641571-11-1

Basic information

• Product Name: 3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline
• Synonyms: 1-(3-Amino-5-trifluoromethylphenyl)-4-methylimidazole;3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline;4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl) benzene amine;3-(trifluoromethyl)-5-(4-methyl-1H-imidazol-1-yl)benzenamine;3-(4-Methyl-iMidazol-1-yl)-5-trifluoro-MethylphenylaMine;3-Amino-5-(4-methyl-1H-imidazol-1-yl)benzotrifluoride;3-(4-Methyl-1H-iMidazol-1-yl)-5-(trifluoroMethyl)benzenaMine;3-(4-Methyl-1H-iMidazol-1-yl)-5-(trifluoroMethyl)benzeneaMine, 3-(4-Methyl-1H-iMidazol-1-yl)-5-(trifluoroMethyl)aniline
• CAS NO: 641571-11-1
• Molecular Formula: C₁₁H₁₀F₃N₃
• Molecular Weight: 241.21
• EINECS: 1308068-626-2
• Product Categories: Amines;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Nilotinib/Tasigna
• Mol File: 641571-11-1.mol
• Article Data: 49

Chemical Properties

• Melting Point: 124-126°C
• Boiling Point: 379.805 °C at 760 mmHg
• Flash Point: 183.5 °C
• Appearance: /
• Density: 1.35
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.553
• Storage Temp.: Refrigerator
• Water Solubility: 228.6mg/L at 25℃
• CAS DataBase Reference: 3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline(CAS DataBase Reference)
• NIST Chemistry Reference: 3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline(641571-11-1)
• EPA Substance Registry System: 3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline(641571-11-1)

Safety Data

• Statements: 41
• Safety Statements: 26-39
• RIDADR: 2811
• HazardClass: 6.1
• PackingGroup: Ⅲ
• Hazardous Substances Data: 641571-11-1(Hazardous Substances Data)

Usage

Chemical Properties

Beige Solid

InChI:InChI=1/C11H10F3N3/c1-7-5-17(6-16-7)10-3-8(11(12,13)14)2-9(15)4-10/h2-6H,15H2,1H3

Synthetic route

4-methyl-1H-imidazole (822-36-6) + [3-bromo-5-(trifluoromethyl)phenyl]amine (54962-75-3) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
With copper(l) iodide; (+)-D-glucosamine hydrochloride; caesium carbonate In water; dimethyl sulfoxide at 90℃; for 12h; Temperature; Concentration;	96.18%
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0) In toluene; tert-butyl alcohol at 120℃; for 8h; Inert atmosphere;	91%
With copper(l) iodide; 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethan-1-one; caesium carbonate In N,N-dimethyl-formamide at 110℃; for 18h; Inert atmosphere; Sealed tube;	91%

C23H18F6N6O → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
With sodium hydroxide In m-xylene; isopropyl alcohol for 25h; Reflux;	92.8%

4-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-imidazole (916975-92-3) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
With iron(III) chloride; hydrazine hydrate; pyrographite In ethanol at 50 - 60℃; Reagent/catalyst; Temperature;	91.3%
With palladium In methanol at 25℃; for 5h;	86%
With palladium on activated charcoal; hydrogen In methanol at 25℃; for 5h;	86%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzohydrazide → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
Stage #1: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzohydrazide With sulfuric acid; sodium nitrite In methanol at 15 - 25℃; for 0.416667h; Stage #2: In methanol at 55 - 75℃; for 0.416667h; Concentration; Reagent/catalyst; Temperature;	90%

N-(3-amino-5-(trifluoromethyl)phenyl)acetamide (455279-96-6) + formaldehyd (50-00-0) + 2-oxopropanal (78-98-8) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
Stage #1: N-(3-amino-5-(trifluoromethyl)phenyl)acetamide With ammonium chloride In ethanol; acetone at 0 - 20℃; Stage #2: formaldehyd; 2-oxopropanal In ethanol; water; acetone at 65 - 70℃;	85.4%

3-(4-methyl-imidazol-1-yl)-5-trifluoromethylbenzoic acid (641571-13-3) + tert-butyl alcohol (75-65-0) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
Stage #1: 3-(4-methyl-imidazol-1-yl)-5-trifluoromethylbenzoic acid; tert-butyl alcohol With diphenyl phosphoryl azide; triethylamine for 16h; Reflux; Stage #2: With sodium hydroxide In propan-1-ol; para-xylene; water for 30h; Solvent; Reagent/catalyst; Reflux;	79.5%

