62-44-2 Usage
Chemical Properties
Different sources of media describe the Chemical Properties of 62-44-2 differently. You can refer to the following data:
1. Phenacetin occurs at room temperature as white, odorless monoclinic prisms. It is soluble in water (more so in hot than cold water), alcohol, glycerol, and acetone and is slightly soluble in benzene. It is unstable to oxidizing agents, iodine, and nitrating agents (IARC 1977).
2. Acetophenetidin is a fine, white, crystalline powder or solid. Odorless with a slightly bitter taste
Uses
Different sources of media describe the Uses of 62-44-2 differently. You can refer to the following data:
1. Phenacetin was used as an analgesic and fever-reducing drug in both human and veterinary medicine for many years. It was introduced into therapy in 1887 and was extensively used in analgesic mixtures until it was implicated in kidney disease (nephropathy) due to abuse of analgesics (Flower et al. 1985) and was withdrawn from the U.S. market in 1983 (Ronco and Flahault 1994, FDA 1998, 1999). Phenacetin also was previously used as a stabilizer for hydrogen peroxide in hair-bleaching preparations (IARC 1980, HSDB 2009).
2. Analgesic, antipyretic. Component of APC tablets, analgesic mixture also containing aspirin and caffeine.
Phenacetin is reasonably anticipated to be a human carcinogen; analgesic mixtures containing Phenacetin are listed as known human carcinogens.
3. glycosylation inhibitor
4. Phenacetin was used as an analgesic and fever-reducing drug in
both human and veterinary medicine for many years until it
was implicated in kidney disease (nephropathy) due to abuse
of analgesics and was withdrawn from the market. Phenacetin
also was previously used as a stabilizer for hydrogen peroxide
in hair-bleaching preparations.
Indications and Usage
Phenacetin is mainly used as an antipyretic analgesic, with slow and lasting effects, treating headaches, neuralgia, joint pain, and fever, and weakly resisting rheumatism and inflammation. Because of toxic side effects and the rapid development of similar drugs, however, it is no longer used alone, only as a raw material in combination with other drugs. Commonly combined with aspirin and caffeine to form a less toxic compound aspirin used to treat the common cold. Can make chlorpheniramine cold tablets by adding a small amount of chlorpheniramine to the above compound, used to treat colds with headache, neuralgia, rheumatism, etc. Can be used as a material for organic synthesis or a pharmaceutical intermediate.
Mechanisms of Action
On its own, phenacetin has no antipyretic or analgesic effects. In vivo, acetaminophen and paracetamol are metabolized and decomposed to create the antipyretic and analgesic effects. Its decomposites with ammonia and phenyl either not only have no antipyretic and analgesic effects, but also are major factors in its side effects.
Side Effects
Long term use may cause renal papillary necrosis and interstitial nephritis, and even induce renal pelvic cancer and bladder cancer. Phenacetin also makes the hemoglobin to form methemoglobin, decreasing blood oxygen carrying capacity, causing cyanosis. In addition, Phenacetin can cause hemolysis and hemolytic anemia, and is toxic to the retina. Long term use may cause also lead to dependence. Countries including America, Britain, German, and Japan have banned Phenacetin, or required packaging to note that it is “not indicated for long-term usage or large doses.”
Carcinogenicity
Different sources of media describe the Carcinogenicity of 62-44-2 differently. You can refer to the following data:
1. Phenacetin is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.
Cancer Studies in Experimental Animals
Dietary administration of phenacetin caused benign and malignant tumors of the urinary tract in mice and rats of both sexes and of the nasal cavity (adenocarcinoma, squamous-cell carcinoma, and transitional-cell carcinoma) in rats of both sexes (Isaka et al. 1979, IARC 1980).
Cancer Studies in Humans
There is limited evidence for the carcinogenicity of phenacetin in humans. There are numerous case reports of kidney cancer (transitionalcell carcinoma of the renal pelvis) among patients who had consumed large amounts of analgesic mixtures containing phenacetin; however, it is not possible to specify which component(s) of the mixture is carcinogenic (IARC 1977, 1980).
https://ntp.niehs.nih.gov/ntp/roc/content/profiles/phenacetinandanalgesicmixtures.pdf
2. Phenacetin is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.
Synthesis of Phenacetin
The preparation of phenacetin is a straightforward, two-step “one-pot” organic synthesis.
