Tricyclohexylphosphine → (5-(4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl)-furan-2-ylmethyl)-carbamic acid tert-butyl ester

HRID 415008Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 415008
Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26](I)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])(=O)C.[K+].[C:54]([O:58][C:59](=[O:67])[NH:60][CH2:61][C:62]1[O:63][CH:64]=[CH:65][CH:66]=1)([CH3:57])([CH3:56])[CH3:55]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.[Pd](Cl)Cl>[C:54]([O:58][C:59](=[O:67])[NH:60][CH2:61][C:62]1[O:63][C:64]([C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][N:20]=[C:19]3[NH:18][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)=[C:3]([Cl:2])[CH:4]=2)=[CH:65][CH:66]=1)([CH3:57])([CH3:55])[CH3:56]

Komponenten

9

Edukt 4

HCID 75806TricyclohexylphosphineHCID 517044Potassium AcetateHCID 4935496Tert-butyl (furan-2-ylmethyl)carbamateHCID 66623345[3-Chloro-4-(3-fluorobenzyloxy)phenyl](6-iodoquinazolin-4-yl)amine hydrochloride

Produkt 1

HCID 66623782(5-(4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl)-furan-2-ylmethyl)-carbamic acid tert-butyl esterAusbeute 46,4 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 24290Palladium ChlorideKatalysatorHCID 74236Tetrabutylammonium BromideKatalysatorHCID 962WaterLösungsmittelHCID 6228DimethylformamideLösungsmittel2×

Reaktionsbedingungen

Temperatur
110 °C

Versuchsvorschrift

[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine hydrochloride (0.913 g, 1.68 mmol) (from Step E, Example 1) is dissolved in DMF (20 ml) and the solution is degassed under nitrogen. The above solution is added over 10 hours to a heated (110° C.) degassed suspension of tricyclohexyl phosphine (0.475 g, 1.7 mmol), palladium dichloride (15.2 mg, 0.086 mmol), potassium acetate (0.35 g, 3.6 mmol), tetra n-butyl ammonium bromide (0.552 g, 2.15 mmol), and Furan-2-ylmethyl-carbamic acid tert-butyl ester (2.9 g, 15 mmol) in DMF (5 ml). Heating is continued for 9 hours after the end of addition. The reaction mixture is cooled, diluted with water and extracted with EtOAc. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography on silica with 10-50% EtOAc:hexanes gradient elution yields 0.450 g (0.78 mmol, 46%) of the clean desired product.

Aufarbeitung

  1. customthe solution is degassed under nitrogen
  2. additionThe above solution is added over 10 hours to
  3. customdegassed
  4. temperatureHeating
  5. additionafter the end of addition
  6. temperatureThe reaction mixture is cooled
  7. extractionextracted with EtOAc
  8. dry with materialThe combined organic extracts are dried (Na2SO4)
  9. concentrationconcentrated under reduced pressure
  10. washFlash chromatography on silica with 10-50% EtOAc:hexanes gradient elution

Quellen und Nachweise

ORD-Eintrag
ord-3fa2b5e762184a6ba8d35b8a9bb59c55
Quelldatensatz
uspto-grants-2012_01
Patentnummer
US08088766B2

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