N-(4-methoxybenzyl)-3-(4-methyl-1H-imidazol-1yl)-5-trifluoromethylaniline → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
With trifluoroacetic acid at 20 - 25℃; for 2h; Reagent/catalyst; Temperature;	78%

4-methyl-1H-imidazole (822-36-6) + 3-iodo-5-trifluoromethylaniline (389571-69-1) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + 3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline

Conditions	Yield
With potassium phosphate at 110℃; for 30h; Reagent/catalyst;	A 65.2% B n/a

4-methyl-1H-imidazole (822-36-6) + [3-bromo-5-(trifluoromethyl)phenyl]amine (54962-75-3) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + 3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline

Conditions	Yield
With copper(l) iodide; caesium carbonate; rac-diaminocyclohexane In diethylene glycol dimethyl ether at 24℃; for 24h; Reagent/catalyst; Inert atmosphere;	A 64.9% B n/a
With copper(I) oxide; potassium phosphate; N1,N2-bis(furan-2-ylmethyl)oxalamide In dimethyl sulfoxide at 120℃; for 24h; Overall yield = 89 %;

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline hydrochloride (917391-26-5) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
With potassium hydrogencarbonate In ethanol; water at 0 - 45℃; for 3.5h; Product distribution / selectivity;	32.8%
With potassium hydrogencarbonate In methanol; water at 20 - 40℃; for 3h; Product distribution / selectivity;

N-(3-(4-methyl-1H-1-imidazolyl)-5-trifluoromethylbenzene) tert-butoxycarbonylamine → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
Stage #1: N-(3-(4-methyl-1H-1-imidazolyl)-5-trifluoromethylbenzene) tert-butoxycarbonylamine With hydrogenchloride In isopropyl alcohol at 60℃; for 5h; Stage #2: With sodium hydrogencarbonate In water; isopropyl alcohol

4-methyl-1H-imidazole (822-36-6) + 3-fluoro-5-trifluoromethylaniline (454-67-1) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
Stage #1: 4-methyl-1H-imidazole With sodium hydride In tetrahydrofuran at 20 - 25℃; for 0.25h; Stage #2: 3-fluoro-5-trifluoromethylaniline In tetrahydrofuran; 1-methyl-pyrrolidin-2-one at 20 - 165℃; for 22.25h; Product distribution / selectivity;

1-fluoro-3-(trifluoromethyl)-5-nitrobenzene (454-73-9) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 8 h / 80 °C 2: palladium / methanol / 5 h / 25 °C View Scheme
Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 8 h / 80 °C 2: palladium on activated charcoal; hydrogen / methanol / 5 h / 25 °C View Scheme
Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 8 h / 80 °C 2: palladium on activated charcoal; hydrogen / methanol / 5 h / 25 °C View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate 2: tin(ll) chloride; hydrogenchloride / water View Scheme

α,α,α-trifluorotoluene (98-08-8) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: nitric acid; sulfuric acid / 2 h / 40 °C 2: nitric acid; sulfuric acid; bromine / 4 h / 70 °C 3: iron; hydrogenchloride / ethanol / 1.5 h / 40 °C 4: D-glucosamine hydrochloride; copper(l) iodide; caesium carbonate / dimethyl sulfoxide; water / 10 h / 100 °C View Scheme
Multi-step reaction with 4 steps 1: nitric acid; sulfuric acid / 8 h / 0 - 20 °C 2: sulfuric acid; bromine / 14 h / 60 - 70 °C / Cooling with ice 3: potassium carbonate; triethylamine; copper(l) iodide; isoquinolin-8-ol / N,N-dimethyl-formamide / 5 h / 100 - 140 °C 4: iron(III) chloride; pyrographite; hydrazine hydrate / ethanol / 50 - 60 °C View Scheme

3-trifluoromethylnitrobenzene (98-46-4) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: nitric acid; sulfuric acid; bromine / 4 h / 70 °C 2: iron; hydrogenchloride / ethanol / 1.5 h / 40 °C 3: D-glucosamine hydrochloride; copper(l) iodide; caesium carbonate / dimethyl sulfoxide; water / 10 h / 100 °C View Scheme
Multi-step reaction with 3 steps 1: sulfuric acid; bromine / 14 h / 60 - 70 °C / Cooling with ice 2: potassium carbonate; triethylamine; copper(l) iodide; isoquinolin-8-ol / N,N-dimethyl-formamide / 5 h / 100 - 140 °C 3: iron(III) chloride; pyrographite; hydrazine hydrate / ethanol / 50 - 60 °C View Scheme

