89796-99-6

Basic information

• Product Name: Aceclofenac
• Synonyms: ACECLOFENAC;ACECLOFENAC-D2;Airtal;Falcol;Gerbin;Glycolic Acid [o-(2,6-Dichloroanilino)phenyl]acetate Ester;PR-82/3;Preservex
• CAS NO: 89796-99-6
• Molecular Formula: C₁₆H₁₃Cl₂NO₄
• Molecular Weight: 354.18
• EINECS: 205-783-4
• Product Categories: Active Pharmaceutical Ingredients;Intermediates & Fine Chemicals;Pharmaceuticals;Lipid signaling;Aromatics;Free Base API;API;AIRTAL
• Mol File: 89796-99-6.mol

Chemical Properties

• Melting Point: 149-153°C
• Boiling Point: 486 °C at 760 mmHg
• Flash Point: 247.7 °C
• Appearance: off-white to light tan/
• Density: 1.455 g/cm³
• Vapor Pressure: 2.93E-10mmHg at 25°C
• Refractive Index: 1.639
• Storage Temp.: -20°C Freezer
• Solubility: Soluble in DMSO
• PKA: 2.60±0.10(Predicted)
• Water Solubility: 32mg/L(32 oC)
• Merck: 14,22
• CAS DataBase Reference: Aceclofenac(CAS DataBase Reference)
• NIST Chemistry Reference: Aceclofenac(89796-99-6)
• EPA Substance Registry System: Aceclofenac(89796-99-6)

Safety Data

• Hazard Codes: T,N
• Statements: 25-36-50/53
• Safety Statements: 26-45-60-61
• RIDADR: UN 2811 6.1 / PGIII
• WGK Germany: 3
• RTECS: CY1577900
• HazardClass: 6.1
• PackingGroup: III
• Hazardous Substances Data: 89796-99-6(Hazardous Substances Data)

Usage

Mechanism of Action

Aceclofenac acts by inhibiting the effect of natural substances known as cyclooxygenase (COX) enzymes. Notably, these enzymes are responsible for making other chemicals in the body, namely prostaglandins. The prostaglandins are normally produced at sites of damages or injury cause inflammation and pain. By blocking the influence of COX enzymes, production of prostaglandins is minimized, meaning that the swelling and pain is eased.

Precautions

Before taking aceclofenac, it is essential to tell the doctor if one has ever had an allergic reaction to any other NSAID, for instance, diclofenac, aspirin, indomethacin, and naproxen; whether one has allergic disorders such as asthma. It is important to alert the doctor if an individual has a heart condition or problem with circulation or blood vessels. Moreover, inform the physician if one has connective tissue disorder, for instance, lupus erythematosus. One should not take the drug if he/she has high blood pressure or has blood-clotting problems.

Chemical Properties

White Crystalline Solid

Originator

Prodes (Prodesfarma) (Spain)

Uses

Different sources of media describe the Uses of 89796-99-6 differently. You can refer to the following data:
1. Labeled Aceclofenac, intended for use as an internal standard for the quantification of Aceclofenac by GC- or LC-mass spectrometry.
2. Aceclofenac is a non-steroidal, anti-inflammatory drug (NSAID) with potent inhibitory activity in several models of inflammation. It is used for the treatment of osteoarthritis and rheumatoid arthritis. It is a Biopharmaceutics classification system class II (BCS class I) drug which has an intermediate half-life of 3-4h and undergoes substantial first pass metabolism. aceclofenac is available either in oral form (tablet) or in topical form (gel).

Definition

ChEBI: Aceclofenac is a monocarboxylic acid that is the carboxymethyl ester of diclofenac. A non-steroidal anti-inflammatory drug related to diclofenac, it is used in the management of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. It has a role as an EC 1.14.99.1 (prostaglandin-endoperoxide synthase) inhibitor, a non-steroidal anti-inflammatory drug and a non-narcotic analgesic. It is a monocarboxylic acid, a carboxylic ester, a secondary amino compound, an amino acid and a dichlorobenzene. It derives from a diclofenac.

