58-15-1

Basic information

• Product Name: Aminophenazone
• Synonyms: 2-dihydro-4-(N.,N-dimethylamino-1,5-dimethyl-2-phenyl-3H-pyrazol-3-one;4-Dimethylamino-2,3-dimethyl-1-phenyl pyrazol－1－one, 97%;4-Dimethylamino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one, Aminopyrine;Amidozon;Aminofebrin;Aminopyrazolin;4-(Dimethylamino)antipyrine, 98+%;4-Dimethylaminoantipyrine,97%
• CAS NO: 58-15-1
• Molecular Formula: C₁₃H₁₇N₃O
• Molecular Weight: 231.3
• EINECS: 200-365-8
• Product Categories: Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Miscellaneous
• Mol File: 58-15-1.mol

Chemical Properties

• Melting Point: 107-109 °C(lit.)
• Boiling Point: 373.38°C (rough estimate)
• Flash Point: 125.9 °C
• Appearance: Off-white to brownish/Crystalline Powder, Crystals and/or Chunks
• Density: 1.0744 (rough estimate)
• Vapor Pressure: 0.000333mmHg at 25°C
• Refractive Index: 1.6140 (estimate)
• Storage Temp.: Refrigerator
• PKA: pKa 5.0 (Uncertain)
• Water Solubility: 5.55 g/100 mL
• Sensitive: Air & Light Sensitive
• Stability: Stable. Incompatible with strong oxidizing agents, strong acids, strong bases. Light sensitive. Degrades under the action of mil
• Merck: 14,474
• CAS DataBase Reference: Aminophenazone(CAS DataBase Reference)
• NIST Chemistry Reference: Aminophenazone(58-15-1)
• EPA Substance Registry System: Aminophenazone(58-15-1)

Safety Data

• Hazard Codes: Xn
• Statements: 22-36/37/38-21/22
• Safety Statements: 26-36-36/37/39
• RIDADR: UN 2811 6.1/PG 3
• WGK Germany: 3
• RTECS: CD2625000
• TSCA: Yes
• HazardClass: 6.1
• PackingGroup: III
• Hazardous Substances Data: 58-15-1(Hazardous Substances Data)

Usage

Chemical Properties

White leaf-like crystals or crystalline powder. Odorless, slightly bitter taste. It is stable in the air, but will deteriorate in sunlight. When there is moisture, it is easy to chemically react with weak oxidants. Soluble in alcohol, chloroform, benzene and ether, soluble in water. The solubility in water increases with the addition of sodium benzoate. Aqueous solutions are weakly alkaline to litmus. The melting point is 107-109°C.

Uses

Aminopyrine is used as an antipyretic and analgesic drug. It belongs to the pyrazolone derivatives having a most toxic and most dangerous analgesic effect and it is a non-narcotic drug. Due to strong adverse effects, its single medicine preparation is gradually replaced by compound preparation.

Application

Oxidation by Fe(VI) has potential to remove N-nitrosodiumethylamine precursors, including 4-dimethylaminoantipyrine, from drinking water. 4-Dimethylaminoantipyrine is itself an effective scavenger of reactive nitrogen compounds nitric oxide and peroxynitrite, important in the inflammatory response.

Preparation

Aminopyrine is synthesized from 4-Aminoantipyrine by catalytic hydrogenation (alkylation). Water is firstly added to the dissolving tank, heated to 50-60°C, put into 4-Aminoantipyrine under stirring, and poured into the hydrogenation tank after complete dissolving. Wash the dissolving tank with water, mix it with the nickel catalyst, and then add it to the hydrogenation tank. The hydrogenation tank was evacuated, then the vacuum valve was closed, hydrogen was introduced, and stirring was started. When the pressure rose to 0.245MPa, the hydrogen was stopped. Add formaldehyde and continue to feed hydrogen. The speed of adding formaldehyde is based on the standard of 1.8-2 cubic meters of hydrogen absorption per 5L of formaldehyde, and the reaction temperature is controlled at 60-85°C. After passing the test, filter by pressure, cool the filtrate to below 25°C, and separate out crystals, which are then filtered to obtain the crude aminopyrine. The crude aminopyrine, ethanol, and activated carbon were heated to 75-80°C, stirred for 1 hour, and filtered under pressure. The filtrate was cooled to 10°C, crystals were precipitated, filtered, washed with ethanol, and air-dried to obtain aminopyrine.

