3-(Trifluoromethyl)aniline → HCID 24862990, compound

HRID 1668917Notes

Reaction equation

HRID 1668917 reaction equation
Cl[C:2]1[C:11]2[C:6](=[C:7]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([NH:23][CH3:24])[N:17]=[CH:16]4)[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:25][C:26]([F:35])([F:34])[C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1.O1CCOCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(OCC)(=O)C.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].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C>[CH3:24][NH:23][C:18]1[N:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:7]3[C:8]([CH3:12])=[CH:9][CH:10]=[C:11]4[C:6]=3[CH:5]=[CH:4][N:3]=[C:2]4[NH:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:34])([F:35])[F:25])[CH:28]=3)[CH:14]=2)[N:19]=1

Participants

8

Reactant 4

HCID 73753-(Trifluoromethyl)anilineHCID 312751,4-DioxaneHCID 2733832Lithium HexamethyldisilazideHCID 58942249HCID 58942249, compound

Product 1

HCID 24862990HCID 24862990, compoundYield 51.4%

Reagents, catalysts & solvents 3

HCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
150 °C

Procedure

6-(1-Chloro-6-methylisoquinolin-5-yl)-N-methylquinazolin-2-amine (8.50 g, 25.4 mmol), 3-(trifluoromethyl)benzenamine (4.30 g, 26.7 mmol), Davephos (0.40 g, 1.02 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.465 g, 0.508 mmol) were equally divided into 6 and added to 6 clear microwave vials along with 10 mL of dioxane in each vial. Nitrogen was bubbled into each vial for 10 min and lithium bis(trimethylsilyl)amide (1.0 M in THF) (50.8 mL, 50.8 mmol) divided into 6 (8.46 mL each) was added to the vials. The vials were then capped and heated to 150° C. in a Personal Chemistry Smith Synthesizer for 10 min. The reaction mixtures were combined and diluted with ethyl acetate. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 20 to 100% EtOAc in hexanes and recrystallization from 3:1 ether/ethyl acetate to give N-methyl-6-(6-methyl-1-(3-(trifluoromethyl)phenylamino)isoquinolin-5-yl)quinazolin-2-amine (6.0 g, 51%) as a white solid. MS (M+H)+ 460.

Workup

  1. customNitrogen was bubbled into each vial for 10 min
  2. additionwas added to the vials
  3. customThe vials were then capped
  4. customThe reaction mixtures
  5. washThe organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate
  6. dry with materialThe organic layer was then dried with sodium sulfate
  7. custompurified by column chromatography on silica gel using
  8. customa gradient of 20 to 100% EtOAc in hexanes and recrystallization from 3:1 ether/ethyl acetate

Sources & evidence

ORD record
ord-15cd46e3a01f45dc820036a9d5b75ed1
Source dataset
uspto-grants-2011_08
Patent number
US07989461B2

Reaction notes

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