51803-78-2

Basic information

• Product Name: Nimesulide
• Synonyms: nimed;4-NITRO-2-PHENOXYMETHANE SULPHONANILIDE;MESULID;AULIN;FANSIDOL;CETIRIZINE DIHYDROCHLORIDE EPC(CRM STANDARD);CETIRIZINE DIHYDROCHLORIDE IMP. E (EP):(RS)-2-[2-[2-[4-[(4-CHLOROPHENYL)-PHENYLMETHYL]PIPERAZIN-1-YL]ETHOXY]ETHOXY]ACETIC ACID MM(CRM STANDARD);CETIRIZINE DIHYDROCHLORIDE MM(CRM STANDARD)
• CAS NO: 51803-78-2
• Molecular Formula: C₁₃H₁₂N₂O₅S
• Molecular Weight: 308.31
• EINECS: 257-431-4
• Product Categories: Active Pharmaceutical Ingredients;All Inhibitors;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Aromatics;Isotope Labelled Compounds;Sulfur & Selenium Compounds;Other APIs
• Mol File: 51803-78-2.mol
• Article Data: 8

Chemical Properties

• Melting Point: 140-146°C
• Boiling Point: 442 °C at 760 mmHg
• Flash Point: 221.1 °C
• Appearance: Yellow Needle-Like Crystals
• Density: 1.451 g/cm³
• Storage Temp.: 2-8°C
• Solubility: Practically insoluble in water, freely soluble in acetone, slightly soluble in anhydrous ethanol.
• PKA: pKa 6.56± 0.03(H2O,t =25,I=0.02)(Approximate)
• Water Solubility: Soluble in water (<50 &#181;g/ml), 1:10 DMSO:PBS (pH 7.2) (<200 &#181;g/ml), ethanol (1 mg/ml), DMSO (15 mg/ml), D
• Stability: Stable. Incompatible with strong oxidizing agents.
• Merck: 14,6548
• CAS DataBase Reference: Nimesulide(CAS DataBase Reference)
• NIST Chemistry Reference: Nimesulide(51803-78-2)
• EPA Substance Registry System: Nimesulide(51803-78-2)

Safety Data

• Hazard Codes: Xn,Xi
• Statements: 22-36/37/38
• Safety Statements: 36-26
• RIDADR: UN 2811 6.1/PG 3
• WGK Germany: 3
• RTECS: PB0970000
• HazardClass: 6.1
• PackingGroup: III
• Hazardous Substances Data: 51803-78-2(Hazardous Substances Data)

Usage

Originator

Riker (USA)

Uses

Different sources of media describe the Uses of 51803-78-2 differently. You can refer to the following data:
1. Antiinflammatory agent. Preferentially inhibits COX-2 over COX-1. Suppresses chemical-induced carcinogenesis in mice and rats. Inhibits LPS-induced TNF-alpha production
2. Labelled Nimesulide (N477500). Antiinflammatory agent. Preferentially inhibits COX-2 over COX-1. Suppresses chemical-induced carcinogenesis in mice and rats. Inhibits LPS-induced TNF-α production.
3. Antiinflammatory;'Cyclooxygenase 2 inhibitor
4. For the treatment of acute pain, the symptomatic treatment of osteoarthritis and primary dysmenorrhoea in adolescents and adults above 12 years old.
5. Labelled Nimesulide . Antiinflammatory agent. Preferentially inhibits COX-2 over COX-1. Suppresses chemical-induced carcinogenesis in mice and rats. Inhibits LPS-induced TNF-α production.;Labeled Nimesulide, intended for use as an internal standard for th
6. Nimesulide is a selective inhibitor of COX-2. The IC50 values are 70 and 1.27 μM for human recombinant COX-1 and -2 (at 20 μM arachidonic acid), respectively, and 22 and 0.03 μM for ovine COX-1 and -2 (at 100 μM arachidonic acid), respectively.[Cayman Chemical]

Brand name

Nimulid.

General Description

Nimesulide, a nonsteroidal anti-inflammatory drug (NSAID) belongs to the sulfonanilide class.

Biological Activity

Selective, orally active cyclooxygenase-2 (COX-2) inhibitor. Produces potent analgesic, anti-inflammatory and antipyretic activities in vivo . Reported to produce fewer gastrointestinal side effects than standard NSAIDs.

