530-78-9

Basic information

• Product Name: Flufenamic acid
• Synonyms: ci440;CN-27,554;CN-27544;Flufacid;Flufenaminsaeure;Fluore-200;Fluphenamic acid;fluphenamicacid
• CAS NO: 530-78-9
• Molecular Formula: C₁₄H₁₀F₃NO₂
• Molecular Weight: 281.23
• EINECS: 208-494-1
• Product Categories: Signalling;ARLEF;Other APIs;Active Pharmaceutical Ingredients;Aromatics;Intermediates & Fine Chemicals;Pharmaceuticals;API's
• Mol File: 530-78-9.mol
• Article Data: 23

Chemical Properties

• Melting Point: 132-135 °C(lit.)
• Boiling Point: 373.903 °C at 760 mmHg
• Flash Point: 179.93 °C
• Appearance: Off-white to gray-green/Crystalline Powder or Chunks
• Density: 1.3380 (estimate)
• Vapor Pressure: 2.97E-06mmHg at 25°C
• Refractive Index: 1.585
• Storage Temp.: Refrigerator
• Solubility: soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide. The solubility of flufenamic acid in these solvents is approximately 11, 39, and 59 mg/ml, respectively.
• PKA: pKa 3.9 (Uncertain);3.85 (Uncertain)
• Water Solubility: 0.0265 g/L (37 ºC)
• Merck: 14,4132
• BRN: 1996069
• CAS DataBase Reference: Flufenamic acid(CAS DataBase Reference)
• NIST Chemistry Reference: Flufenamic acid(530-78-9)
• EPA Substance Registry System: Flufenamic acid(530-78-9)

Safety Data

• Hazard Codes: Xn
• Statements: 22-36/38
• Safety Statements: 26
• RIDADR: UN 2811 6.1/PG 3
• WGK Germany: 3
• RTECS: CB4375000
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 530-78-9(Hazardous Substances Data)

Usage

Description

Flufenamic acid (FFA), namely N-(alpha,alpha,alpha-trifluorom-tolyl) anthranilic acid (CI-440), is an aromatic amino acid consisting of anthranilic acid carrying an N-(trifluoromethyl)phenyl substituent. It is an effective drug in the treatment of special types of migraine. Its anti-inflammatory and analgesic effects were recognized in the 1960s (Winder et al., 1963) and thus FFA is included in the family of non-steroidal anti-inflammatory drugs (NSAIDs) with mefenamic, meclofenamic (MFA) and niflumic acids (NA). Anti-inflammatory actions occur mainly through reduction of prostaglandin synthesis from arachidonic acid by inhibiting the cyclo-oxygenases.

Chemical Properties

Fluomic acid is a Pale-Yellow or light yellow-green crystal or crystalline powder with bitter taste. It is almost insoluble in water and can be dissolved in 50% ethanol. It is a non-hormonal anti-inflammatory and analgesic drug. It was prepared by photolysis of the corresponding benzotriazinone.

Originator

Flufenamic acid,AroKor Holdings Inc.

Uses

Different sources of media describe the Uses of 530-78-9 differently. You can refer to the following data:
1. Flufenamic acid is used for moderate pain and dysmenorrhea, but it should not be used for more than 1 week due to the possibility of nephrotoxicity, gastrointestinal toxicity, and anemia. It is frequently used in combination with the anticoagulant warfarin, the effect of which is strengthened when combined with flufenamic acid.
2. An NSAID found to be a reversible gap junction blocker

Definition

ChEBI: flufenamic acid is an aromatic amino acid consisting of anthranilic acid carrying an N-(trifluoromethyl)phenyl substituent. An analgesic and anti-inflammatory, it is used in rheumatic disorders. It has a role as an EC 1.14.99.1 (prostaglandin-endoperoxide synthase) inhibitor, a non-steroidal anti-inflammatory drug, a non-narcotic analgesic and an antipyretic. It is an aromatic amino acid and an organofluorine compound. It derives from a diphenylamine, an anthranilic acid and a (trifluoromethyl)benzene. It is a conjugate acid of a flufenamate.

Manufacturing Process

A mixture 31.3 g of o-chlorobenzoic acid, 32.2 g of trifluoromethyl-maminobenzene, 3 g of copper powder, 13.8 g of waterless potassium carbonate and 100 ml amyl alcohol was refluxed for 4 hours. To the cooled mixture was added 25 ml of 10 N solution NaOH and the mixture was concentrated and filtrated. Addition to the filtrate hydrochloric acid and water give a sediment of 2-((3-trifluromethyl)phenyl)aminobenzoic acid. After recrystallization from hexane 2-((3-trifluromethyl)phenyl)aminobenzoic acid have melting point 134-136°C.