Brand name

Airtal; Gerbin

Biochem/physiol Actions

Non-steroidal, anti-inflammatory drug (NSAID), with selectivity for COX-2 over COX-1.

Drug interactions

Potentially hazardous interactions with other drugs ACE inhibitors and angiotensin-II antagonists: antagonism of hypotensive effect; increased risk of nephrotoxicity and hyperkalaemia. Analgesics: avoid concomitant use of 2 or more NSAIDs, including aspirin (increased side effects); avoid with ketorolac (increased risk of side effects and haemorrhage). Antibacterials: possible increased risk of convulsions with quinolones. Anticoagulants: effects of coumarins and phenindione enhanced; possibly increased risk of bleeding with heparins, dabigatran and edoxaban - avoid long term use with edoxaban. Antidepressants: increased risk of bleeding with SSRIs and venlaflaxine. Antidiabetic agents: effects of sulphonylureas enhanced. Antiepileptics: possibly increased phenytoin concentration. Antivirals: increased risk of haematological toxicity with zidovudine; concentration possibly increased by ritonavir. Ciclosporin: may potentiate nephrotoxicity Cytotoxics: reduced excretion of methotrexate; increased risk of bleeding with erlotinib. Diuretics: increased risk of nephrotoxicity; antagonism of diuretic effect, hyperkalaemia with potassium-sparing diuretics. Lithium: excretion decreased. Pentoxifylline: increased risk of bleeding. Tacrolimus: increased risk of nephrotoxicity.

Metabolism

About two-thirds of a dose is excreted in the urine, mainly as hydroxymetabolites, the principal one being 4-hydroxyaceclofenac. A small amount is converted to diclofenac.

InChI:InChI=1/C16H13Cl2NO4/c17-11-5-3-6-12(18)16(11)19-13-7-2-1-4-10(13)8-15(22)23-9-14(20)21/h1-7,19H,8-9H2,(H,20,21)

Synthetic route

2-((2,6-dichlorophenyl)amino)phenylacetoxyacetic acid tert-butyl ester (139272-68-7) → aceclofenac (89796-99-6)

Conditions	Yield
With hydrogenchloride; acetic anhydride; acetic acid In water at 60℃; for 3h; Temperature;	98.5%
With formic acid In acetone at 65℃; for 0.166667h; Reagent/catalyst; Solvent; Temperature; Microwave irradiation;	96.3%
With aluminum (III) chloride; acetic anhydride; acetic acid at 60 - 65℃; for 2.5h; Reagent/catalyst; Temperature; Large scale;	83%
With trifluoroacetic acid In dichloromethane at 20℃; for 7h;	57%
With formic acid at 40℃;

tert-butyl-[2-(2,6-dichloroanilino) phenyl] acetoxy acetate → aceclofenac (89796-99-6)

Conditions	Yield
With formic acid In toluene at 0 - 35℃; for 2h; Product distribution / selectivity;	95%
With formic acid; trifluoroacetic acid In toluene at 25 - 40℃; for 2.5 - 5.5h; Product distribution / selectivity;
With formic acid In toluene at 0 - 50℃; for 2 - 4.5h; Product distribution / selectivity;

aceclofenac benzyl ester (100499-89-6) → aceclofenac (89796-99-6)

Conditions	Yield
With hydrogen; palladium on activated charcoal

diclofenac sodium (15307-79-6) → aceclofenac (89796-99-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: dimethylformamide 2: H2 / Pd/C View Scheme
Multi-step reaction with 2 steps 1: potassium iodide / acetonitrile / 0.25 h / 30 °C / Microwave irradiation 2: formic acid / acetone / 0.17 h / 65 °C / Microwave irradiation View Scheme
Multi-step reaction with 2 steps 1: potassium iodide / ethanol / 3 h / 61 - 65 °C / Large scale 2: acetic acid; acetic anhydride; aluminum (III) chloride / 2.5 h / 60 - 65 °C / Large scale View Scheme