Biochem/physiol Actions

Highly selective cyclooxygenase-2 inhibitor.

Clinical Use

Nimesulide is a nonsteroidal antiinflammatory/analgesic agent useful in the treatment of rheumatoid arthritis, as well as acute inflammation such as that induced by periodontal surgery or urinary tract infections.

References

https://en.wikipedia.org/wiki/Nimesulide https://www.drugbank.ca/drugs/DB04743

InChI:InChI=1/C13H12N2O5S/c1-21(18,19)14-12-8-7-10(15(16)17)9-13(12)20-11-5-3-2-4-6-11/h2-9,14H,1H3

Synthetic route

sodium N-(methylsulfonyl)-N-(4-nitro-2-phenoxyphenyl)sulfamate → nimesulide (51803-78-2)

Conditions	Yield
With hydrogenchloride In water pH=~ 2;	100%

1-amino-2-phenoxy-4-nitrobenzene (5422-92-4) + methanesulfonyl chloride (124-63-0) → nimesulide (51803-78-2)

Conditions	Yield
Stage #1: 1-amino-2-phenoxy-4-nitrobenzene; methanesulfonyl chloride With triethylamine In dichloromethane at 20℃; for 23h; Cooling with ice; Stage #2: With sodium hydroxide In water for 16h; Reflux;	74.3%

nimesulide radical anion → nimesulide (51803-78-2) + 4-nitrosonimesulide

Conditions	Yield
In N,N-dimethyl-formamide at 25℃; pH=9.0; Kinetics; Disproportionation;

N-(2-Phenoxyphenyl)-methansulfonamid (51765-51-6) → nimesulide (51803-78-2)

Conditions	Yield
With sulfuric acid; nitric acid; acetic acid for 1h; Activation energy; Temperature;

2-Amino-5-nitrophenol (121-88-0) → nimesulide (51803-78-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: acetic acid / Reflux 2.1: copper diacetate; pyridine N-oxide; pyridine; oxygen / dichloromethane / 72 h / 20 °C / Molecular sieve 3.1: hydrazine hydrate / methanol / 6 h / Reflux 4.1: triethylamine / dichloromethane / 23 h / 20 °C / Cooling with ice 4.2: 16 h / Reflux View Scheme

2-(2-hydroxy-4-nitrophenyl)isoindoline-1,3-dione (117346-07-3) → nimesulide (51803-78-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: copper diacetate; pyridine N-oxide; pyridine; oxygen / dichloromethane / 72 h / 20 °C / Molecular sieve 2.1: hydrazine hydrate / methanol / 6 h / Reflux 3.1: triethylamine / dichloromethane / 23 h / 20 °C / Cooling with ice 3.2: 16 h / Reflux View Scheme

2-(4-nitro-2-phenoxyphenyl)isoindoline-1,3-dione → nimesulide (51803-78-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrazine hydrate / methanol / 6 h / Reflux 2.1: triethylamine / dichloromethane / 23 h / 20 °C / Cooling with ice 2.2: 16 h / Reflux View Scheme

nimesulide (51803-78-2) → N-(4-amino-2-phenoxy phenyl) methanesulfonamide (51765-60-7)

Conditions	Yield
With 5% Pd(II)/C(eggshell); hydrogen In ethyl acetate at 27℃; for 3h;	100%
With hydrogenchloride; tin In water at 90℃; for 3h;	100%
With hydrogen; palladium on activated charcoal In ethanol Ambient temperature;	97%

nimesulide (51803-78-2) + methyl iodide (74-88-4) → N-Methyl-N-(4-nitro-2-phenoxy-phenyl)-methanesulfonamide (51765-67-4)

Conditions	Yield
Stage #1: nimesulide With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: methyl iodide In N,N-dimethyl-formamide at 0 - 20℃; for 12h; Inert atmosphere;	99%
With potassium carbonate In acetonitrile for 5h;	77%

nimesulide (51803-78-2) → C13H10(2)H2N2O5S

Conditions	Yield
With [(1,5-cyclooctadiene)Ir(1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene)(PPh3)]PF6; deuterium In dichloromethane at 20℃; for 2h; Sealed tube;	96%

tetrafluoroboric acid diethyl ether (67969-82-8) + nimesulide (51803-78-2) + 2,3,7,8-tetrafluorothianthrene-S-oxide → C25H15F4N2O5S3(1+)*BF4(1-)

