Toluene → N-(4-(3-fluoro-7-methoxyquinolin-4-yloxy)phenyl)-4-(4-(trifluoromethyl)phenyl) phthalazin-1-amine

HRID 503549Notes

Reaction equation

HRID 503549 reaction equation
C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.Cl[C:31]1[C:40]2[C:35](=[CH:36][C:37]([O:41][CH3:42])=[CH:38][CH:39]=2)[N:34]=[CH:33][C:32]=1[F:43].[F:44][C:45]([F:71])([F:70])[C:46]1[CH:51]=[CH:50][C:49]([C:52]2[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:55]([NH:62][C:63]3[CH:68]=[CH:67][C:66]([OH:69])=[CH:65][CH:64]=3)=[N:54][N:53]=2)=[CH:48][CH:47]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>O.C(Cl)Cl.CS(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:43][C:32]1[CH:33]=[N:34][C:35]2[C:40]([C:31]=1[O:69][C:66]1[CH:65]=[CH:64][C:63]([NH:62][C:55]3[C:56]4[C:61](=[CH:60][CH:59]=[CH:58][CH:57]=4)[C:52]([C:49]4[CH:50]=[CH:51][C:46]([C:45]([F:71])([F:70])[F:44])=[CH:47][CH:48]=4)=[N:53][N:54]=3)=[CH:68][CH:67]=1)=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=2

Participants

10

Reactant 5

HCID 1140TolueneHCID 10796Cesium carbonateHCID 2734941(1,1'-Binaphthalen)-2-yldi-tert-butylphosphineHCID 594273204-chloro-3-fluoro-7-methoxyQuinolineHCID 1363817254-(4-(4-(Trifluoromethyl)phenyl)phthalazin-1-ylamino)phenol

Product 1

HCID 59427330N-(4-(3-fluoro-7-methoxyquinolin-4-yloxy)phenyl)-4-(4-(trifluoromethyl)phenyl) phthalazin-1-amine

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
100 °C

Procedure

Racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (84 mg, 210 μmol), 4-chloro-3-fluoro-7-methoxyquinoline (67 mg, 315 μmol), 4-(4-(4-(trifluoromethyl)phenyl)phthalazin-1-ylamino)phenol (80 mg, 210 μmol), cesium carbonate (137 mg, 420 μmol), and Pd2 dba3 (96 mg, 105 μmol) were combined in a resealable tube, and the tube was purged with nitrogen. Toluene (1049 μl, 210 μmol) was added and the tube was sealed and heated to 100° C. overnight. Analysis by LCMS showed incomplete conversion to product. The reaction mixture was diluted with water and DCM, and the water layer was separated and extracted first with DCM followed by ethyl acetate. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The dark residue was taken up in DCM and hexanes, and a precipitate formed. The solid was filtered and purified by preparative HPLC. The crude reaction mixture was taken up in minimal DMSO and methanol and purified on the Gilson {15-85% (0.1% TFA in CH3CN) in H2O over 20 min}. Clean product containing fractions were combined and neutralized with saturated aqueous NaHCO3 then extracted with ethyl acetate, dried over MgSO4, filtered and concentrated in vacuo to afford N-(4-(3-fluoro-7-methoxyquinolin-4-yloxy)phenyl)-4-(4-(trifluoromethyl)phenyl) phthalazin-1-amine as a tan solid. Further purification was accomplished by silica gel chromatography (90:10 CH2Cl2:MeOH). N-(4-(3-fluoro-7-methoxyquinolin-4-yloxy)phenyl)-4-(4-(trifluoromethyl)phenyl) phthalazin-1-amine was afforded as a tan solid. MS [M+H]=557.0. Calc'd for C19H21N5O: 556.15.

Workup

  1. customthe tube was purged with nitrogen
  2. customthe tube was sealed
  3. customthe water layer was separated
  4. extractionextracted first with DCM
  5. dry with materialThe combined organic extracts were dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customhexanes, and a precipitate formed
  9. filtrationThe solid was filtered
  10. custompurified by preparative HPLC
  11. customThe crude reaction mixture
  12. custommethanol and purified on the Gilson {15-85% (0.1% TFA in CH3CN) in H2O over 20 min}
  13. additionClean product containing fractions
  14. extractionthen extracted with ethyl acetate
  15. dry with materialdried over MgSO4
  16. filtrationfiltered
  17. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-4b04fc3a6603485e9c8cbf7a784773f9
Source dataset
uspto-grants-2010_08
Patent number
US07776857B2

Reaction notes

Loading…