Ammonium Chloride → 6-(6-Methoxymethyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (4-methyl-3-trifluoromethyl-phenyl)-amide

HRID 1094517Notes

Reaction equation

HRID 1094517 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C[Al](C)C.C[O:18][C:19]([C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:31][C:32]3[CH:37]=[C:36]([CH2:38][O:39][CH3:40])[N:35]=[CH:34][N:33]=3)=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)=O.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O.O>[CH3:12][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:31][C:32]4[CH:37]=[C:36]([CH2:38][O:39][CH3:40])[N:35]=[CH:34][N:33]=4)=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:7][C:6]=1[C:8]([F:9])([F:10])[F:11]

Participants

9

Reactant 4

HCID 25517Ammonium ChlorideHCID 27377154-Methyl-3-(trifluoromethyl)anilineHCID 16682925TrimethylaluminumHCID 591759786-(6-Methoxymethyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid methyl ester

Product 1

HCID 236532046-(6-Methoxymethyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (4-methyl-3-trifluoromethyl-phenyl)-amide

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

In a dried vessel, 68 mg (0.388 mMol) 5-amino-2-methylbenzotrifluoride are dissolved in 7 ml toluene and cooled in an ice bath. Then 580 μl Me3Al (2 M in toluene; 1.16 mMol) are added via syringe. After 1 h at rt, a solution of 126 mg (0.388 mMol) 6-(6-methoxymethyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid methyl ester in 1.5 ml THF is added and the solution is stirred for ½ h in an oil bath of 110° C. The solution is cooled in an ice bath and hydrolyzed with 13 ml of a sat. NH4Cl solution. After 15 min stirring, the mixture is diluted with EtOAc and water, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; CH2Cl2/acetone 99:1→19:1) and crystallization from DIPE/hexane gives the title compound: m.p.: 188° C.; Anal.: C, H, N, F; MS: [M+1]+=468; TLC (CH2Cl2/acetone 9:1): Rf=0.32; 1H-NMR (DMSO-d6): δ ppm 10.85 (s, HN), 8.69 (s, 1H), 8.28 (d, 1H), 8.24 (s, 1H), 8.10 (d, 1H), 7.93 (d, 1H), 7.90 (s, 1H), 7.80 (d, 1H), 7.66 (t, 1H), 7.48 (d, 1H), 7.44 (d, 1H), 7.07 (s, 1H), 4.50 (s, H2C), 3.4 (s, H3C), 2.43 (s, H3C).

Workup

  1. temperaturecooled in an ice bath
  2. stirringAfter 15 min stirring
  3. customthe aq. phase separated off
  4. extractionextracted twice with EtOAc
  5. washThe organic layers are washed with water and brine
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated
  8. customChromatography (Combi Flash; CH2Cl2/acetone 99:1→19:1) and crystallization from DIPE/hexane

Sources & evidence

ORD record
ord-1554b615204d45989ce667d29e900f2a
Source dataset
uspto-grants-2012_03
Patent number
US08133886B2

Reaction notes

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