Dimethylformamide → Letrozole

HRID 2375439Notes

Reaction equation

HRID 2375439 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 70.5%

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. An aliquot was withdrawn from the reaction mixture, diluted with a mixture of water and acetonitrile and analyzed by HPLC. The letrozole content was 83%, the isoletrozole content was 11.4%, while the content of 4,4′-dicyanobenzophenone was 1.6%. 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 120.5 g of crude letrozole in 70.5% yield, having a purity of 96% by HPLC, (containing 3.5% 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. customAn aliquot was withdrawn from the reaction mixture
  5. additiondiluted with a mixture of water and acetonitrile
  6. temperatureAfter cooling to a temperature of 25° C., acetic acid (57.6 ml)
  7. additionwas added
  8. additionDMF (414 ml) and water (1760 ml) were added to the reaction mixture
  9. customto form a suspension (two liquid phases
  10. temperatureAfter heating the suspension to 60° C. the resulting mixture
  11. temperatureto cool to 25° C. for one hour
  12. temperaturethe mixture was cooled to 20° C.
  13. additionmixed at that temperature for 2 hours
  14. washThe precipitated crystals were washed with water (80 ml)
  15. customdried

Sources & evidence

ORD record
ord-60ea46a3210b4f108dfc5195cd1c96e0
Source dataset
uspto-grants-2008_12
Patent number
US07465749B2

Reaction notes

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