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

HRID 1725134Notes

Reaction equation

HRID 1725134 reaction equation
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]

Participants

9

Reactant 4

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

Product 1

HCID 66623782(5-(4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl)-furan-2-ylmethyl)-carbamic acid tert-butyl esterYield 46.4%

Reagents, catalysts & solvents 4

HCID 24290Palladium ChlorideCatalystHCID 74236Tetrabutylammonium BromideCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent2×

Conditions

Temperature
110 °C

Procedure

[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.

Workup

  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

Sources & evidence

ORD record
ord-c3139e7cd356450faede16d21c8d1acb
Source dataset
uspto-grants-2009_02
Patent number
US07488823B2

Reaction notes

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