Cesium carbonate → 4-[3-(4-Chloro-3-trifluoromethyl-phenylamino)-benzo[1,2,4]triazin-7-yloxy]-pyridine-2-carboxylic acid methylamide trifluoroacetate salt

HRID 387427

Reaction equation

HRID 387427 reaction equation
C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:47](=[O:50])([O-])[O-:48].[Cs+].[Cs+].Br[C:54]1[CH:55]=[CH:56][C:57]([Cl:64])=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:59]=1.[CH3:65][NH:66][C:67]([C:69]1[CH:74]=[C:73]([O:75][C:76]2[CH:86]=[CH:85][C:79]3[N:80]=[C:81]([NH2:84])[N:82]=[N:83][C:78]=3[CH:77]=2)[CH:72]=[CH:71][N:70]=1)=[O:68]>CN(C)C=O>[F:61][C:60]([F:63])([F:62])[C:47]([OH:48])=[O:50].[CH3:65][NH:66][C:67]([C:69]1[CH:74]=[C:73]([O:75][C:76]2[CH:86]=[CH:85][C:79]3[N:80]=[C:81]([NH:84][C:54]4[CH:55]=[CH:56][C:57]([Cl:64])=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:59]=4)[N:82]=[N:83][C:78]=3[CH:77]=2)[CH:72]=[CH:71][N:70]=1)=[O:68]

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 679594-Bromo-2-chloro-alpha,alpha,alpha-trifluorotolueneHCID 634876Binap, (A+-)-HCID 591353294-((3-Aminobenzo[e][1,2,4]triazin-7-yl)oxy)-N-methylpicolinamide

Product 1

HCID 875382034-[3-(4-Chloro-3-trifluoromethyl-phenylamino)-benzo[1,2,4]triazin-7-yloxy]-pyridine-2-carboxylic acid methylamide trifluoroacetate salt

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

To a vial with 2 mL of anhydrous dimethylformamide under argon atmosphere were added 15.4 mg (0.0168 mmol, 0.05 equivalent) of tris(dibenzyllideneatone) dipalladium(0), 21.0 mg (0.033 mmol, 0.1 equivalent) of BINAP, 220.0 mg (0.675 mmol, 2.0 equivalent) of anhydrous cesium carbonate, 175.1 mg (0.675 mmol, 2.0 equivalent) of 5-bromo-2-chlorobenzotrifluoride, and 100 mg (0.337 mmol, 1.0 equivalent) of 4-(3-amino-benzo[1,2,4]triazin-7-yloxy)-pyridine-carboxylic acid methylamide, in that particular order. Argon gas was bubbled through the mixture for 5 min. Then the vial was capped and the reaction mixture was heated to 120° C. with stirring under argon atmosphere for 18 hours. At this point LC/MS indicated about 40% conversion to the product. As pointed out in the previous examples, the longer reaction times result in the formation of the by-product and partial decomposition. So, the reaction mixture was allowed to cool down to ambient temperature, filtered through 0.3 μm syringe filter and purified by reverse-phase prep-HPLC using acetonitrile/water mixture with 0.1% of TFA.

Workup

  1. customArgon gas was bubbled through the mixture for 5 min
  2. customThen the vial was capped
  3. customthe longer reaction times
  4. customresult in the formation of the by-product and partial decomposition
  5. temperatureto cool down to ambient temperature
  6. filtrationfiltered through 0.3 μm syringe
  7. filtrationfilter
  8. custompurified by reverse-phase

Sources & evidence

ORD record
ord-d789d86f8f92460e9527288aa2450738
Source dataset
uspto-grants-2013_02
Patent number
US08372971B2

Linked notes

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