Brand name

Arlef (Parke-Davis).

Therapeutic Function

Antiinflammatory, Antirheumatic

Biological Activity

Flufenamic acid is a nonsteroidal anti-inflammatory drug (NSAID). Inhibits calcium-activated chloride channels (CaCCs). Also increases currents through TRPC6 channels and inhibits currents through TRPC3 and TRPC7 channels.

Synthesis

Flufenamic acid, N-(α,α,α-trifluoro-m-tolyl)anthranylic acid (3.2.18), is synthesized by the reaction of 2-chlorobenzoic acid with 3-trifluoromethylaniline in the presence of potassium carbonate and copper filings [78,79].

InChI:InChI=1/C14H10F3NO2/c15-14(16,17)9-4-3-5-10(8-9)18-12-7-2-1-6-11(12)13(19)20/h1-8,18H,(H,19,20)

Synthetic route

2-(3-trifluoromethyl-phenylamino)-benzoic acid (diethylcarbamoylmethyl-methyl-carbamoyloxy)-methyl ester → sarcosine diethylamide (44897-15-6) + flufenamic acid (530-78-9)

Conditions	Yield
With human plasma In phosphate buffer at 37℃; pH=7.4;	A n/a B 100%

2-(3-trifluoromethyl-phenylamino)-benzoic acid diethylcarbamoylmethylcarbamoyloxymethyl ester → 2-amino-N,N-diethylacetamide (34105-57-2) + flufenamic acid (530-78-9)

Conditions	Yield
With human plasma In phosphate buffer at 37℃; pH=7.4;	A n/a B 100%

2-diethylcarbamoyl-pyrrolidine-1-carboxylic acid 2-(3-trifluoromethyl-phenylamino)-benzoyloxymethyl ester → flufenamic acid (530-78-9) + (2S)-N',N'-diethylpyrrolidinecarboxamide (41721-01-1)

Conditions	Yield
With human plasma In phosphate buffer at 37℃; pH=7.4;	A 100% B n/a

2-(3-trifluoromethyl-phenylamino)-benzoic acid 1-diethylcarbamoyl-2-phenyl-ethylcarbamoyloxymethyl ester → flufenamic acid (530-78-9) + N-(phenylalanyl)-N,N-diethylamine (40847-09-4)

Conditions	Yield
With human plasma In phosphate buffer at 37℃; pH=7.4;	A 100% B n/a

2-(3-trifluoromethyl-phenylamino)-benzoic acid 1-benzyl-2-morpholin-4-yl-2-oxo-ethylcarbamoyloxymethyl ester → flufenamic acid (530-78-9) + N-(phenylalanyl)morpholine (141834-13-1)

Conditions	Yield
With human plasma In phosphate buffer at 37℃; pH=7.4;	A 100% B n/a

2-(3-trifluoromethyl-phenylamino)-benzoic acid 1-benzyl-2-oxo-2-piperidin-1-yl-ethylcarbamoyloxymethyl ester → flufenamic acid (530-78-9) + (2S)-2-amino-3-phenyl-1-(piperidin-1-yl)propan-1-one (102292-89-7)

Conditions	Yield
With human plasma In phosphate buffer at 37℃; pH=7.4;	A 100% B n/a

2-((3-(trifluoromethyl)phenyl)amino)benzonitrile (13481-62-4) → flufenamic acid (530-78-9)

Conditions	Yield
With potassium hydroxide In ethanol; water at 95℃; for 20h;	98%

3-trifluoromethylaniline (98-16-8) + ortho-chlorobenzoic acid (118-91-2) → flufenamic acid (530-78-9)

Conditions	Yield
With potassium carbonate; copper In N,N-dimethyl-formamide for 2h; Heating;	60%
With copper(l) iodide; copper; potassium carbonate In N,N-dimethyl-formamide for 0.333333h; Heating; ultrasonic irradiation;	24%
(i) aq. KOH, (ii) /BRN= 387672/, Cu; Multistep reaction;

2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid,methyl ester (2765-91-5) → flufenamic acid (530-78-9)