C35H29Cl2NO10 → aceclofenac (89796-99-6)

Conditions	Yield
With simulated intestinalfluid In methanol at 37℃; pH=7.4; Reagent/catalyst; pH-value; Solvent;

1,10-Phenanthroline (66-71-7) + zirconyl nitrate + water (7732-18-5) + aceclofenac (89796-99-6) → C28H22Cl2N3O6Zr(1+)*NO3(1-)*9H2O

Conditions	Yield
With potassium hydroxide In acetone for 8h; Reflux;	89.35%

aceclofenac (89796-99-6) → C16H13Cl2NO5 + C14H11Cl2NO3 + 2-[(2,6-dichlorophenyl)amino]phenylacetic acid methyl ester (15307-78-5)

Conditions	Yield
In methanol at 20℃; for 6h; UV-irradiation;	A 7% B 5% C 88%

1,10-Phenanthroline (66-71-7) + copper(II) acetate monohydrate (6046-93-1) + aceclofenac (89796-99-6) → C28H24Cl2CuN3O6(1+)*C2H3O2(1-)*6H2O

Conditions	Yield
With potassium hydroxide In acetone for 8h; Reflux;	80.04%

1,10-Phenanthroline (66-71-7) + nickel(II) acetate tetrahydrate (6018-89-9) + aceclofenac (89796-99-6) → C28H24Cl2N3NiO6(1+)*C2H3O2(1-)*3H2O

Conditions	Yield
With potassium hydroxide In acetone for 8h; Reflux;	78.08%

1,10-Phenanthroline (66-71-7) + lanthanide(III)chloride heptahydrate + aceclofenac (89796-99-6) → C28H24Cl2LaN3O6(2+)*9H2O*2Cl(1-)

Conditions	Yield
With potassium hydroxide In acetone for 8h; Reflux;	76.11%

4-acetaminophenol (103-90-2) + aceclofenac (89796-99-6) → C24H20Cl2N2O5 (1452834-52-4)

Conditions	Yield
With trichlorophosphate In pyridine at 5℃; for 4h;	73%

1,10-Phenanthroline (66-71-7) + zinc(II) acetate dihydrate (5970-45-6) + aceclofenac (89796-99-6) → C28H24Cl2N3O6Zn(1+)*C2H3O2(1-)*3H2O

Conditions	Yield
With potassium hydroxide In acetone for 8h; Reflux;	72.53%

ethanol (64-17-5) + aceclofenac (89796-99-6) → 2-(2-[(2',6'-dichlorophenyl)amino]phenyl)acetoxyacetate

Conditions	Yield
With sulfuric acid for 6h; Reflux;	65%

methanol (67-56-1) + aceclofenac (89796-99-6) → C17H15Cl2NO4 (139272-66-5)

Conditions	Yield
With tert.-butylnitrite at 40℃; for 48h;	63%
With sulfuric acid Reflux;

aceclofenac (89796-99-6) + 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose (4064-06-6) → 1,2,3,4-di-O-isopropylidene-D-α-galactopyranose-6-yl 2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)acetic acid

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 4h;	62%

{(1R,2R)-cyclohexane-1,2-diamine}dichloridoplatinum(II) (38780-40-4, 52691-24-4, 61848-70-2, 61848-66-6, 61848-62-2) + aceclofenac (89796-99-6) → C22H26Cl3N3O4Pt

Conditions	Yield
With sodium carbonate; silver nitrate In N,N-dimethyl-formamide at 20℃; for 24h; Darkness;	50%

potassium ethyl methylmalonate (103362-70-5) + aceclofenac (89796-99-6) → ethyl 4-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)-2-methyl-3-oxobutanoate