In a 10-mL Erlenmeyer flask place 0.20 g (1.46 mmol) of p-phenetidine (MW 137) and 3.50 mL of water.
Add 4 drops only (about 1.0 mmol) of concentrated (12 M) hydrochloric acid, which should dissolve the amine completely. Do not be concerned if some undissolved material remains. Add a spatula-tip of activated carbon (decolorizing charcoal) to the solution, swirl the solution on a hot plate for a few minutes, and remove the charcoal by pipette filtration into a clean 10-mL flask.
Note: If a very slight color persists in the pphenetidine hydrochloride solution, do not repeat the decolorizing procedure but continue with the remainder of the experiment. If the solution is fairly dark, however, a second decolorizing charcoal treatment may be necessary.
Prepare a weakly basic solution by dissolving 0.24 g (2.92 mmol) of sodium acetate (MW 82) in 0.80 mL of water in a 10-mL flask. Set this solution aside for later use.
Warm the p-phenetidine hydrochloride solution on a hot plate. Add 0.20 mL (0.22 g, 2.20 mmol) of acetic anhydride (MW 102) while swirling the solution. Add the sodium acetate solution all at once, and swirl the solution vigorously to insure mixing. Allow the solution to stand at room temperature for 5 minutes. If no crystals form, add 1 or 2 drops of acetic anhydride.
Cool the reaction mixture by immersing the flask in an ice-water bath, and swirl the mixture vigorously until the crude phenacetin crystallizes. Collect the crystals by suction filtration. Wash the crystals with a portion of cold water.
Purify the crystals by recrystallization from water. Collect the crystals by suction filtration and air dry the crystals.
https://www.stolaf.edu/people/hansonr/chem253/expt4_2008_phenacetin.pdf
Originator
Phenacetin ,Environmental Health
Definition
ChEBI: Phenacetin is a member of the class of acetamides that is acetamide in which one of the hydrogens attached to the nitrogen is substituted by a 4-ethoxyphenyl group. It has a role as a non-narcotic analgesic, a peripheral nervous system drug and a cyclooxygenase 3 inhibitor. It is a member of acetamides and an aromatic ether. It is functionally related to a N-phenylacetamide, a 4-ethoxyaniline and a paracetamol.
Manufacturing Process
A mixture of 10 g of 4-ethoxyaniline and 8.6 g of acetic anhydride in 28 g of dry benzene was refluxed for 4 hours. To the reaction mixture was added a small amount of Na2S2O4. After cooling the phenacetin was crystallized; yield 12.5 g (96%), M.P. 136°C.
Brand name
[Names previously used: Acetophenetidin;
Acetphenetidin.];292-comprimes 369, pulvules 3p bugesic;Acetylosal;Acifein;Acromas;Acropac;Algocratine;Alumidyne;Amypron;Amypylo-n;Angifebrine;Anodin;Antiflu des;Apadine;Apidin;Apracur;Arcin;Asceine;Ascophen;Ascthimindon;Asfeen;Ban-o-pain;Bexophene;Bromo quinina;Butal compound;Butorinal;Calmante muri;Capacetyl;Capramin;Caps dr knapp;Capsula dr. knapp;Ceachin;Cefinal;Cequinyl fort;Chloracet;Citramol;Codopyrin;Codral;Conta-schmerz;Coricidin f;Cotradol;Darvocomp-n;Darvon compuesto 65;Darvon n compuesto;Dentocaps;Dolafort;Dolomo;Doloxene comp forte, capsules;Dolviron;Doregrippin;Doscafis;Doviron;Drinacet;Estrifen;Femcaps;Fenascor;Fenbutal;Flexalgit;Florital;Fonal;Fridol;Friocellin;Funapann;Gripanidan;Harbureta;Hemagene taylor;Icn 65;Influenza tabs;Isollyl;Isomidon;Katagrip;Lekasin;Linarol;Manasul;Mardon;Migesic;Mironal;Monacet;Myolate;Neopyrine;Nevral vit b1 b6;Novacetol;Novosephalgin;Olfano;Omniadol;Papnin;Para-grip;Parametten;Pargesic compound;Pasadex;Pedigel;Phenacetine powder;Phenorial;Polypyrine;Poxy;Procomp-65;Prodigestan;Prodolor;Protension;Quadrochin;Rectoral;Refagan;Repro;Respritin;Rhinazol;Rinurel;Rinutan;Robaxisan-pm;Ron-drive;Rumicine;S antineuralgic;S fc;Sacadol;Sadaspir;Sedalmerck;Sk 65 compound caps.;Soma compound;Soma compuesto;Sonalgin;Spacin;Spasmindon;Spasmo-compralgyl;Synalogos-dc;T h;Tetrex-apc;Tetrracydin;Tiiomapirina;Tomapiena;Triplex;Uga-no;Vandar-65;Vasogesic;Vicks action 500;Zactirin compound-100.