Conditions	Yield
With water; potassium hydroxide In ethanol at 100℃; Inert atmosphere;	55%
Stage #1: 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid,methyl ester With potassium hydroxide In ethanol; water at 20 - 100℃; Inert atmosphere; Stage #2: With hydrogenchloride In water at 0℃; pH=2; Inert atmosphere;	55%
With water; potassium hydroxide In ethanol at 100℃;	55%
With hydrazine hydrate In methanol

2-Iodobenzoic acid (88-67-5) + 3-trifluoromethylaniline (98-16-8) → flufenamic acid (530-78-9)

Conditions	Yield
With water; copper; potassium carbonate
With 4-methyl-morpholine; copper(I) oxide In 1,4-dioxane at 100℃; for 3h; Ullmann Condensation; Inert atmosphere;

1-(3'-trifluoromethyl-phenyl)-1,2-dihydro-3,1-benzoxazin-4-one (32509-03-8) → flufenamic acid (530-78-9)

Conditions	Yield
With water In methanol at 20℃; Rate constant; pH from 2.0 to 8.0, half-live-time;

3-trifluoromethylaniline (98-16-8) + potassium 2-bromobenzoate (16497-87-3) → flufenamic acid (530-78-9)

Conditions	Yield
With N-ethylmorpholine;; copper diacetate In N,N-dimethyl-formamide at 145℃; for 3h;

1-(3'-trifluoromethyl-phenyl)-2-chloromethyl-1,2-dihydro-3,1-benzoxazin-4-one (137488-39-2) → flufenamic acid (530-78-9)

Conditions	Yield
With water In methanol at 20℃; Rate constant; pH from 2.0 to 9.0, half-live-time;

1-(3'-trifluoromethyl-phenyl)-2-methoxymethyl-1,2-dihydro-3,1-benzoxazin-4-one (137488-40-5) → flufenamic acid (530-78-9)

Conditions	Yield
With water In methanol at 20℃; Rate constant; pH from 2.0 to 9.0, half-live-time;

1-(3'-trifluoromethyl-phenyl)-2-ethoxycarbonyl-1,2-dihydro-3,1-benzoxazin-4-one (137488-41-6) → flufenamic acid (530-78-9)

Conditions	Yield
With water In methanol at 37℃; Rate constant; pH from 2.0 to 9.0, half-live-time;

2-<<3-(Trifluormethyl)phenyl>amino>benzoeaeure-2-oxopropylester (137138-25-1) → flufenamic acid (530-78-9)

Conditions	Yield
With buffer pH 8.0 In 1,4-dioxane; acetonitrile at 57℃; half-life time of hydrolysis at different pH;

sodium salt of {N-(α,α,α-trifluoro-m-tolyl)anthranilic acid} (1977-00-0) → flufenamic acid (530-78-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 39 percent / tetrabutylammonium bromide; Et3N / tetrahydrofuran / 24 h / 20 °C 2: 100 percent / human plasma / aq. phosphate buffer / 37 °C / pH 7.4 View Scheme

methyl 2-(trifluoromethylsulfonyloxy)benzoate (17763-70-1) + 3-trifluoromethylaniline (98-16-8) → flufenamic acid (530-78-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / toluene / 120 °C / Inert atmosphere 2: water; potassium hydroxide / ethanol / 100 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / toluene / 20 - 120 °C / Inert atmosphere 2.1: potassium hydroxide / ethanol; water / 20 - 100 °C / Inert atmosphere 2.2: 0 °C / pH 2 / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / toluene / 120 °C 2: water; potassium hydroxide / ethanol / 100 °C View Scheme

3-trifluoromethylaniline (98-16-8) + 2-bromobenzoic-acid (88-65-3) → flufenamic acid (530-78-9)

Conditions	Yield
With 4-methyl-morpholine; copper(II) oxide In 1,4-dioxane Inert atmosphere; Reflux;

flufenamic acid (530-78-9) + 1-Adamantanamine (768-94-5) → C10H17N*C14H10F3NO2

Conditions	Yield
In methanol at 20℃;	100%

flufenamic acid (530-78-9) + naphthalen-2-ylmethylamine (2018-90-8) → C14H10F3NO2*C11H11N

Conditions	Yield
In methanol at 20℃;	100%

tryptamine (61-54-1) + flufenamic acid (530-78-9) → C14H10F3NO2*C10H12N2

Conditions	Yield
In methanol at 20℃;	100%

flufenamic acid (530-78-9) + serinol (534-03-2) → C14H10F3NO2*C3H9NO2

Conditions	Yield
In methanol at 20℃;	100%

flufenamic acid (530-78-9) + 2-(3,4-dimethoxyphenyl)-ethylamine (120-20-7) → C14H10F3NO2*C10H15NO2