[3-bromo-5-(trifluoromethyl)phenyl]amine (54962-75-3) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; dmap / toluene 1.2: 5 h 2.1: trifluoroacetic acid / 2 h / 20 - 25 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium cyanoborohydride / tetrahydrofuran / 24 h / 20 °C 2.1: 8-quinolinol; 1-methyl-pyrrolidin-2-one / water / Inert atmosphere 2.2: 5 h / 140 - 145 °C / Inert atmosphere 3.1: trifluoroacetic acid / 2 h / 20 - 25 °C View Scheme

ethyl 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoate → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrazine hydrate / ethanol / 16 h / 78 °C 2.1: sodium nitrite; sulfuric acid / methanol / 0.42 h / 15 - 25 °C 2.2: 0.42 h / 55 - 75 °C View Scheme

sodium 3-bromo-5-trifluoromethylbenzoate → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: trans-N,N'-dimethyl-1,2-cyclohexyldiamine; potassium phosphate; copper(l) iodide / N,N-dimethyl-formamide / 60 h / 115 °C / Molecular sieve 1.2: 30 - 35 °C / Molecular sieve 2.1: hydrazine hydrate / ethanol / 16 h / 78 °C 3.1: sodium nitrite; sulfuric acid / methanol / 0.42 h / 15 - 25 °C 3.2: 0.42 h / 55 - 75 °C View Scheme

3-bromo-5-(trifluoromethyl)benzoic acid (328-67-6) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: trans-N,N'-dimethyl-1,2-cyclohexyldiamine; potassium phosphate; copper(l) iodide / N,N-dimethyl-formamide / 72 h / 115 °C / Molecular sieve 1.2: Molecular sieve 2.1: hydrazine hydrate / methanol / 16 h / 65 °C 3.1: sodium nitrite; sulfuric acid / methanol / 0.42 h / 15 - 25 °C 3.2: 0.42 h / 55 - 75 °C View Scheme
Multi-step reaction with 3 steps 1.1: trans-N,N'-dimethyl-1,2-cyclohexyldiamine; potassium phosphate; copper(l) iodide / 1,4-dioxane / 72 h / 115 °C / Molecular sieve 2.1: hydrazine hydrate / methanol / 16 h / 65 °C 3.1: sodium nitrite; sulfuric acid / methanol / 0.42 h / 15 - 25 °C 3.2: 0.42 h / 55 - 75 °C View Scheme

3-(4-methyl-imidazol-1-yl)-5-trifluoromethylbenzoic acid (641571-13-3) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrazine hydrate / methanol / 16 h / 65 °C 2.1: sodium nitrite; sulfuric acid / methanol / 0.42 h / 15 - 25 °C 2.2: 0.42 h / 55 - 75 °C View Scheme

3-bromo-5-trifluoromethylbenzoic acid methyl ester → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: trans-N,N'-dimethyl-1,2-cyclohexyldiamine; potassium phosphate; copper(l) iodide / N,N-dimethyl-formamide / 105 °C / Molecular sieve 2.1: hydrazine hydrate / methanol / 16 h / 65 °C 3.1: sodium nitrite; sulfuric acid / methanol / 0.42 h / 15 - 25 °C 3.2: 0.42 h / 55 - 75 °C View Scheme

3-fluoro-5-trifluoromethyl-benzonitrile (149793-69-1) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium carbonate; dihydrogen peroxide / dimethyl sulfoxide; water / 1.5 h / 25 - 35 °C 2.1: sodium amide / N,N-dimethyl acetamide / 1 h / 25 - 35 °C 2.2: 12 h / 25 - 85 °C 3.1: sodium hydroxide; bromine / water / 3.33 h / 0 - 95 °C View Scheme

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide (917391-28-7) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
With bromine; sodium hydroxide In water at 0 - 95℃; for 3.33333h;	80 g

3-bromo-5-fluorobenzotrifluoride (130723-13-6) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydride / 1-methyl-pyrrolidin-2-one 2: palladium diacetate / toluene 3: hydrogenchloride / water View Scheme

1-[3-bromo-5-(trifluoromethyl)phenyl]-4-methyl-1H-imidazole (917391-27-6) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: palladium diacetate / toluene 2: hydrogenchloride / water View Scheme

C24H18F3N3 → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
With hydrogenchloride In water