Therapeutic Function
Analgesic
World Health Organization (WHO)
Phenacetin, an aniline derivative, was introduced into medicine
as an antipyretic over a century ago. It subsequently gained recognition as an
analgesic and was available in many proprietary analgesic preparations. However,
in the 1940s its habitual use was first implicated as the cause of
methaemoglobinaemia and chronic haemolysis. Since 1950 there have been many
reports published indicating that abusive use is associated with cumulative renal
damage. Evidence also exists to suggest that it may have a carcinogenic potential.
The drug has been withdrawn in many countries but may remain available in others.
(Reference: (WHODI) WHO Drug Information, 1, 5, 1980)
Synthesis Reference(s)
Synthesis, p. 168, 1995 DOI: 10.1055/s-1995-3868
General Description
Phenacetin is an odorless fine white crystalline solid with a lightly bitter taste. Used as an analgesic medicine.
Air & Water Reactions
Insoluble in water.
Reactivity Profile
Phenacetin react with oxidizing agents, iodine and nitrating agents.
Fire Hazard
Flash point data for Phenacetin are not available but Phenacetin is probably combustible.
Biochem/physiol Actions
Substrate of CYP1A2 and CYP2D6.
Safety Profile
Confirmed carcinogen producing tumors of the lildney and bladder. A human poison by an unspecified route. Poison by intravenous and possibly other routes. Moderately toxic by several routes. Human systemic effects by ingestion: cyanosis, liver damage, and methemoglobinemiacarboxyhemo-globinemia. Experimental teratogenic data. Other experimental reproductive effects. Mutation data reported. Chronic effects consist of weight loss, insomnia, shortness of breath, weakness, and often aplastic anemia. When heated to decomposition it emits toxic fumes of NOx,.
Potential Exposure
Phenacetin is used as an analgesic and antipyretic drug. It is used alone or in combination with aspirin and caffeine for mild to moderate muscle pain relief. Phenacetin has also been used as a stabilizer for hydrogen peroxide in hair bleaching preparations. A laboratory reagent. In veterinary medicine; it is used as an analgesic and antipyretic.
Environmental Fate
Phenacetin occurs at room temperature as white, odorless
monoclinic prisms. It is soluble in water, alcohol, glycerol, and
acetone and is slightly soluble in benzene. It is unstable to oxidizing agents, iodine, and nitrating agents. Phenacetin has
a melting point of 134–135 °C; log Kow of 1.58; water solubility
of 30 mg l-1 at 25 °C; and vapor pressure of 0.00316mmHg at
25 °C.Phenacetin’s former use and production as an analgesic may
have allowed release into the environment through various
waste streams. Phenacetin exists both as vapor and as particulate
if released to air. The vapor phase is expected to be readily
degraded by reaction with photochemically produced hydroxyl
radicals with a half-life reaction of 22 h. The particular phase,
however, is removed by wet and dry deposition reactions.