Conditions	Yield
In methanol at 20℃;	100%

flufenamic acid (530-78-9) + phenethylamine (64-04-0) → C14H10F3NO2*C8H11N

Conditions	Yield
In methanol at 20℃;	100%

flufenamic acid (530-78-9) → N-(3-trifluoromethylphenyl)aniline (101-23-5)

Conditions	Yield
With triethylsilane; palladium diacetate; 2,2-dimethylpropanoic anhydride; 1,4-di(diphenylphosphino)-butane In toluene at 160℃; for 15h; chemoselective reaction;	97%

flufenamic acid (530-78-9) → 2-(3-(trifluoromethyl)phenylamino)benzohydrazide (39492-79-0)

Conditions	Yield
With hydrazine hydrate at 250℃; under 12929 Torr; for 0.0666667h; Microwave irradiation; Neat (no solvent);	96%
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine hydrate / 15 h / Reflux View Scheme

flufenamic acid (530-78-9) + phosphonic acid diethyl ester (762-04-9) → diethyl (2-((3-(trifluoromethyl)phenyl)amino)phenyl)phosphonate

Conditions	Yield
With palladium diacetate; 2,2-dimethylpropanoic anhydride; triethylamine; 1,4-di(diphenylphosphino)-butane In 1,4-dioxane at 160℃; for 15h; Inert atmosphere; Schlenk technique;	96%

formaldehyd (50-00-0) + flufenamic acid (530-78-9) → 1-(3'-trifluoromethyl-phenyl)-1,2-dihydro-3,1-benzoxazin-4-one (32509-03-8)

Conditions	Yield
With zinc(II) chloride In dichloromethane for 2h; Ambient temperature;	93%
In ethanol; water for 1h; Heating;

flufenamic acid (530-78-9) + o-toluidine (95-53-4) → 3-Trifluormethyl-2'-(2-methyl-phenylcarbamoyl)-diphenylamin (21240-02-8)

Conditions	Yield
With N,N-bis[2-oxo-3-oxazolidinyl]phosphorodiamidic chloride; triethylamine In dichloromethane at 20 - 25℃; for 1h;	92%

Thiomorpholin (123-90-0) + flufenamic acid (530-78-9) → thiomorpholino(2-((3-(trifluoromethyl)phenyl)amino)phenyl)methanone

Conditions	Yield
With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 4h;	92%

flufenamic acid (530-78-9) → 2-<<3-(trifluoromethyl)phenyl>amino>benzamide (13481-61-3)

Conditions	Yield
Stage #1: flufenamic acid With thionyl chloride In toluene for 1h; Reflux; Stage #2: With ammonium hydroxide	92%
Stage #1: flufenamic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 50℃; for 0.5h; Stage #2: With ammonium hydroxide; 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 50℃; for 5h;	70.3%

Magnolol (528-43-8) + flufenamic acid (530-78-9) → 5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl-2-((3-(trifluoromethyl)phenyl)amino)benzoate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 1h;	91%
With dmap In dichloromethane at 25 - 30℃;	91%

flufenamic acid (530-78-9) + orthoformic acid triethyl ester (122-51-0) → 1-(3'-trifluoromethyl-phenyl)-2-ethoxy-1,2-dihydro-3,1-benzoxazin-4-one (137488-38-1)

Conditions	Yield
With toluene-4-sulfonic acid In toluene for 4h; Heating;	89%

flufenamic acid (530-78-9) + trimethyl orthoformate (149-73-5) → 1-(3'-trifluoromethyl-phenyl)-2-methoxy-1,2-dihydro-3,1-benzoxazin-4-one (137488-37-0)

Conditions	Yield
With toluene-4-sulfonic acid In toluene for 4h; Heating;	89%

flufenamic acid (530-78-9) + acetic acid (64-19-7) → 2-(dimethylamino)ethyl 2-[[3-trifluoromethylphenyl]amino]thiobenzoate acetate

Conditions	Yield
Stage #1: captamine; flufenamic acid With dicyclohexyl-carbodiimide In chloroform at 20℃; for 3h; Stage #2: acetic acid In chloroform	88.5%

flufenamic acid (530-78-9) + thiophenol (108-98-5) → S-phenyl 2-((3-(trifluoromethyl)phenyl)amino)benzothioate

