide

Product 1

HCID 60877EmtricitabineYield 82%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

The 5'-O-butyrate of (+)-FTC (0.47 mmol, 149 mg) was dissolved in 16 mL of a solution of 4:1 pH 8 buffer:CH3CN. The clear solution was stirred and treated with 26 mg of pig liver esterase (PLE-A). The progress of the reaction was monitored by HPLC (FIG. 4). After 20 hours (52% conversion), the reaction mixture was extracted with 2×80 mL of CHCl3 and 80 mL of ethyl acetate. The organic layer extracts were combined, dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation. The resulting residue was eluted on 2×1000 m pTLC plates using ethyl acetate as eluant (double elution) to give, after isolation, 53 mg (36% based on starting material) of FTC butyrate which was determined to have 98% enantiomeric excess (e.e.) by HPLC analysis. The enantiomerically-enriched butyrate was then treated with 1.6 mL of methanol followed by 0.38 mmol (20 mg) of sodium methoxide. The resulting mixture was stirred at room temperature, and the progress of the reaction was monitored by HPLC. The reaction was completed within 30 minutes. The solvent was removed by rotary evaporation to give a crude white solid (76 mg) that was eluted on a 1000 m pTLC using 5:1 ethyl acetate:ethanol. (-)-FTC was isolated as a white solid (33 mg; 82% yield). HPLC analysis of the FTC as its 5'-O-acetate derivative showed 97% e.e.; [α](20,D) -120.5° (c=0.88; abs. ethanol).

Workup

  1. additiontreated with 26 mg of pig liver esterase (PLE-A)
  2. extractionthe reaction mixture was extracted with 2×80 mL of CHCl3 and 80 mL of ethyl acetate
  3. dry with materialdried over anhydrous MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated by rotary evaporation
  6. washThe resulting residue was eluted on 2×1000 m pTLC plates
  7. wash(double elution)
  8. customto give
  9. stirringThe resulting mixture was stirred at room temperature
  10. waitThe reaction was completed within 30 minutes
  11. customThe solvent was removed by rotary evaporation
  12. customto give a crude white solid (76 mg) that
  13. washwas eluted on a 1000 m

Sources & evidence

ORD record
ord-49f50ee84cb04103877faf2ed0624f56
Source dataset
uspto-grants-2000_09
Patent number
US06114343

Reaction notes

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