261952-01-6

Basic information

• Product Name: 4-Methyl-3-(trifluoromethyl)benzoic acid
• Synonyms: RARECHEM AL BO 0960;MTF-BOA-4ME;4-METHYL-3-(TRIFLUOROMETHYL)BENZOIC ACID;3-TRIFLUOROMETHYL-P-TOLUIC ACID;4-Methyl-3-(Trifluoromethyl)benzoic Acid 3-(Trifluoromethyl)-4-Methylbenzoic Acid;4-Methyl-3-(trifluoromethyl)benzoic acid, 97+%;3-TRIFLUOROMETHYL-4-METHYL BENZOIC ACID,98%;5-Carboxy-2-methylbenzotrifluoride
• CAS NO: 261952-01-6
• Molecular Formula: C₉H₇F₃O₂
• Molecular Weight: 204.15
• Product Categories: Benzoic acid;Fluorine series
• Mol File: 261952-01-6.mol
• Article Data: 2

Chemical Properties

• Melting Point: 182-186°C
• Boiling Point: 233oC at 760 mmHg
• Flash Point: 94.7oC
• Appearance: /
• Density: 1.24g/cm3
• Vapor Pressure: 0.0573mmHg at 25°C
• Refractive Index: 1.463
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: soluble in Methanol
• PKA: 3.94±0.10(Predicted)
• CAS DataBase Reference: 4-Methyl-3-(trifluoromethyl)benzoic acid(CAS DataBase Reference)
• NIST Chemistry Reference: 4-Methyl-3-(trifluoromethyl)benzoic acid(261952-01-6)
• EPA Substance Registry System: 4-Methyl-3-(trifluoromethyl)benzoic acid(261952-01-6)

Safety Data

• Hazard Codes: Xi,T+,Xn
• Statements: 36/37/38-26/27/28-36-22
• Safety Statements: 26-37/39-24/25-37
• HazardClass: IRRITANT
• Hazardous Substances Data: 261952-01-6(Hazardous Substances Data)

Usage

Chemical Properties

Light brown solid

Uses

4-Methyl-3-(trifluoromethyl)benzoic acid, can be used as an intermediate in the synthesis of Bafetinib (B109050), which is a substituted benzamide derivative structurally related to STI-571 (Imatinib Mesylate). It was identified as highly potent Bcr-Abl kinase inhibitor. It is a COVID19-related research product.

InChI:InChI=1/C9H6F3N/c1-6-2-3-7(5-13)8(4-6)9(10,11)12/h2-4H,1H3

Synthetic route

4-methyl-3-(trifluoromethyl)benzonitrile → 4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6)

Conditions	Yield
Stage #1: 4-methyl-3-(trifluoromethyl)benzonitrile With water; sodium hydroxide In ethanol for 6h; Reflux; Stage #2: With hydrogenchloride In ethanol; water

para-methylbenzonitrile (104-85-8) → 4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: silver carbonate; sodium carbonate; dipotassium peroxodisulfate / dichloromethane / 10 h / 120 °C / Schlenk technique; Sealed tube 2: sodium hydroxide; water / ethanol / 6 h / Reflux View Scheme

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) → 4-dibromomethyl-3-trifluoromethyl-benzoic acid (1303518-35-5)

Conditions	Yield
With N-Bromosuccinimide In tetrachloromethane for 1h; Reflux; UV-irradiation;	100%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane; water for 24h; Reflux;	100%

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) → 3-bromo-4-methyl-5-trifluoromethylbenzoic acid

Conditions	Yield
With N-Bromosuccinimide; sulfuric acid at 20℃; for 16h;	100%
With N-Bromosuccinimide; sulfuric acid at 20℃; for 16h;	98%

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) + methanol (67-56-1) → 4-methyl-3-(trifluoromethyl)benzoic acid methyl ester (116419-94-4)

Conditions	Yield
With sulfuric acid Reflux;	96%
sulfuric acid for 6h; Reflux;	95%
With sulfuric acid Reflux;	95%

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) → C9H6F3NO4 (1070886-95-1)

Conditions	Yield
With sulfuric acid; nitric acid at 100℃; for 1.5h;	96%

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) + 3-acetylenephenylamine (54060-30-9) → N-(3-ethynylphenyl)-4-methyl-3-(trifluoromethyl)benzamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 18h; Schlenk technique; Inert atmosphere;	95.2%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere;	95.2%

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) + methyl iodide (74-88-4) → 4-methyl-3-(trifluoromethyl)benzoic acid methyl ester (116419-94-4)

Conditions	Yield
With potassium carbonate In acetone at 20℃; for 24h;	95%
Stage #1: 4-methyl-3-(trifluoromethyl)benzoic acid With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; for 18h;
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18h;

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) + N,O-dimethylhydroxylamine*hydrochloride (6638-79-5) → N-methoxy-N,4-dimethyl-3-(trifluoromethyl)benzamide (1173793-77-5)

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	86%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 6h;