Conditions	Yield
Stage #1: flufenamic acid With oxalyl dichloride In dichloromethane Stage #2: thiophenol With triethylamine In dichloromethane	88%

flufenamic acid (530-78-9) + R,S-5-Brom-2,2-dimethyl-1,3-dioxolan-4-on (134674-19-4) → 2-<3-(Trifluormethyl)phenylamino>-benzoesaeure-(2,2-dimethyl-1,3-dioxolan-4-on-5-yl)ester (134674-24-1)

Conditions	Yield
With triethylamine In acetone Ambient temperature;	87%

flufenamic acid (530-78-9) + (2E)-3-phenyl-2-propen-1-ol (4407-36-7) → cinnamyl 2-(3-(trifluoromethyl)phenylamino)benzoate

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide at 20℃; for 4h;	87%

methanol (67-56-1) + flufenamic acid (530-78-9) → 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid,methyl ester (2765-91-5)

Conditions	Yield
With sulfuric acid for 12h; Heating;	86%
With sulfuric acid for 100h; Heating;
With sulfuric acid for 16h; Heating;
With sulfuric acid Reflux;

chloroacetaldehyde dimethyl acetal (97-97-2) + flufenamic acid (530-78-9) → 1-(3'-trifluoromethyl-phenyl)-2-chloromethyl-1,2-dihydro-3,1-benzoxazin-4-one (137488-39-2)

Conditions	Yield
With toluene-4-sulfonic acid In toluene for 4h; Heating;	86%

flufenamic acid (530-78-9) + Ethyl diethoxyacetate (6065-82-3) → 1-(3'-trifluoromethyl-phenyl)-2-ethoxycarbonyl-1,2-dihydro-3,1-benzoxazin-4-one (137488-41-6)

Conditions	Yield
With toluene-4-sulfonic acid In toluene for 5h; Heating;	86%

Upstream product

• 88-67-5 2-Iodobenzoic acid 
• 98-16-8 3-trifluoromethylaniline 
• 118-91-2 ortho-chlorobenzoic acid 
• 32509-03-8 1-(3'-trifluoromethyl-phenyl)-1,2-dihydro-3,1-benzoxazin-4-one 
• 16497-87-3 potassium o-bromobenzoate 
• 137488-39-2 1-(3'-trifluoromethyl-phenyl)-2-chloromethyl-1,2-dihydro-3,1-benzoxazin-4-one 
• 137488-40-5 1-(3'-trifluoromethyl-phenyl)-2-methoxymethyl-1,2-dihydro-3,1-benzoxazin-4-one 
• 137488-41-6 1-(3'-trifluoromethyl-phenyl)-2-ethoxycarbonyl-1,2-dihydro-3,1-benzoxazin-4-one 
• 137138-25-1 2-<<3-(Trifluormethyl)phenyl>amino>benzoeaeure-2-oxopropylester 
• 2765-91-5 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid,methyl ester 
• 88-65-3 2-bromobenzoic-acid 
• 13481-62-4 2-((3-(trifluoromethyl)phenyl)amino)benzonitrile 
• 17763-70-1 methyl 2-(trifluoromethylsulfonyloxy)benzoate 
• 1977-00-0 sodium salt of {N-(α,α,α-trifluoro-m-tolyl)anthranilic acid} 

Downstream Products

• 137488-39-2 1-(3'-trifluoromethyl-phenyl)-2-chloromethyl-1,2-dihydro-3,1-benzoxazin-4-one 
• 137138-25-1 2-<<3-(Trifluormethyl)phenyl>amino>benzoeaeure-2-oxopropylester 
• 137488-40-5 1-(3'-trifluoromethyl-phenyl)-2-methoxymethyl-1,2-dihydro-3,1-benzoxazin-4-one 
• 137488-41-6 1-(3'-trifluoromethyl-phenyl)-2-ethoxycarbonyl-1,2-dihydro-3,1-benzoxazin-4-one 
• 137488-37-0 1-(3'-trifluoromethyl-phenyl)-2-methoxy-1,2-dihydro-3,1-benzoxazin-4-one 
• 2765-91-5 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid,methyl ester 
• 1167995-24-5 2-[N,N-bis(2-pyridylmethyl)amino]ethyl 2-(3-trifluoromethylphenylamino)benzoate 
• 87816-74-8 Flufenamic acid glucuronide 
• 39492-79-0 2-(3-(trifluoromethyl)phenylamino)benzohydrazide 

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