Conditions	Yield
With 2,3,7,8-tetrafluorothianthrene; trifluoroacetic anhydride In acetonitrile at 0 - 25℃; regioselective reaction;	93%

tetrafluoroboric acid diethyl ether (67969-82-8) + sodium tetrafluoroborate (13755-29-8) + nimesulide (51803-78-2) + 2,3,7,8-tetrafluorothianthrene-S-oxide → C25H15F4N2O5S3(1+)*BF4(1-)

Conditions	Yield
Stage #1: tetrafluoroboric acid diethyl ether; nimesulide; 2,3,7,8-tetrafluorothianthrene-S-oxide With trifluoroacetic anhydride In acetonitrile at 0 - 25℃; for 3h; Sealed tube; Stage #2: sodium tetrafluoroborate In dichloromethane; water	93%

nimesulide (51803-78-2) + silver nitrate → Ag-NMS (1364966-82-4)

Conditions	Yield
With KOH In water ligand, AgNO3, and KOH (1:1.1:1.1 molar ratio), stirred at room temp. for 1 h; ppt. filtered off, washed (water), dried (P2O5), elem. anal.;	89%

nimesulide (51803-78-2) + benzyl bromide (100-39-0) → N-benzyl-N-(4-nitro-2-phenoxyphenyl)methanesulfonamide

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4h; Inert atmosphere;	88%

nimesulide (51803-78-2) + propargyl bromide (106-96-7) → C16H14N2O5S (1601552-74-2)

Conditions	Yield
With potassium carbonate In acetone at 20℃;	85%
Stage #1: nimesulide With potassium carbonate In acetone at 20℃; for 0.5h; Inert atmosphere; Stage #2: propargyl bromide In acetone at 20℃; for 24h; Inert atmosphere;	80.6%

4-Phenyl-1-butene (768-56-9) + nimesulide (51803-78-2) → N-(2-phenoxy-4-((1-phenylbutyl)amino)phenyl)methanesulfonamide

Conditions	Yield
With nickel(II) iodide; 6,6'-dimethyl-2,2'-bipyridine; (dimethoxy)methylsilane In N,N-dimethyl acetamide at 0 - 50℃; for 12.1667h; Inert atmosphere; Sealed tube; regioselective reaction;	83%

nimesulide (51803-78-2) → 4-nitro-2-phenoxymethanesulfonanilide sodium salt

Conditions	Yield
With sodium In tetrahydrofuran for 4h; Heating;	79%
With sodium hydroxide In water at 45℃; for 1h; Temperature;

methanol (67-56-1) + nimesulide (51803-78-2) → N-(4-(dimethylamino)-2-phenoxyphenyl)methanesulfonamide

Conditions	Yield
With aluminum (III) chloride; water In acetonitrile at 20℃; Irradiation;	78%
With palladium 10% on activated carbon; potassium tert-butylate at 150℃; for 60h;

formaldehyd (50-00-0) + nimesulide (51803-78-2) → N-(4-(methylamino)-2-phenoxyphenyl)methanesulfonamide

Conditions	Yield
With hydrogen In 1,4-dioxane at 60℃; under 7500.75 Torr; for 24h; Autoclave;	77%

nimesulide (51803-78-2) + N-methyl-O-((4-nitrophenyl)sulfonyl)hydroxylammonium trifluoromethanesulfonate → N-(2-(4-(methylamino)phenoxy)-4-nitrophenyl)methanesulfonamide + N-(2-(2-(methylamino)phenoxy)-4-nitrophenyl)methanesulfonamide

Conditions	Yield
With ferrous(II) sulfate heptahydrate at 40℃; for 16h; regioselective reaction;	A 64% B 10%

nimesulide (51803-78-2) + p-toluenesulfonyl chloride (98-59-9) → 4-methyl-N-(methylsulfonyl)-N-(4-nitro-2-phenoxyphenyl)benzenesulfonamide

Conditions	Yield
With sodium carbonate In water at 35℃; pH=8 - 10;	56%

2-chloromethyl-1H-benzimidazole (4857-04-9) + nimesulide (51803-78-2) → N-((1H-benzo[d]imidazol-2-yl)methyl)-N-(4-nitro-2-phenoxyphenyl)methanesulfonamide

Conditions	Yield
Stage #1: nimesulide With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h; Inert atmosphere; Stage #2: 2-chloromethyl-1H-benzimidazole In N,N-dimethyl-formamide at 25 - 60℃;	56%