Definition

ChEBI: Aminopyrine is a pyrazolone that is 1,2-dihydro-3H-pyrazol-3-one substituted by a dimethylamino group at position 4, methyl groups at positions 1 and 5 and a phenyl group at position 2. It exhibits analgesic, anti-inflammatory, and antipyretic properties. It has a role as a non-steroidal anti-inflammatory drug, a non-narcotic analgesic, an antipyretic, an environmental contaminant and a xenobiotic. It is a tertiary amino compound and a pyrazolone.

Brand name

Adexogan;Agevis;Algimicin anttitermico;Amidazopen;Amidozen;Anoixal;Antigripina;Areumal;Axiston;Balbion;Barsedan;Baukal suppositories;Bayer 1387 p;Bronchisan;Brufaneuseol;Butapyrine;Capsyka dr knapf;Capysal;Chinopyrin;Cibalgin;Ciclazon;Clinit;Coffan;Compral;Cusayth;Demolpas;Dentigoa;Depiral c;Dexa escopyrin;Dha 51;Dialpyrin;Digisab;Dimametten;Dimopyrin;Diprin;Dolo-attirin;Dolo-optineural;Dolorphen;Dolovosano;Donobin;Duerin;Dysmensan;Escopyrinus;Espasnatex;Eufibran;Euprogan;Febren;Febrosolvin;Fenodone;Fever;Flivalgin;Flumil;Framidone;Ftalazon;Funapon;Galenopyrin;Glucopirina;Glucopitina;Helvagit-f;Hemicraneal;Hisense-p;Influnal depot;Inst;Irgapyrine;Isoftal;Kalmine;Katareuma;Lagaflex;Latepyrine;Lauroanginol;Manslu;Medispanmin;Meloka;Neuro-demoplast;Nifedon;Nikartrone;Nostress;Optineural(analgesic);Optipax;Osadrine;Osmotipax;P.s.b.p.;Piracodid;Piradenil;Piradol;Pirasco;Piraseptolo.

World Health Organization (WHO)

Aminophenazone, a pyrazolone derivative, has been used as an antiinflammatory and analgesic agent for over a century. Its use has been associated with cases of bone marrow depression and agranulocytosis and more recently it has been claimed to have a carcinogenic potential. Products containing aminophenazone have been formally withdrawn in many countries and marketing has been voluntarily suspended in others. Elsewhere, however, proprietary preparations containing this ingredient may remain available. (Reference: (WHODI) WHO Drug Information, 3, 9, 1977)

General Description

Small colorless crystals or white crystalline powder. Aqueous solution slightly alkaline to litmus. pH (5% water solution) 7.5-9. Odorless. Slightly bitter taste.

Air & Water Reactions

Water soluble.

Reactivity Profile

Aminophenazone is sensitive to exposure to light. Aminophenazone is readily attacked by mild oxidizing agents in the presence of water. Aminophenazone is incompatible with acacia, apomorphine, aspirin, chloral hydrate, iodine and tannic acid.

Fire Hazard

Flash point data for Aminophenazone are not available; however, Aminophenazone is probably combustible.

Biochem/physiol Actions

Antipyrine was found to be nonmutagenic when screened against Salmonella typhimurium tester strains TA100, TA98, TA97, TA102 and TA104.

Safety Profile

Human poison by unspecified route. Experimental poison by ingestion, subcutaneous, intramuscular,intravenous, and intraperitoneal routes. Moderately toxic by parenteral route. Experimental teratogenic and reproductive effects. Questionable carcinogen when mixed with NaNO2 (1:l). Mutation data reported. Can cause bone marrow depression resulting in leucopenia. Has been implicated in development of aplastic anemia. A tranquilizer. When heated to decomposition it emits toxic fumes of NOx.

Metabolism

Aminopyrine is very slowly metabolized by normal neonate. In older infants, a higher amount of exhaled 13-CO2 is observed. In chicken aminopyrine-N-demethylase inhibits the activities of some important P-450 enzymes. It is mostly metabolized through N-demethylation to form monomethyl-4-antipyrine and formaldehyde, which can be measured by colorimetry Nash. Aminopyrine Ndemethylase is almost equal to isoform CYP-3A4 and closely linked to the methylation reaction of drugs.why Aminopyrine Banned?

Purification Methods

It crystallises from pet ether, sublimes between 80o and 90o, and forms metal complexes. [Beilstein 25 H 452, 25 III/IV 3555.]