Conditions	Yield
Stage #1: aceclofenac With 1,1'-carbonyldiimidazole Inert atmosphere; Stage #2: potassium ethyl methylmalonate With magnesium chloride Inert atmosphere;	43%

trans-2-pentenal (1576-87-0) + tert-butylisonitrile (119072-55-8, 7188-38-7) + tert-butyl N-tosyloxycarbamate (105838-14-0) + aceclofenac (89796-99-6) → tert-butyl (2S,3R)-2-{2-(tert-butylamino)-1-[2-(2-{2-[(2,6-dichlorophenyl)amino]phenyl}acetoxy)acetoxy]-2-oxoethyl}-3-ethylaziridine-1-carboxylate

Conditions	Yield
Stage #1: trans-2-pentenal; tert-butyl N-tosyloxycarbamate With (S)-α,α-bis(4-hexylphenylthio)-2-pyrrolidinemethanol trimethylsilylether; sodium carbonate In ethanol; water at 20℃; for 0.666667h; Green chemistry; Stage #2: tert-butylisonitrile; aceclofenac In ethanol; water at 20℃; for 24h; Passerini Condensation; Green chemistry; diastereoselective reaction;	33%

2-nitroxyethylammonium nitrate (4665-58-1) + aceclofenac (89796-99-6) → (N-(2-(nitrooxy)ethyl)carbamoyl)methyl 2-(2-((2,6-dichlorophenyl)-amino)phenyl)acetate (183195-09-7)

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride	13%

aceclofenac (89796-99-6) → [2-(2,6-dichloroanilino)phenyl]acetic acid (15307-86-5)

Conditions	Yield
With sodium hydroxide for 3h; Heating;

aceclofenac (89796-99-6) → 4'-hydroxy aceclofenac

Conditions	Yield
With NADPH-generating system In acetonitrile at 37℃; for 3h; pH=7.4; aq. phosphate buffer;

aceclofenac (89796-99-6) + β-cyclodextrine → aceclofenac-β-cyclodextrin (1:1) inclusion complex

Conditions	Yield
In methanol; water for 0.75h;

formaldehyd (50-00-0) + 3,6-dinitro-9H-carbazole (3244-54-0) + aceclofenac (89796-99-6) → C29H20Cl2N4O8 (1246212-64-5)

Conditions	Yield
In methanol Mannich reaction; Cooling with ice; Reflux;

3,6-dinitro-9H-carbazole (3244-54-0) + benzaldehyde (100-52-7) + aceclofenac (89796-99-6) → C35H24Cl2N4O8 (1246212-56-5)

Conditions	Yield
In methanol Mannich reaction; Cooling with ice; Reflux;

3,6-dinitro-9H-carbazole (3244-54-0) + aceclofenac (89796-99-6) + acetaldehyde (75-07-0) → C30H22Cl2N4O8 (1246212-52-1)

Conditions	Yield
In methanol Mannich reaction; Cooling with ice; Reflux;

3,6-dinitro-9H-carbazole (3244-54-0) + aceclofenac (89796-99-6) + 4-dimethylamino-benzaldehyde (100-10-7) → C37H29Cl2N5O8 (1246212-60-1)

Conditions	Yield
In methanol Mannich reaction; Cooling with ice; Reflux;

aceclofenac (89796-99-6) → 2-chloro-2-oxoethyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate (1227857-41-1)

Conditions	Yield
With thionyl chloride In benzene
With thionyl chloride at 20℃; for 18h; Temperature;
With thionyl chloride In tetrahydrofuran for 1.5h; Microwave irradiation;

aceclofenac (89796-99-6) → 2-[(2,6-dichlorophenyl)amino]-N1-(phenyl)-N4-phenylacetoxyacetamidobenzenesulfonamide (1262333-96-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: thionyl chloride / benzene 2: N,N-dimethyl-formamide / 24 h / 10 - 130 °C View Scheme

Upstream product

• 100499-89-6 aceclofenac benzyl ester 
• 15307-79-6 diclofenac sodium 
• 139272-68-7 2-((2,6-dichlorophenyl)amino)phenylacetoxyacetic acid tert-butyl ester 