2-nitrochalcone (53744-31-3, 7473-93-0) + nimesulide (51803-78-2) → C28H23N3O4S

Conditions	Yield
With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; potassium carbonate In ethanol at 90℃; for 1h; Schlenk technique; Inert atmosphere;	54%

nimesulide (51803-78-2) + fenofibrate boronic acid → isopropyl 2-methyl-2-(4-(4-(N-(4-(methylsulfonamido)-3-phenoxyphenyl)sulfamoyl)benzoyl)phenoxy)propanoate

Conditions	Yield
With sodium metabisulfite; lithium phosphate; choline chloride In N,N-dimethyl-formamide at 130℃; for 10h; Inert atmosphere;	50%
With sodium metabisulfite; lithium phosphate; choline chloride; water In N,N-dimethyl-formamide at 130℃; for 10h; Schlenk technique; Inert atmosphere;	50%

nimesulide (51803-78-2) → C13H10(3)H2N2O5S

Conditions	Yield
With tritium; [(1,5-cyclooctadiene)Ir(1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene)(PPh3)]PF6 In Isopropyl acetate at 20℃; for 4h;	12%

nimesulide (51803-78-2) → N-(4-amino-2-phenoxy phenyl) methanesulfonamide (51765-60-7) + 4-Hydroxy-Nimesulide (109032-22-6)

Conditions	Yield
With sodium tetrahydroborate; oxygen; Cl8-5,10,15,20-tetraphenylporphyrinatoiron(III) chloride at 25℃; for 2h;	A 11 % Chromat. B 4.5 % Chromat.

nimesulide (51803-78-2) → N-(4-amino-2-phenoxy phenyl) methanesulfonamide (51765-60-7) + 4-nitrosonimesulide + 4-hydroxylamine nimesulide (503552-34-9)

Conditions	Yield
With sodium tetrahydroborate; meso-tetraphenylporphyrin iron(III) chloride In methanol; dichloromethane at 20℃; for 1h; Product distribution; Further Variations:; Catalysts;

nimesulide (51803-78-2) → 4-hydroxylamine nimesulide (503552-34-9)

Conditions	Yield
With ammonium chloride; zinc

nimesulide (51803-78-2) → 4-nitrosonimesulide

Conditions	Yield
Multi-step reaction with 2 steps 1: Zn; NH4Cl 2: potassium dichromate / 0 °C View Scheme

nimesulide (51803-78-2) → N-(4-Cyano-2-phenoxy-phenyl)-methanesulfonamide

Conditions	Yield
Multi-step reaction with 2 steps 1: 97 percent / H2 / 10percent Pd/C / ethanol / Ambient temperature 2: 1.) NaNO2, aq. HCl, 2.) NaCN / 1.) 5 deg C, 2.) H2O, benzene, from 0 to 40 deg C, 1.5 h View Scheme

nimesulide (51803-78-2) → N-[2-Phenoxy-4-(1H-tetrazol-5-yl)-phenyl]-methanesulfonamide

Conditions	Yield
Multi-step reaction with 3 steps 1: 97 percent / H2 / 10percent Pd/C / ethanol / Ambient temperature 2: 1.) NaNO2, aq. HCl, 2.) NaCN / 1.) 5 deg C, 2.) H2O, benzene, from 0 to 40 deg C, 1.5 h 3: 1.) Me3SnN3, 2.) silica gel / 1.) toluene, reflux, 24 h, 2.) MeOH, RT, 4 h View Scheme

Upstream product

• 5422-92-4 1-amino-2-phenoxy-4-nitrobenzene 
• 124-63-0 methanesulfonyl chloride 
• 117346-07-3 2-(2-hydroxy-4-nitrophenyl)isoindoline-1,3-dione 
• 121-88-0 5-Nitro-2-aminophenol 
• 51765-51-6 N-(2-Phenoxyphenyl)-methansulfonamid 

Downstream Products

• 51765-67-4 N-Methyl-N-(4-nitro-2-phenoxy-phenyl)-methanesulfonamide 
• 94-13-3 nipasol 
• 62-44-2 4-ethoxyacetanilide 
• 5422-92-4 1-amino-2-phenoxy-4-nitrobenzene 
• 99-76-3 methyl 4-hydroxylbenzoate 
• 99-96-7 4-hydroxy-benzoic acid 
• 1247004-17-6 N-[4-(2,5-dioxopyrrolidin-1-yl)-2-phenoxyphenyl]methanesulfonamide 