InChI:InChI=1/C13H17N3O/c1-10-12(14(2)3)13(17)16(15(10)4)11-8-6-5-7-9-11/h5-9H,1-4H3

Upstream product

• 74-88-4 methyl iodide 
• 77-78-1 dimethyl sulfate 
• 41002-34-0 4-hydrazinyl-N,N-dimethylbenzenamine 
• 846602-78-6 5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-ylamine 
• 64-17-5 ethanol 
• 52526-36-0 2,3-dimethyl-1-phenyl-4-trimethylammonium-3-pyrazolin-5-one iodide 
• 50-00-0 formaldehyd 
• 83-07-8 4-amino-2,3-dimethyl-1-phenylpyrazolin-5-one 
• 80-48-8 methyl p-toluene sulfonate 
• 30672-29-8 1,5-dimethyl-4-nitro-2-phenyl-1H-pyrazole-3(2H)-one 
• 81944-03-8 4-dimethylamino-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one; compound with 3,3-diethyl-1H-pyridine-2,4-dione 
• 71-43-2 benzene 
• 64-18-6 formic acid 
• 2122-46-5 phenoxy radical 

Downstream Products

• 81944-03-8 4-dimethylamino-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one; compound with 3,3-diethyl-1H-pyridine-2,4-dione 
• 52899-00-0 4-dimethylamino-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one; compound with 5-allyl-5-isopropyl-barbituric acid 
• 80311-78-0 2-Dimethylamino-2-methoxy-3-[(E)-methylimino]-N-phenyl-butyramide 
• 3229-70-7 phenolate 
• 16136-29-1 L-cysteine 
• 22113-51-5 p-cresolate 
• 1492-51-9 2-Amino-ethanethiol anion 
• 147919-61-7 (3R,4S,5S,6R)-3,4,5-Trimethyl-N,5-diphenyl-2-oxomorpholin-3-carboxamid 
• 20227-79-6 3-methylphenolate anion 
• 28752-68-3 2,2'-azinobis(3-ethylbenzthiazolinesulfonate) 
• 50-53-3 2-chloro-N,N-dimethyl-10H-phenothiazine-10-propanamine 
• 60-80-0 antipyrine 
• 40055-99-0 glutathionate 
• 101-42-8 fenuron 

Relevant articles and documents

Redox mediation in the peroxidase-catalyzed oxidation of aminopyrine: Possible implications for drug-drug interactions

Many drugs, industrial pollutants, and other xenobiotics are known to be oxidized by peroxidases to potentially harmful free-radical intermediates. We have examined the possibility that certain compounds, acting as efficient peroxidase substrates, may stimulate the formation of reactive free radicals by acting as mediators of electron transfer reactions (redox mediators). To explore this hypothesis, we have investigated the interaction of two well- known peroxidase substrates, chlorpromazine and aminopyrine. As shown by ESR and UV-visible spectroscopy, chlorpromazine radical was able to oxidize aminopyrine to aminopyrine cation radical. The rate constant for this rapid, pH-dependent, reaction was estimated to be 1 x 107 M-1 s-1 at pH 4.5. Transient-state and steady-state kinetic studies both showed that rate constants for chlorpromazine oxidation to its cation radical by horseradish peroxidase (HRP) were about 100-fold greater than for the corresponding HRP- catalyzed oxidation of aminopyrine to its cation radical. When both aminopyrine and chlorpromazine were present with HRP and H2O2, aminopyrine cation radical formation was stimulated 100-fold. Concomitantly, the accumulation of chlorpromazine cation radical was completely inhibited in the presence of aminopyrine. Similar results were obtained when lactoperoxidase, myeloperoxidase, or the myeloperoxidase mimic HOCl were substituted for HRP. These data suggest that chlorpromazine can act as a redox mediator for peroxidase-catalyzed oxidation of aminopyrine and other chemicals. We suggest that some peroxidase substrates, acting as redox mediators, may stimulate the production of toxic free-radical intermediates from various drugs and other xenobiotics. As such, this may have implications for a number of adverse effects caused by these xenobiotic chemicals.