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) → (4-methyl-3-(trifluoromethyl)phenyl)methanol

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 25℃; for 12h;	77.2%

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) + 3-bromo-1,1,1-trifluoroacetone (431-35-6) → C12H6F6O2

Conditions	Yield
With dipotassium hydrogenphosphate; bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate; silver(I) acetate; XPhos In 2,2,2-trifluoroethanol at 140℃; for 24h; Sealed tube;	75%
With dipotassium hydrogenphosphate; bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; silver(I) acetate In 2,2,2-trifluoroethanol at 140℃; for 24h;	65%

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) + 8-methyl-2,8-diazaspiro[4.5]decane → C18H23F3N2O

Conditions	Yield
Stage #1: 4-methyl-3-(trifluoromethyl)benzoic acid With 1,1'-carbonyldiimidazole In dichloromethane at 0℃; for 2.5h; Inert atmosphere; Stage #2: 8-methyl-2,8-diazaspiro[4.5]decane In dichloromethane at 20℃; for 12h; Inert atmosphere;	69%

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) + Ethyl bromodifluoroacetate (667-27-6) → C12H11F3O4

Conditions	Yield
With 1,4-diaza-bicyclo[2.2.2]octane; palladium diacetate; copper(II) acetate monohydrate at 100℃; for 24h; Sealed tube;	55%

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) + 3-(5-amino-2-methylphenyl)-7-((3-amino-4-methylphenyl)-amino)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one → N-(3-(7-((3-amino-4-methylphenyl)amino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 14h; Inert atmosphere;	52%

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) + 3-(5-amino-2-methylphenyl)-1-methyl-7-((6-methylpyridin-3-yl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one → 4-methyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)phenyl)-3-(trifluoromethyl)benzamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere;	48%

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) + 5-((5-amino-2-methylbenzyl)amino)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester (1616628-98-8) → 5-[(2-methyl-5-(4-methyl-3-(trifluoromethyl)benzoylamino)benzyl)amino]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester (1616670-12-2)

Conditions	Yield
Stage #1: 4-methyl-3-(trifluoromethyl)benzoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: 5-((5-amino-2-methylbenzyl)amino)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester In N,N-dimethyl-formamide at 20℃;	26%

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) + C14H18N4O3 → (E)-N-(1-(3-hydroxypropyl)-5-(3-oxomorpholino)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-methyl-3-(trifluoromethyl)benzamide

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide; acetonitrile at 20℃; for 1h;	22%

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) → 4-(bromomethyl)-3-(trifluoromethyl)benzoic acid (859213-39-1)

Conditions	Yield
With sodium bromate; sodium hydrogensulfite In ethyl acetate
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 1.5h; Heating / reflux; irradiated with a 125 W lamp;
With sodium bromate; sodium hydrogensulfite In Isopropyl acetate; water at 30 - 60℃; Heating / reflux;

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) + ethanol (64-17-5) → 4-methyl-3-trifluoromethyl-benzoic acid ethyl ester (859026-99-6)

Conditions	Yield
With sulfuric acid Heating;
With sulfuric acid for 23h; Heating / reflux;
With sulfuric acid Reflux;
With sulfuric acid Reflux; Inert atmosphere;

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) → 4-(bromomethyl)-3-(trifluoromethyl)benzoyl chloride (948553-14-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: NaBrO3; NaHSO3 / ethyl acetate 2: (COCl)2; DMF / CH2Cl2 / 20 °C View Scheme
Multi-step reaction with 2 steps 1: sodium hydrogensulfite; sodium bromate / water; Isopropyl acetate / Reflux 2: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 5 h / 20 °C View Scheme

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) → 4-bromomethyl-3-trifluoromethyl-benzoic acid ethyl ester (859027-01-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: H2SO4 / Heating 2: N-bromosuccinimide / (PhCO)2O2 / CCl4 / Heating View Scheme
Multi-step reaction with 2 steps 1: sodium hydrogensulfite; sodium bromate / ethyl acetate; water / 20 - 50 °C 2: sulfuric acid / 80 °C View Scheme
Multi-step reaction with 2 steps 1: sodium bromate; sodium hydrogensulfite / water; ethyl acetate / 20 - 50 °C 2: sulfuric acid / 80 °C View Scheme

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) → 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl) benzoic acid (859027-02-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: H2SO4 / Heating 2: N-bromosuccinimide / (PhCO)2O2 / CCl4 / Heating 3: K2CO3 / tetrahydrofuran / 20 °C 4: aq. NaOH / Heating View Scheme
Multi-step reaction with 4 steps 1: sulfuric acid / Reflux 2: N-Bromosuccinimide; Perbenzoic acid / tetrachloromethane; water / 6 h / Reflux 3: potassium carbonate / acetonitrile / Reflux; Inert atmosphere 4: lithium hydroxide; water / tetrahydrofuran / 4 h / Reflux View Scheme
Multi-step reaction with 4 steps 1: potassium carbonate / acetone / 24 h / 20 °C 2: N-Bromosuccinimide; dibenzoyl peroxide / chloroform / 18 h / Reflux 3: chloroform / 3 h / 20 °C 4: sodium hydroxide / ethanol / 3 h / 20 °C View Scheme