Relevant articles and documents

Identification of the decomposition products in an industrial nitration process under thermal runaway conditions

Directive 96/82/EC on the control of major-accident hazards involving dangerous substances, so-called Seveso II Directive, requires inventorying of dangerous substances which are believed might be generated during loss of control of an industrial chemical process. In the present work a nitration process that has underlined a potential risk of thermal runaway has been studied. A kinetic model has been developed and validated using the calorimetric data from a Mettler RC1 and a differential scanning calorimeter, along with the commercial software BatchCAD. The model has been later used to simulate the behavionr of an industrial reactor under abnormal conditions and to evaluate their consequences. Finally, the conditions that lead to thermal runaway scenarios have been reproduced to identify the decomposition products, as Seveso II Directive requires, using thermogravimetry and adiabatic calorimetry coupled with FTIR gas analyser.

Isomeric methoxy analogs of nimesulide for development of brain cyclooxygense-2 (COX-2)-targeted imaging agents: Synthesis, in vitro COX-2-inhibitory potency, and cellular transport properties

Nimesulide analogs bearing a methoxy substituent either at the ortho-, meta- or para-position on the phenyl ring, were designed, synthesized, and evaluated for potential as radioligands for brain cyclooxygenase-2 (COX-2) imaging. The synthesis of nimesulide and regioisomeric methoxy analogs was based on the copper-mediated arylation of phenolic derivatives for the construction of diaryl ethers. These isomeric methoxy analogs displayed lipophilicity similar to that of nimesulide itself, as evidenced by their HPLC log P7.4 values. In vitro inhibition studies using a colorimetric COX (ovine) inhibitor-screening assay demonstrated that the para-methoxy substituted analog retains the inhibition ability and selectivity observed for parent nimesulide toward COX-2 enzyme, whereas the meta- and ortho-methoxy substituents detrimentally affected COX-2-inhibition activity, which was further supported by molecular docking studies. Bidirectional transport cellular studies using Caco-2 cell culture model in the presence of the P-glycoprotein (P-gp) inhibitor, verapamil, showed that P-gp did not have a significant effect on the efflux of the para-methoxy substituted analog. Further investigations using the radiolabeled form of the para-methoxy substituted analog is warranted for in vivo characterization.

Nimesulide derivative method for its preparation and a pharmaceutical composition containing the same

A product of Formula (I): wherein X has the meanings stated in the description.Moreover, a method of preparing the product of Formula (I) and a pharmaceutical composition that contains said product of Formula (I) are also described.

Method for the treatment and prevention of cachexia

Cachexia, including anorexia and other forms of weight loss, is a frequent complication of acute and chronic infections, and result from induction of cytokines, prostaglandins, and other inflammatory mediators that are critical for pathogen elimination. The present invention includes methods for the treatment or prevention of cachexic conditions while maintaining the production of factors essential for infection control through the administration of an effective amount of a cyclooxygenase-2 selective inhibiting compound.

Controlled release anti-inflammatory oral formulation and a process for the preparation thereof

A controlled release anti-inflammatory nimesulide oral formulation. The formulation comprises 45-65% by weight of nimesulide and 10-30% by weight of hydrophilic polymer as retardant with pharmaceutically acceptable auxiliary agents and/or excipients. The nimesulide is partially or fully dispersed in the hydrophilic polymer. The process for the preparation of the formulation comprises mixing the nimesulide with the hydrophilic polymer and pharmaceutically acceptable auxiliary agents and/or excipients.

Antiangiogenic combination therapy for the treatment of cancer

The present invention provides combinations of a DNA topoisomerase I inhibiting agent and a selective COX-2 inhibiting agent for preventing, treating, and/or reducing the risk of developing a neoplasia disorder in a mammal.

Controlled release formulations of nimesulide and a process for the manufacture thereof

A controlled release formulation in the form of oral dosage for treating inflamatory and pain disorders by administering Nimesulide in combination with hyprohilic matrix forming polymer to produce granules together with pharmaceutically acceptable excipients including binders and lubricants, tableted as per the commonly used pharmaceutical technology, said oral formulation provides a drug release of nimesulide for extended period of 24 hours.