Microwave assisted Biology-Oriented Drug Synthesis (BIODS) of new N,N′-disubstituted benzylamine analogous of 4-aminoantipyrine against leishmaniasis – In vitro assay and in silico-predicted molecular interactions with key metabolic targets

Biology-Oriented Drug Synthesis (BIODS) deals with the simple chemical transformations on the commercially available drugs in order to enhance their new and diversified pharmacological profile. It opens new avenues for the rapid development of drug candidates for neglected tropical diseases (NTDs). Leishmaniasis is one of the NTDs which spread by the bite of sandflies (plebotomine). It ranges from cutaneous self-healing leishmaniasis to life threatening visceral leishmaniasis, known as kala-azar. The current treatment options include the use of pentamidine, miltefosine, and amphotericin B drugs. Unfortunately, all currently available drugs are associated with adverse effects, such as severe nephron- and cardiotoxicity, pancreatitis, and hepatotoxicity. This warrants the development of new drugs against leishmaniasis. Moreover, emergence of resistance against the current medications further worsens the conditions. With this objective, new N, N′-disubstituted benzylamine derivatives of ampyrone (4-aminoantipyrine) were synthesized by using ultrasonication, and microwave assistance. All derivatives were found to be new, except 1, 4, and 11. All the compounds were evaluated for their anti-leishmanial activity, and cellular cytotoxicity. Among them, compounds 4, 5, 8, and 9 showed a significant anti-leishmanial activity in vitro, in comparison to standard drug, miltefosine (IC50 = 25.78 ± 0.2 μM). These compounds were also docked against various metabolic enzymes to predict their interactions and mechanism of action, and were found to act via targeting important enzymes of various metabolic pathways.

General catalytic methylation of amines with formic acid under mild reaction conditions

A general catalytic protocol for the methylation of amines has been developed applying, for the first time, formic acid as the C1 building block and silanes as reducing agents. A broad range of aromatic and aliphatic, both primary and secondary, amines has been converted to the corresponding tertiary amines including [N-13C]-labelled drugs in good to excellent yields under mild conditions. Methylation made easy: A general catalytic protocol for the methylation of amines has been developed applying, for the first time, formic acid as the C1 building block and silanes as reducing agents. A broad range of aromatic and aliphatic, both primary and secondary, amines has been converted to the corresponding tertiary amines, including [N-13C]-labelled drugs, in good to excellent yields at mild conditions (see scheme; dppp=(1,3-bis(diphenylphosphino)propane)).

Pyrazolone methylamino piperidine derivatives as novel CCR3 antagonists

The discovery and optimization of a novel class of potent CCR3 antagonists is described. Details of synthesis and SAR are given together with some ADME properties of selected compounds. An optimal balance between activities, physicochemical properties, and in vitro metabolic stability was reached by the proper choice of substituents.

Oxidation of Aminopyrine by Hypochlorite to a Reactive Dication: Possible Implications for Aminopyrine-Induced Agranulocytosis

Aminopyrine is associated with a high incidence of agranulocytosis. It is known to be oxidized by peroxidases and hypochlorous acid to a blue cation radical. It has been proposed that the mechanism by which hypochlorous acid oxidizes aminopyrine to a cation radical involves N-chlorination followed by loss of a chlorine radical. Another possible mechanism is loss of HCl to form an iminium ion and subsequent reaction with another molecule of aminopyrine and a hydrogen ion to form two radical cations. This mechanism would lead to incorporation of a hydrogen from water; however, using a deuterated analog, we found no hydrogen incorporation, thus providing strong evidence against this mechanism. Using a stopped-flow diode array spectrophotometer to study the reaction between aminopyrine and hypochlorous acid, an intermediate with a λmax at ca. 420 nm was observed in the formation of the cation radical. We propose that this represents a dication formed by the loss of chloride ion from N-chloroaminopyrine. This intermediate is very reactive, with a half-life of approximately 15 ms, and in addition to being the precursor of the cation radical, it also appears to react with two molecules of water to form several other products that were observed and are consistent with the proposed dication intermediate. Similar stable products were formed when aminopyrine was oxidized by the combination of myeloperoxidase, hydrogen peroxide, and chloride or activated neutrophils. The reactive dication formed by neutrophil-derived hypochlorous acid could be responsible for aminopyrine-induced agranulocytosis.

Aminopyrine and Antipyrine Free Radical-cations: Pulse Radiolysis Studies of One-electron Transfer Reactions

Absolute rate constants for the reaction of a variety of electrophilic free radicals with the pyrazoline derivatives aminopyrine and antipyrine have been measured by pulse radiolysis.In the case of aminopyrine the resulting radical cation is a particularly stable species ε325 5.35*103 dm3 mol-1 cm-1).Both compounds are readily oxidised to their respective radical-cations with the one-electron oxidation potential of antipyrine (E0 1.1-1.6 V) being higher than that of aminopyrine (E0 0.26-0.5 V).Studies of the reaction of the radical-cations with reducing agents suggest that aminopyrine in particular may prove to be a useful reference compound in studies of free radical one-electron oxidations.