5-(trifluoromethyl)benzene-1,3-diamine (368-53-6) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / toluene / 0 - 10 °C 2.1: ammonium chloride / ethanol; acetone / 0 - 20 °C 2.2: 65 - 70 °C View Scheme
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 0 - 10 °C 2.1: ammonium chloride / ethanol; acetone / 0 - 20 °C 2.2: 65 - 70 °C View Scheme

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + carbon monoxide (201230-82-2) + 5-bromo-2-methylphenyl(4-(pyridin-3-yl)pyrimidin-2-yl)-carbamic acid tert-butyl ester → nilotinib (641571-10-0)

Conditions

Yield

Stage #1: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline; carbon monoxide; 5-bromo-2-methylphenyl(4-(pyridin-3-yl)pyrimidin-2-yl)-carbamic acid tert-butyl ester With bis(benzonitrile)palladium(II) dichloride; triethylamine; 1,2-bis-(diphenylphosphino)ethane; phenol In N,N-dimethyl-formamide at 90 - 105℃; under 6000.6 Torr; for 48h; Molecular sieve; Inert atmosphere; Autoclave; Stage #2: With trifluoroacetic acid In ethanol Inert atmosphere; Stage #3: With potassium hydroxide In ethanol; water pH=6 - 9; Reagent/catalyst; Solvent; Pressure; Inert atmosphere;

100%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + 3-acetylamino-4-methylbenzoic acid (6946-14-1) → 3-acetamido-4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethylphenyl]benzamide

Conditions	Yield
Stage #1: 3-acetylamino-4-methylbenzoic acid With thionyl chloride In dichloromethane for 4h; Reflux; Stage #2: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline With triethylamine; aniline In dichloromethane for 8h; Reflux;	95.1%
Stage #1: 3-acetylamino-4-methylbenzoic acid With thionyl chloride In dichloromethane for 4h; Reflux; Stage #2: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline With triethylamine In dichloromethane for 8h; Reflux;	94.7%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + 3-((tert-butoxycarbonyl)amino)-4-methylbenzoic acid methyl ester (330807-44-8) → N-(2-methyl-5-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)phenyl)carbamic acid tert-butyl ester

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at -10 - 0℃; Reagent/catalyst; Solvent; Temperature;	95%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + 4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzoic acid (641569-94-0) → nilotinib (641571-10-0)

Conditions	Yield
Stage #1: 4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}benzoic acid With thionyl chloride In 1-methyl-pyrrolidin-2-one at 60℃; for 1.25h; Stage #2: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline In 1-methyl-pyrrolidin-2-one at 90℃; for 3h; Product distribution / selectivity;	94%
Stage #1: 4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}benzoic acid With thionyl chloride In 1-methyl-pyrrolidin-2-one at 60℃; for 1.25h; Stage #2: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline In 1-methyl-pyrrolidin-2-one at 90℃; for 3h; Stage #3: With sodium hydroxide In 1-methyl-pyrrolidin-2-one; water at 80℃; pH=11 - 12; Product distribution / selectivity;	94%
Stage #1: 4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}benzoic acid With thionyl chloride In 1-methyl-pyrrolidin-2-one at 60℃; for 1.5h; Stage #2: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline In 1-methyl-pyrrolidin-2-one at 90℃; for 0.5h;	90%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) → 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)azide

Conditions	Yield
Stage #1: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline With hydrogenchloride; sodium nitrite In water at 0 - 5℃; for 1.5h; Stage #2: With sodium azide In water at 0 - 5℃; for 3h;	93.73%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + C17H13ClN4O → 4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-(pyridin-2-yl)pyrimidin-2-yl)amino)benzamide

Conditions	Yield
Stage #1: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline; C17H13ClN4O In 1-methyl-pyrrolidin-2-one at 60℃; for 3h; Stage #2: With potassium hydroxide In 1-methyl-pyrrolidin-2-one; water at 80℃; Stage #3: With potassium carbonate In 1-methyl-pyrrolidin-2-one; water at 40 - 60℃; for 2h; Solvent;	93%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + methyl 3-azido-4-methylbenzoate (855304-57-3) → 3-azido-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (1408000-52-1)

Conditions	Yield
With potassium tert-butylate In tetrahydrofuran at -20 - 20℃;	92%
With potassium tert-butylate In tetrahydrofuran at -20 - 20℃;	92%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]benzoic acid ethyl ester → nilotinib (641571-10-0)

Conditions	Yield
With trimethylaluminum In toluene for 5h; Concentration; Time; Reflux;	91%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + acetyl chloride (75-36-5) → N-[3-(4-methyl-1H-1-imidazolyl)-5-trifluoromethylbenzene]acetamide