Phenacetin can enter the environment through leaching into
groundwater when released into the soil with moderate
mobility. When released into the water, it does not adsorb to
suspended solids and sediment, but is expected to be inert to
reaction with naturally occurring oxidants found in water with
a half-life of more than 30 days. Phenacetin has an estimated
bioconcentration factor of less than 100, and is not expected to
significantly bioaccumulate. Volatilization is insignificant.
Shipping
UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required.
Purification Methods
Crystallise it from H2O or EtOH, and its solubility in H2O is 0.08% (at ~10o) and 1.2% (at ~100o), and in EtOH it is 6.7% (at ~10o) and 36% (at ~100o). Alternatively it can be purified by solution in cold dilute alkali and re-precipitating by addition of acid to neutralisation point. Dry it in air. [Beilstein 13 H 461, 13 IV 1092.]
Toxicity evaluation
It is unclear how phenacetin induces nephropathy. Studies
proposed that phenacetin’s metabolite, acetaminophen (paracetamol),
leads to lipid peroxidation that damages kidney cells
through cyclooxygenases reaction that catalyzes the conversion
of paracetamol into N-acetyl-p-benzoquinoneimine (NAPQI).
NAPQI, in turn, depletes glutathione via nonenzymatic
conjugation to glutathione, a naturally occurring antioxidant.With the depletion of glutathione, kidney cells are more
susceptible to oxidative damage.
Incompatibilities
Oxidizing agents, iodine and nitrating agents.
Waste Disposal
It is inappropriate and possibly dangerous to the environment to dispose of expired or waste pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If possible, return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged, and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator. Consult with environmental regulatory agencies for guidance on acceptable disposal practices. Generators of waste containing this contaminant (≥100 kg/mo) must conform with EPA regulations governing storage, transportation, treatment, and waste disposal. Permanganate oxidation, microwave plasma treatment, alkaline hydrolysis or incineration.
Check Digit Verification of cas no
The CAS Registry Mumber 62-44-2 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 6 and 2 respectively; the second part has 2 digits, 4 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 62-44:
(4*6)+(3*2)+(2*4)+(1*4)=42
42 % 10 = 2
So 62-44-2 is a valid CAS Registry Number.
InChI:InChI=1/C10H13NO2/c1-3-13-10-6-4-9(5-7-10)11-8(2)12/h4-7H,3H2,1-2H3,(H,11,12)
62-44-2Relevant articles and documents
Preparation method of acetamide compound
-
Paragraph 0035-0047, (2021/05/19)
The invention discloses a preparation method of an acetamide compound, the preparation method comprises the following steps: reacting tetracarbonyl dichloride rhodium, 1, 3-bis (diphenylphosphine) propane, tungsten carbonyl, sodium phosphate, sodium iodide, water, a nitro compound and dimethyl carbonate at 120 DEG C for 24 hours, and after the reaction is completed, performing post-treatment to obtain the acetamide compound. According to the preparation method, dimethyl carbonate serves as a C1 source and also serves as a green solvent, operation is easy, reaction starting raw materials are low in price and easy to obtain, the tolerance range of substrate functional groups is wide, and reaction efficiency is high. Various acetamide compounds can be synthesized according to actual needs, so that the practicability of the method is widened while the operation is convenient.
A novel construction of acetamides from rhodium-catalyzed aminocarbonylation of DMC with nitro compounds
Bao, Zhi-Peng,Miao, Ren-Guan,Qi, Xinxin,Wu, Xiao-Feng
supporting information, p. 1955 - 1958 (2021/03/02)
Dimethyl carbonate (DMC), an environment-friendly compound prepared from CO2, shows diverse reactivities. In this communication, an efficient procedure using DMC as both a C1 building block and solvent in the aminocarbonylation reaction with nitro compounds has been developed. W(CO)6acts both a CO source and a reductant here.