Downstream Products

• 15307-86-5 [2-(2,6-dichloroanilino)phenyl]acetic acid 
• 15307-78-5 2-[(2,6-dichlorophenyl)amino]phenylacetic acid methyl ester 
• 183195-09-7 (N-(2-(nitrooxy)ethyl)carbamoyl)methyl 2-(2-((2,6-dichlorophenyl)-amino)phenyl)acetate 
• 229308-90-1 4'-hydroxy aceclofenac 
• 1246212-64-5 C₂₉H₂₀Cl₂N₄O₈ 
• 1246212-56-5 C₃₅H₂₄Cl₂N₄O₈ 
• 1246212-52-1 C₃₀H₂₂Cl₂N₄O₈ 
• 1246212-60-1 C₃₇H₂₉Cl₂N₅O₈ 
• 1227857-41-1 2-chloro-2-oxoethyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate 
• 1262333-96-9 2-[(2,6-dichlorophenyl)amino]-N₁-(phenyl)-N₄-phenylacetoxyacetamidobenzenesulfonamide 
• 1262333-97-0 2-[(2,6-dichlorophenyl)amino]-N₁-(2-nitrophenyl)-N₄-phenylacetoxyacetamidobenzenesulfonamide 
• 1262333-98-1 2-[(2,6-dichlorophenyl)amino]-N₁-(3-nitrophenyl)-N₄-phenylacetoxyacetamidobenzenesulfonamide 
• 1262333-99-2 2-[(2,6-dichlorophenyl)amino]-N₁-(4-nitrophenyl)-N₄-phenylacetoxyacetamidobenzenesulfonamide 
• 1262334-00-8 2-[(2,6-dichlorophenyl)amino]-N₁-(2-methylphenyl)-N₄-phenylacetoxyacetamidobenzenesulfonamide 

Relevant articles and documents

Method for industrially producing aceclofenac

The invention relates to a method for industrially producing aceclofenac. The method comprises the following steps: mixing organic acid, a water removal agent and Lewis acid, fully stirring, and adding aceclofenac tert-butyl ester for acidolysis reaction. The method is mild in reaction condition, high in reaction rate, free of high temperature and high energy consumption, easy and convenient to operate, environmentally friendly, economical and free of participation or generation of major pollutants, most solvents can be recycled, emission of waste solvents is reduced, and therefore the cost isreduced, and the environment is protected.

METHODS FOR PREPARING ACECLOFENAC AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME

The present invention relates to a method for preparing aceclofenac and a pharmaceutical preparation comprising aceclofenac prepared by using the same, and provides a method for preparing aceclofenac that can obtained in a more uniform particle size compared to the prior art. The pharmaceutical preparation containing aceclofenac prepared according to the method of the present invention has a small particle size, uniformity and excellent dispersibility, and can minimize a content of excipients, and thus can be applied to various pharmaceutical composition formulations without limitation.COPYRIGHT KIPO 2021

Preparation method of aceclofenac

The invention discloses a microwave-assisted preparation method of aceclofenac. The method is as follows: under the microwave condition, a compound 2 and a compound 3 are reacted to form a compound 4under the catalysis of KI; and under the microwave condition, a reaction of the compound 4 is carried out in a mixed solvent of formic acid and acetone. According to the method, the acidolysis of aceclofenac tert-butyl ester is carried out in the mixture of formic acid and acetone under the microwave condition, the acidolysis method has high selectivity, the fracture of the ethoxyl group in aceclofenac tert-butyl ester is reduced to the lowest limit, the conversion rate of the acidolysis reaction is high, the diclofenac content in the product is extremely small, the product is easy to refine,and the purity is high.

