7-Chloro-4-(4-fluoro-3,5-dimethylphenyl)quinazoline → 4-(4-Fluoro-3,5-dimethylphenyl)-7-(3,3,3-trifluoropropyl)quinazoline

HRID 1056446Notes

Reaction equation

HRID 1056446 reaction equation
Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[C:16]([CH3:18])[C:15]([F:19])=[C:14]([CH3:20])[CH:13]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[I-].[F:22][C:23]([F:28])([F:27])[CH2:24][CH2:25][Zn+]>C(O[Pd]OC(=O)C)(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2N(C)C)CCCCC1.C1COCC1>[F:19][C:15]1[C:16]([CH3:18])=[CH:17][C:12]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH2:25][CH2:24][C:23]([F:28])([F:27])[F:22])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:13][C:14]=1[CH3:20]

Participants

6

Reactant 2

HCID 1212668267-Chloro-4-(4-fluoro-3,5-dimethylphenyl)quinazolineHCID 178506322HCID 178506322, compound

Product 1

HCID 1212668234-(4-Fluoro-3,5-dimethylphenyl)-7-(3,3,3-trifluoropropyl)quinazolineYield 98.8%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 441561692'-(Dicyclohexylphosphino)-N2,N2,N6,N6-tetramethyl[1,1'-biphenyl]-2,6-diamineCatalystHCID 8028TetrahydrofuranSolvent

Procedure

7-chloro-4-(4-fluoro-3,5-dimethylphenyl)quinazoline (2.75 g, 9.59 mmol), 2′-(dicyclohexylphosphino)-N2,N2,N6,N6-tetramethyl-[1,1′-biphenyl]-2,6-diamine (CPhos) (0.34 g, 0.77 mmol), and diacetoxypalladium (0.090 g, 0.38 mmol) and 100 mL anhydrous THF were placed in an oven dried three neck round bottom flask. The system was evacuated and purged with nitrogen three times. (3,3,3-trifluoropropyl)zinc(II) iodide (86 ml, 19.2 mmol) was added via syringe. Upon completion of the reaction, it was quenched with ammonium chloride solution then transferred to a separatory funnel with ethyl acetate. The aqueous was partitioned off, then the organics were washed once with brine, dried with sodium sulfate, filtered and concentrated down. The crude solid was purified with silica gel using DCM to 90/10 DCM/ethyl acetate solvent system to get 3.3 g of a brownish-red solid. The 3.3 g solid was purified using C18 cartridges using 80/20 to 85/15 acetonitrile/water solvent system. The combined fractions were concentrated down then dried in the vacuum oven overnight to get 2.36 g of a white solid for a 71% yield.

Workup

  1. customdried three neck round bottom flask
  2. customThe system was evacuated
  3. custompurged with nitrogen three times
  4. customUpon completion of the reaction, it
  5. customwas quenched with ammonium chloride solution
  6. customthen transferred to a separatory funnel with ethyl acetate
  7. customThe aqueous was partitioned off
  8. washthe organics were washed once with brine
  9. dry with materialdried with sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated down
  12. customThe crude solid was purified with silica gel

Sources & evidence

ORD record
ord-3ba8db11ed794a3eb0763ca2be47a1f3
Source dataset
uspto-grants-2016_07
Patent number
US09397302B2

Reaction notes

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