Ammonium Chloride → 6-(2-Amino-pyrimidin-4-yloxy)-benzofuran-3-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide

HRID 556360Notes

Reaction equation

HRID 556360 reaction equation
[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C[Al](C)C.C[O:18][C:19]([C:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=3)=[CH:29][C:24]=2[O:23][CH:22]=1)=O.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19]([C:21]2[C:25]3[CH:26]=[CH:27][C:28]([O:30][C:31]4[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=4)=[CH:29][C:24]=3[O:23][CH:22]=2)=[O:18])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 753774-Fluoro-3-(trifluoromethyl)anilineHCID 16682925TrimethylaluminumHCID 575564496-(2-Amino-pyrimidin-4-yloxy)-benzofuran-3-carboxylic acid methyl ester

Product 1

HCID 247627956-(2-Amino-pyrimidin-4-yloxy)-benzofuran-3-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
10 °C

Procedure

In a dried vessel, 108 mg (0.60 mMol) 4-fluoro-3-trifluoromethyl-aniline are dissolved in 10 ml toluene and cooled to 10° C. Then 900 μl Me3Al (2 M in toluene; 1.8 mMol) are added via syringe. After 1 h at rt, a suspension of 171 mg (0.599 mMol) 6-(2-amino-pyrimidin-4-yloxy)-benzofuran-3-carboxylic acid methyl ester (Step 9.6) in 5 ml THF is added and the reaction mixture is stirred for 40 min in an oil bath of 110° C. The solution is cooled in ice and hydrolyzed with 20 ml of a sat. NH4Cl. After 10 min stirring, the mixture is filtered through Celite, the solid washed extensively with EtOAc and water, the aq. phase separated from the filtrate and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; EtOAc) and crystallization from EtOAc/hexane 1:1 gives the title compound: MS: [M+1]+=433; TLC(hexane/EtOAc 1:9): Rf=0.22.

Workup

  1. additionis added
  2. stirringAfter 10 min stirring
  3. filtrationthe mixture is filtered through Celite
  4. washthe solid washed extensively with EtOAc and water
  5. customthe aq. phase separated from the filtrate
  6. extractionextracted with EtOAc
  7. washThe organic layers are washed with water and brine
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated
  10. customColumn chromatography (SiO2; EtOAc) and crystallization from EtOAc/hexane 1:1

Sources & evidence

ORD record
ord-7dfa513e312c4d0baa155cb6d530615c
Source dataset
uspto-grants-2011_11
Patent number
US08058276B2

Reaction notes

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