Cyclic (Alkyl)(amino)carbene Ligand-Promoted Nitro Deoxygenative Hydroboration with Chromium Catalysis: Scope, Mechanism, and Applications
Zhao, Lixing,Hu, Chenyang,Cong, Xuefeng,Deng, Gongda,Liu, Liu Leo,Luo, Meiming,Zeng, Xiaoming
supporting information, p. 1618 - 1629 (2021/01/25)
Transition metal catalysis that utilizes N-heterocyclic carbenes as noninnocent ligands in promoting transformations has not been well studied. We report here a cyclic (alkyl)(amino)carbene (CAAC) ligand-promoted nitro deoxygenative hydroboration with cost-effective chromium catalysis. Using 1 mol % of CAAC-Cr precatalyst, the addition of HBpin to nitro scaffolds leads to deoxygenation, allowing for the retention of various reducible functionalities and the compatibility of sensitive groups toward hydroboration, thereby providing a mild, chemoselective, and facile strategy to form anilines, as well as heteroaryl and aliphatic amine derivatives, with broad scope and particularly high turnover numbers (up to 1.8 × 106). Mechanistic studies, based on theoretical calculations, indicate that the CAAC ligand plays an important role in promoting polarity reversal of hydride of HBpin; it serves as an H-shuttle to facilitate deoxygenative hydroboration. The preparation of several commercially available pharmaceuticals by means of this strategy highlights its potential application in medicinal chemistry.
Sulfuryl Fluoride Mediated Synthesis of Amides and Amidines from Ketoximes via Beckmann Rearrangement
Gurjar, Jitendra,Fokin, Valery V.
supporting information, p. 10402 - 10405 (2020/07/25)
A metal-free and redox-neutral method for Beckmann rearrangement employing inexpensive and readily available SO2F2 gas is described. The reported transformation proceeds at ambient temperature and is compatible with a wide range of sterically and electronically diverse aromatic, heteroaromatic, aliphatic and lignin-like oximes providing amides in good to excellent yields. The reaction proceeds through the formation of an imidoyl fluoride intermediate that can also be used for the synthesis of amidines.
Preparation and Antibacterial Activity of Some New 4-(2-Heterylidenehydrazinyl)-7-chloroquinoline Derivatives
Le, Trong Duc,Pham, Ngoc Nam,Nguyen, Tien Cong
, (2018/04/30)
N-(4-Substituted phenyl)acetamides, which were prepared from acetic anhydride and p-substituted anilines, were utilized as precursors for reactions to Vilsmeier-Haack reagent to form 6-substituted-2-chloroquinoline-3-carbaldehydes 3a-c. Meanwhile, a similar reagent was applied to 1-[1-(4-substituted phenyl)ethylidene]-2-phenylhydrazines as substrates, which were synthesized from phenylhydrazine hydrochloride and p-substituted acetophenones, and 1,3-diarylpyrazole-4-carbaldehydes 3d-f were observed as a result. Reactions between the aldehydes 3a-f and 7-chloro-4-hydrazinylquinoline 2, obtained from reaction of 4,7-dichloroquinoline 1 and hydrazine hydrate, formed six new hydrazone compounds, namely, 4-{2-[(6-substituted-2-chloroquinolin-3-yl)methylidene]hydrazinyl}-7-chloroquinolines 4a-c and 4-(2-{[3-(4-substituted phenyl)-1-phenyl-1H-pyrazol-4-yl]methylene}hydrazinyl)-7-chloroquinolines 4d-f. The chemical structures of all synthesized compounds were elucidated by the analysis of IR, 1H, 13C-NMR, and HRMS spectral data. Additionally, all of the synthesized hydrazones were evaluated in terms of cytotoxic activity against four strains of bacteria and four strains of fungus at several concentrations of substrates. As a result, three of them, 4a-c, possess the good ability as growth inhibitor of Bacillus subtilis and Aspergillus Niger at the concentration of 25 μg/mL and 50 μg/mL, respectively, while compound 4e only shows a cytotoxic activity against Aspergillus Niger at the concentration of 25 μg/mL.
Synthesis and mesomorphic properties of 2,4-bis(4′-n-pentyloxybenzoyloxy)- benzylidine-4″- n-alkoxyaniline
Hamad, Wali M.,Azeez, Hashim J.,Al-Dujaili, Ammar H.
