Dimethylformamide → Letrozole

HRID 2375440Notes

Reaction equation

HRID 2375440 reaction equation
N1C=[CH:4][N:3]=[N:2]1.Br[CH:7]([C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1.[CH3:24][N:25](C=O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:10]1[C:11]([C:14]#[N:15])=[CH:12][CH:13]=[C:8]([CH:7]([N:2]2[N:3]=[CH:4][N:25]=[CH:24]2)[C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[CH:9]=1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 20350980HCID 20350980, compoundHCID 178418936HCID 178418936, compound

Product 1

HCID 3902LetrozoleYield 65.7%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
60 °C

Procedure

A reactor was charged with triazole (104 g, 1.5 moles) and bromo-bis(4-cyanophenyl)methane (108 g, 0.6 mole) followed by addition of DMF (720 ml) and toluene (1080 ml), and the impeller speed was set at 800 RPM. The temperature was raised to 60° C. and potassium carbonate was added (83.5 g, 0.6 mole). Then, the temperature was raised to 80° C. and mixing was maintained at this temperature during about 1.5 hours. Then, air was bubbled at the same temperature for about 15 minutes at 3500 ml/minute air flow. An aliquot was withdrawn from the reaction mixture, diluted with a mixture of water and acetonitrile and injected to HPLC. The letrozole content was 73%, the isoletrozole content was 8.7% and the content of 4.4′-dicyano-benzophenone was 16.2%. After cooling to a temperature of 25° C., acetic acid (57.6 ml) was added. DMF (414 ml) and water (1760 ml) were added to the reaction mixture to form a suspension (two liquid phases and a solid inter-phase in between). After heating the suspension to 60° C. the resulting mixture was allowed to cool to 25° C. for one hour and then the mixture was cooled to 20° C. and mixed at that temperature for 2 hours. The precipitated crystals were washed with water (80 ml) and dried to obtain 112.3 g of crude letrozole in 65.7% yield, having a purity of 98.5% by HPLC, (containing 1.2% isoletrozole).

Workup

  1. temperatureThen, the temperature was raised to 80° C.
  2. additionmixing
  3. temperaturewas maintained at this temperature during about 1.5 hours
  4. customThen, air was bubbled at the same temperature for about 15 minutes at 3500 ml/minute air flow
  5. customAn aliquot was withdrawn from the reaction mixture
  6. additiondiluted with a mixture of water and acetonitrile
  7. temperatureAfter cooling to a temperature of 25° C., acetic acid (57.6 ml)
  8. additionwas added
  9. additionDMF (414 ml) and water (1760 ml) were added to the reaction mixture
  10. customto form a suspension (two liquid phases
  11. temperatureAfter heating the suspension to 60° C. the resulting mixture
  12. temperatureto cool to 25° C. for one hour
  13. temperaturethe mixture was cooled to 20° C.
  14. additionmixed at that temperature for 2 hours
  15. washThe precipitated crystals were washed with water (80 ml)
  16. customdried

Sources & evidence

ORD record
ord-27ab6586f2014aa0a270e0e763f91721
Source dataset
uspto-grants-2008_12
Patent number
US07465749B2

Reaction notes

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