Aceclofenac preparation method

The invention belongs to the technical field of medicine and particularly relates to an aceclofenac preparation method. The method includes: using aceclofenac tert-butyl ester as the raw material, andperforming acid hydrolysis on the aceclofenac tert-butyl ester in the mixed solvent of low-molecular organic acid, hydrogen halide aqueous solution and low-molecular organic anhydride to obtain crudeaceclofenac; refining the crude aceclofenac in low-molecular organic acid to obtain the refined aceclofenac. By the method which is easy to operate, capable of increasing production efficiency and suitable for industrial production, the yield and purity of the aceclofenac can be increased evidently.

Synthesis and pharmacological evaluation of mutual prodrugs of aceclofenac with quercetin, vanillin and l-tryptophan as gastrosparing NSAIDS

Synthesis, physicochemical characterization and pharmacological evaluation of mutual prodrugs of aceclofenac with quercetin, vanillin and l-tryptophan have been attempted to develop novel gastrosparing NSAIDs, devoid of ulcerogenic side effects. The structures of synthesized prodrugs were confirmed by IR, 1H NMR, 13C NMR and mass spectroscopy. The hydrolysis kinetics studies were performed in simulated gastric fluid, simulated intestinal fluid and rat fecal matter. Its anti-inflammatory and ulcer index were analyzed along with estimation of biochemical parameters (GWM and Hexosamine), oxidative parameters (LPO, GSH, CAT, and SOD) and protein estimation. The results indicated that the synthesized prodrugs are chemically stable, biolabile and possesses optimum lipophilicity. They also exhibited retention of anti-inflammatory activity with reduced ulcerogenicity. The study showed that the mutual prodrugs are better in action compared to the parent drug and have fewer gastrointestinal side effects.

A PROCESS FOR THE PREPARATION OF [2-(2,6-DICHLORO ANILINO) PHENYL] ACETOXY ACETIC ACID

Process for manufacture of 2-(2,6-dichlooranilino)phenyl acetoxy acetic acid is provided. The process comprises of acid hydrolysis 2-tert-butoxy-2-oxoethyl {2[(2,6-dichlorophenyl) amino]phenyl)acetate in presence of a strong acid cationic exchange resin with S03H group on -Divinylbenzene copolymer beads in presence of a solvent to yield compounds of formula 1. The compounds so obtained have shown Non-Steroidal anti-inflammatory activity.

Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use related applications

The invention describes novel nitrosated nonsteroidal antiinflammatory drugs (NSAIDs) and pharmaceutically acceptable salts thereof, and novel compositions comprising at least one nitrosated NSAID, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or at least one therapeutic agent. The invention also provides novel compositions comprising at least one nitrosated NSAID, and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one therapeutic agent. The invention also provides novel kits comprising at least one nitrosated NSAID, and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent. The invention also provides methods for treating inflammation, pain and fever; for treating gastrointestinal disorders; for facilitating wound healing; for treating and/or preventing gastrointestinal, renal and/or respiratory toxicities resulting from the use of nonsteroidal antiinflammatory compounds; for treating inflammatory disease states and/or disorders; and for treating and/or preventing ophthalmic diseases and/or disorders.

Crystal structure and spectroscopic study of 2-phenylacetoxyacetic acid (Aceclofenac)

The crystal structure of the title compound has been determined.The crystals are monoclinic: P21/n(NO. 14), a = 12.279(7), b = 8.223(1), c = 15.504(7) Angstroem, β = 96.16(2) deg, Vo = 1556(2) Angstroem3, Z = 4, Dx = 1.511 g cm-3, λ = (MoKα) = 0.71069 Angstroem.The structure was solved by direct methods and refined with 1970 reflections to a final R value of 0.057.Analytical, mass, spectral, and physicochemical data are also reported.

2-[(2,6-Dichlorophenyl)amino]phenylacetoxyacetyl derivatives and therapeutic compositions containing same

2-[(2,6-Dichlorophenyl)amino]phenylacetoxyacetyl derivatives are disclosed which have anti-inflammatory and analgesic properties. A method for making the foregoing compounds is also disclosed wherein a 2-[(2,6-dichlorophenyl)amino]phenylacetic acid salt is reacted with a benzyl haloacetate.