Conditions	Yield
With triethylamine In dichloromethane at 0 - 35℃; for 2h;	90.1%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + methyl 4-methyl-3 -[[4-(pyridin-3-yl)pyrimidin-2-yl]amino]benzoate (917392-54-2) → nilotinib (641571-10-0)

Conditions	Yield
With potassium tert-butylate In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere;	90%
With sodium t-butanolate In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere;	81%
With potassium tert-butylate In tetrahydrofuran at -5 - 20℃; for 30h; Inert atmosphere; Large scale;	68%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + di-tert-butyl dicarbonate (24424-99-5) → N-(3-(4-methyl-1H-1-imidazolyl)-5-trifluoromethylbenzene) tert-butoxycarbonylamine

Conditions	Yield
With triethylamine In dichloromethane at 0 - 35℃; for 12h;	86.5%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + methyl 4-methyl-3-(4-(pyridin-3-yl)thiazol-2-ylamino)benzoate (1186620-63-2) → N-(5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-benzamide (1234798-38-9)

Conditions	Yield
With potassium tert-butylate In tetrahydrofuran at -20 - 20℃;	86%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + 3-iodo-4-methylbenzoyl chloride (52107-98-9) → 3-iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (926922-18-1)

Conditions	Yield
Stage #1: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline; 3-iodo-4-methylbenzoyl chloride In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: With dmap; N-ethyl-N,N-diisopropylamine In tetrahydrofuran	85%
With dmap; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 2h;	4.60 g
With N-ethyl-N,N-diisopropylamine; dmap In tetrahydrofuran at 20℃; for 2h;

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + 4-methyl-3-(4-pyrazine-2-yl-pyrimidine-2-yl-amino)-benzoic acid ethyl ester (926038-04-2) → Radotinib

Conditions	Yield
Stage #1: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline With potassium tert-butylate In tetrahydrofuran at -20℃; for 0.5h; Stage #2: 4-methyl-3-(4-pyrazine-2-yl-pyrimidine-2-yl-amino)-benzoic acid ethyl ester In tetrahydrofuran at -20 - 20℃;	85%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + 3-iodo-4-toluic acid (82998-57-0) → 3-iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (926922-18-1)

Conditions	Yield
With dmap; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; thionyl chloride; water	84.3%
Stage #1: 3-iodo-4-toluic acid With thionyl chloride for 6h; Stage #2: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline With N-ethyl-N,N-diisopropylamine In chloroform at 60℃; for 5h;	57%
Stage #1: 3-iodo-4-toluic acid With thionyl chloride for 1h; Reflux; Stage #2: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline With dmap; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 2h;

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + 3-((tert-butoxycarbonyl)amino)-4-methylbenzoic acid ethyl ester → N-(2-methyl-5-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)phenyl)carbamic acid tert-butyl ester

Conditions	Yield
With potassium tert-butylate In N,N-dimethyl-formamide at -10 - -5℃; Reagent/catalyst; Solvent; Temperature;	84%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + 4-methyl-3-(4-pyrazine-2-yl-pyrimidine-2-yl-amino)-benzoic acid methyl ester (1207665-71-1) → Radotinib

Conditions	Yield
Stage #1: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline With potassium tert-butylate In tetrahydrofuran at -20℃; for 0.5h; Stage #2: 4-methyl-3-(4-pyrazine-2-yl-pyrimidine-2-yl-amino)-benzoic acid methyl ester In tetrahydrofuran at -20 - 20℃; Product distribution / selectivity;	83%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + methyl 3-(4-oxopyrimidin-2-ylamino)-4-methylbenzoate (1451042-82-2) → 4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(6-oxo-1,6-dihydropyrimidin-2-ylamino)benzamide (1451042-83-3)

Conditions	Yield
With potassium tert-butylate In tetrahydrofuran at -5 - 20℃; for 16h; Inert atmosphere;	83%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + 4-methyl-3-(4-thiazole-2-yl-pyrimidine-2-yl-amino)benzoic acid ethyl ester (926038-03-1) → 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-trifluoromethyl-phenyl]-3-(4-thiazole-2-yl-pyrimidine-2-yl-amino)benzamide

Conditions	Yield
Stage #1: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline With potassium tert-butylate In tetrahydrofuran at -20℃; for 0.5h; Stage #2: 4-methyl-3-(4-thiazole-2-yl-pyrimidine-2-yl-amino)benzoic acid ethyl ester In tetrahydrofuran at -20 - 20℃;	81%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + methyl 4-formylbenzoate (1571-08-0) → methyl 4-({[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]amino}methyl)benzoate