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) → 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoic acid ethyl ester (859027-00-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: H2SO4 / Heating 2: N-bromosuccinimide / (PhCO)2O2 / CCl4 / Heating 3: K2CO3 / tetrahydrofuran / 20 °C View Scheme
Multi-step reaction with 3 steps 1: sodium bromate; sodium hydrogensulfite / water; ethyl acetate / 20 - 50 °C 2: sulfuric acid / 80 °C 3: potassium carbonate / tetrahydrofuran; N,N-dimethyl-formamide / 4 h / 20 °C View Scheme

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) → 4-(bromomethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide (859213-40-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: NaBrO3; NaHSO3 / ethyl acetate 2: (COCl)2; DMF / CH2Cl2 / 20 °C 3: K2CO3 / dioxane / 20 °C View Scheme

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) → 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoyl chloride dihydrochloride

Conditions	Yield
Multi-step reaction with 5 steps 1: H2SO4 / Heating 2: N-bromosuccinimide / (PhCO)2O2 / CCl4 / Heating 3: K2CO3 / tetrahydrofuran / 20 °C 4: aq. NaOH / Heating 5: SOCl2 / Heating View Scheme

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) → 4-[3-(dimethylamino)azetidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide

Conditions	Yield
Multi-step reaction with 4 steps 1: NaBrO3; NaHSO3 / ethyl acetate 2: (COCl)2; DMF / CH2Cl2 / 20 °C 3: K2CO3 / dioxane / 20 °C 4: K2CO3 / dimethylformamide / 20 °C View Scheme

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) → 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide (641614-88-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: NaBrO3; NaHSO3 / ethyl acetate 2: (COCl)2; DMF / CH2Cl2 / 20 °C 3: K2CO3 / dioxane / 20 °C 4: K2CO3 / dimethylformamide / 20 °C View Scheme

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) → N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide

Conditions	Yield
Multi-step reaction with 6 steps 1: H2SO4 / Heating 2: N-bromosuccinimide / (PhCO)2O2 / CCl4 / Heating 3: K2CO3 / tetrahydrofuran / 20 °C 4: aq. NaOH / Heating 5: SOCl2 / Heating 6: pyridine / 20 °C View Scheme

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) → 4-[(R)-3-(dimethylamino)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide

Conditions	Yield
Multi-step reaction with 4 steps 1: NaBrO3; NaHSO3 / ethyl acetate 2: (COCl)2; DMF / CH2Cl2 / 20 °C 3: K2CO3 / dioxane / 20 °C 4: K2CO3 / dimethylformamide / 20 °C View Scheme

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) → Bafetinib

Conditions	Yield
Multi-step reaction with 4 steps 1: NaBrO3; NaHSO3 / ethyl acetate 2: (COCl)2; DMF / CH2Cl2 / 20 °C 3: K2CO3 / dioxane / 20 °C 4: K2CO3 / dimethylformamide / 20 °C View Scheme

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) → 4-[(S)-3-(dimethylaminomethyl)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide

Conditions	Yield
Multi-step reaction with 4 steps 1: NaBrO3; NaHSO3 / ethyl acetate 2: (COCl)2; DMF / CH2Cl2 / 20 °C 3: K2CO3 / dioxane / 20 °C 4: K2CO3 / dimethylformamide / 20 °C View Scheme

4-methyl-3-(trifluoromethyl)benzoic acid (261952-01-6) → 4-[(R)-3-(dimethylaminomethyl)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide

Conditions	Yield
Multi-step reaction with 4 steps 1: NaBrO3; NaHSO3 / ethyl acetate 2: (COCl)2; DMF / CH2Cl2 / 20 °C 3: K2CO3 / dioxane / 20 °C 4: K2CO3 / dimethylformamide / 20 °C View Scheme

Upstream product

• 104-85-8 para-methylbenzonitrile 
• 261952-06-1 4-methyl-3-(trifluoromethyl)benzonitrile 

Downstream Products

• 859026-99-6 4-methyl-3-trifluoromethyl-benzoic acid ethyl ester 
• 116419-94-4 4-methyl-3-(trifluoromethyl)benzoic acid methyl ester 

Relevant articles and documents

Silver-Catalyzed C-H Trifluoromethylation of Arenes Using Trifluoroacetic Acid as the Trifluoromethylating Reagent

Direct trifluoromethylation of arenes using TFA as the trifluoromethylating reagent was achieved with Ag as the catalyst. This reaction not only provides a new protocol for aryl C-H trifluoromethylation, but the generation of CF3· from TFA may prove useful in other contexts and could potentially be extended to other trifluoromethylation reactions. (Chemical Equation Presented).