, p. 67 - 75 (2017/09/25)
The synthesis and mesomorphic properties of a new series of 2,4-bis(4′-npentyloxybenzoyloxy)- benzylidine-4″ -n-alkoxyaniline (DC5An) are reported. The molecular structure of compounds was confirmed by FTIR, 1H-NMR, 13C-NMR, mass spectroscopy and elemental analysis. The mesomorphic properties were studied by differential scanning calorimetry (DSC) and polarizing optical microscopy (POM) measurements. All compounds of the series exhibit nematic (N) and smectic C (SmC) phases. The first four homologues (DC5A1-DC5A4) display a N mesophase, whereas the highest homologues (DC5A5-DC5A10) exhibit an enantiotropic dimorphism N and SmC phases. The mesomorphic properties of the present series are compared and discussed with other structurally related series.
Preparation and crystallization method of phenacetin
-
Paragraph 0039, (2016/11/24)
The invention discloses a preparation and crystallization method of phenacetin, and belongs to the field of chemical industry. According to the preparation and crystallization method, p-phenetidine is reacted with an acid in water so as to obtain a p-phenetidine salt; the p-phenetidine salt is reacted with an anhydride in a buffer solution system; after reaction, a mixed solution of water and an organic solvent is added into an obtained reaction solution, and phenacetin crystals are obtained via stirring. Product yield is high; two-step reaction total yield is higher than 92%; the obtained products are crystalline solids; stability is high; purity is high, and is higher than 99%; reaction time is short; reaction conditions are mild; product separation operation is simple; direct filtering separation can be carried out after reaction; and batch production period is shortened greatly.
Highly efficient dehydrogenative cross-coupling of aldehydes with amines and alcohols
Deshidi, Ramesh,Rizvi, Masood Ahmad,Shah, Bhahwal Ali
, p. 90521 - 90524 (2015/11/11)
A common protocol for the synthesis of amides, esters and α-ketoesters via cross dehydrogenative coupling of aldehydes and amines/alcohols has been developed. The method is applicable to a wide variety of alcohols and amines as well as aliphatic and aromatic aldehydes. Also, the use of acetaldehyde for acetylation and ethyl glyoxalate to access 2-oxo-amino esters is presented for the first time.
A metal-free approach for transamidation of amides with amines in aqueous media
Srinivas, Mahesuni,Hudwekar, Abhinandan D.,Venkateswarlu, Vunnam,Reddy, G. Lakshma,Kumar, K. A. Aravinda,Vishwakarma, Ram A.,Sawant, Sanghapal D.
supporting information, p. 4775 - 4779 (2015/07/20)
An efficient, environmentally benign and a mild protocol for transamidation of amides with a variety of amines in the presence of K2S2O8 using stoichiometric quantity in aqueous conditions has been established. This method works under conventional thermal conditions and in microwave irradiation as well. A series of amides have been prepared using this reaction and this is a greener protocol for transamidation, which offers a diverse kind of substrate scope with exclusive product formation (yields 90-98%).
Synthesis of secondary amides from N-Substituted amidines by tandem oxidative rearrangement and isocyanate elimination
Debnath, Pradip,Baeten, Mattijs,Lefvre, Nicolas,Van Daele, Stijn,Maes, Bert U. W.
supporting information, p. 197 - 209 (2015/03/03)
In this work an efficient tandem process transforming N-substituted amidines into secondary amides has been described. The process involves N-acylurea formation by reaction of the substrate with bis(acyloxy)(phenyl)-λ3-iodane followed by isocyanate elimination. The periodinane reagents are obtained from the commercially available phenyl-iodine(III) diacetate [PhI(OAc)2, (PIDA)] by ligand exchange with carboxylic acids. The N-substituted amidine substrates are easily synthesized from readily available nitriles. The method is applicable for secondary amide synthesis, based on both aliphatic and (hetero)aromatic amines, including challenging amides consisting of sterically hindered acids and amines. Moreover, the protocol allows one to combine steric bulk with electron deficiency in the target amides (aniline based). Such compounds are difficult to synthesize efficiently based on classical condensation reactions involving carboxylic acids and amines. Overall, the synthetic protocol transforms a nitrile into a secondary amide in both aliphatic and (hetero)aromatic systems.