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In chloroform at 20℃;	81%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + 4-methyl-3-(4-thiazole-2-yl-pyrimidine-2-yl-amino)benzoic acid methyl ester (1207665-69-7) → 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-trifluoromethyl-phenyl]-3-(4-thiazole-2-yl-pyrimidine-2-yl-amino)benzamide

Conditions	Yield
Stage #1: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline With potassium tert-butylate In tetrahydrofuran at -20℃; for 0.5h; Stage #2: 4-methyl-3-(4-thiazole-2-yl-pyrimidine-2-yl-amino)benzoic acid methyl ester In tetrahydrofuran at -20 - 20℃; Product distribution / selectivity;	80%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + 3-(4-imidazole-1-yl-pyrimidine-2-yl amino)-4-methyl-benzoic acid methyl ester (1207665-73-3) → 3-(4-imidazole-1-yl-pyrimidine-2-yl-amino)-4-methyl-N-[3-(4-methyl-imidazole-1-yl)-5-trifluoromethyl-phenyl] benzamide

Conditions	Yield
Stage #1: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline With sodium t-butanolate In tetrahydrofuran at -20℃; for 0.5h; Stage #2: 3-(4-imidazole-1-yl-pyrimidine-2-yl amino)-4-methyl-benzoic acid methyl ester In tetrahydrofuran at -20 - 20℃; Product distribution / selectivity;	76%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + 3-(4-imidazole-1-yl-pyrimidine-2-yl-amino)-4-methyl-benzoic acid ethyl ester (926038-10-0) → 3-(4-imidazole-1-yl-pyrimidine-2-yl-amino)-4-methyl-N-[3-(4-methyl-imidazole-1-yl)-5-trifluoromethyl-phenyl] benzamide

Conditions	Yield
Stage #1: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline With potassium tert-butylate In tetrahydrofuran at -20℃; for 0.5h; Stage #2: 3-(4-imidazole-1-yl-pyrimidine-2-yl-amino)-4-methyl-benzoic acid ethyl ester In tetrahydrofuran at -20 - 20℃;	73%

Upstream product

• 822-36-6 4-methyl-1H-imidazole 
• 54962-75-3 [3-bromo-5-(trifluoromethyl)phenyl]amine 
• 368-53-6 5-(trifluoromethyl)benzene-1,3-diamine 
• 455279-96-6 N-(3-amino-5-(trifluoromethyl)phenyl)acetamide 
• 50-00-0 formaldehyd 
• 78-98-8 2-oxopropanal 
• 389571-69-1 3-iodo-5-trifluoromethylaniline 
• 917391-27-6 1-[3-bromo-5-(trifluoromethyl)phenyl]-4-methyl-1H-imidazole 
• 130723-13-6 3-bromo-5-fluorobenzotrifluoride 
• 917391-28-7 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide 
• 149793-69-1 3-fluoro-5-trifluoromethyl-benzonitrile 
• 187331-46-0 3-bromo-5-trifluoromethylbenzoic acid methyl ester 
• 641571-13-3 3-(4-methyl-imidazol-1-yl)-5-trifluoromethylbenzoic acid 
• 328-67-6 3-bromo-5-(trifluoromethyl)benzoic acid 

Downstream Products

• 895519-92-3 6-methyl-N-{3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl}-5-[4-(pyrid-3-yl)pyrimid-2-yl-amino]nicotinamide 
• 926922-18-1 3-iodo-4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]benzamide 
• 926037-48-1 Radotinib 
• 1451042-83-3 4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(6-oxo-1,6-dihydropyrimidin-2-ylamino)benzamide 
• 641571-10-0 nilotinib 
• 1246817-85-5 C₂₈H₂₂F₃N₇O₂ 

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PROBLEM TO BE SOLVED: To provide a method for highly selectively producing 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline from 3-bromo-5-trifluoromethylaniline. SOLUTION: There is provided a method for producing 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline, which comprises (1) a step of obtaining 3-iodo-5-trifluoromethylaniline by reacting 3-bromo-5-trifluoromethylaniline and an iodizing agent in a solvent in the presence of a transition metal catalyst and a compound represented by the formula [6] (wherein, R1 and R2 are the same or different and represents an alkyl group, W represents a divalent hydrocarbon group) and (2) a step of obtaining 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline by reacting the 3-iodo-5-trifluoromethylaniline obtained in the step (1) and 4-methyl-1H-imidazole in the presence of a base. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT