103-90-2 Usage
Antipyretic analgesic
The chemiacal name of Acetaminophen is N-(4-hydroxy phenyl) acetamide and the trade name is paracetamol belonging to acetanilide antipyretic analgesics. It was first synthesized by Morse in 1878 and first used in clinic by VonMering in 1893. It has become an over the counter drug in the USA since 1955 and our country started production at the end of the 1950’s. Acetaminophen is a white crystalline or a crystalline powder in appearance with melting point from 168℃ to 172℃, odorless, slightly bitter taste, freely soluble in hot water or ethanol, dissolved in acetone, practically insoluble in cold water and petroleum ether. It is stable below 45℃ but will be hydrolyzed into p-aminophenol when exposed to humid air, then oxidized further. The color grades gradually from pink to brown then to black, so it should be sealed and stored in a cool and dry place.Acetaminophen?has the antipyretic activity by inhibiting the synthesis of hypothalamic thermoregulation prostaglandins and its strength of antipyretic effect is similar to aspirin. On the other hand, Acetaminophen?can produce analgesic effect by inhibiting the synthesis of prostaglandins in the central nervous system and blocking impulses of nociceptive nerve endings, but weaker than aspirin. Compared with aspirin, Acetaminophen?has minor irritation, few allergic reactions and other advantages. Its antipyretic and analgesic effect is similar to phenacetin, and ??the use of Acetaminophen increases due to limiting or banning using phenacetin in many countries.In clinical, it is mainly used for fever and headache caused by cold and relieving mild to moderate pain such as joint pain, muscle pain, neuralgia, migraine, dysmenorrhea, cancer pain, postoperative analgesia and so on. It can be used for patients who are allergic to aspirin, intolerant of aspirin, or unsuited for aspirin, such as patients with varicella, hemophilia and other hemorrhagic disease (patients having anticoagulant therapy included), as well as patients with slight peptic ulcer and gastritis. In addition, it also can be used for the synthesis of benorylate and used as asymmetric synthetic intermediates, photographic chemicals and stabilizer of hydrogen peroxide.
Chemical property
Obtain prism crystallization from ethanol. Melting point 169-171℃, relative density 1.293(21/4℃). Soluble in ethanol, acetone and hot water, difficult to dissolve in water, insoluble in petroleum ether and benzene. Odorless, bitter. The pH value of saturated aqueous solution is 5.5-6.5.
Pharmacological Actions
Acetaminophen is used as antipyretic analgesics. It has the antipyretic activity by means of mediated peripheral vasodilation and perspiration caused by inhibiting the cyclooxygenase which selectively inhibiting the synthesis of hypothalamic thermoregulation prostaglandins, and its strength of antipyretic effect is similar to aspirin. As a peripheral analgesic, it can produce analgesic effect by inhibiting the synthesis and release of prostaglandins and increasing pain threshold. However, its action is weaker than aspirin and it is only effective for mild to moderate pain. There is no obvious anti-inflammation effect.
Pharmacokinetics
Different sources of media describe the Pharmacokinetics of 103-90-2 differently. You can refer to the following data:
1. The oral absorption is rapid and complete, and the peak time occurs 0.5～2h later. The plasma protein binding rate is 25%～50%. This product is equally distributed in the body, 90%～95% is metabolized in the liver and mainly excreted from the kidney combining with glucuronic acid? and about 3% exits the body unchanged in the urine within 24h. Its half-life (t1/2) is 1～4h (average 2h). In case of renal insufficiency t1/2 is not affected, but t1/2 of patients with hepatic insufficiency, newborns or elderly patients may increase and t1/2 of children may decrease. It can be secreted by milk.
2. Paracetamol is absorbed rapidly from the small intestine after oral
administration; peak plasma concentrations are reached after 30–60min. It
may also be given rectally and intravenously (either as paracetamol or the
prodrug propacetamol). It has good oral bioavailability (70%–90%); rectal absorption is more variable (bioavailability ~50%–80%) with a longer time to
reach peak plasma concentration. The plasma half-life is approximately 2–3 h.
Paracetamol is metabolised by hepatic microsomal enzymes mainly to the
glucuronide, sulphate and cysteine conjugates. None of these metabolites is
pharmacologically active. Aminimal amount of the metabolite N-acetyl-pamino-
benzoquinone imine is normally produced by cytochrome P450–
mediated hydroxylation. This reactive toxic metabolite is rendered harmless
by conjugation with liver glutathione, then excreted renally as mercapturic
derivatives. With larger doses of paracetamol, the rate of formation of the
reactive metabolite exceeds that of glutathione conjugation, and the reactive
metabolite combines with hepatocellular macromolecules, resulting in cell
death and potentially fatal hepatic failure. The formation of this metabolite is
increased by drugs inducing cytochrome P450 enzymes, such as barbiturates
or carbamazepine.
Preparation method
1. Using nitrobenzene as raw material
In the presence of concentrated sulfuric acid and sixteen alkyl methyl ammonium chloride, nitrobenzene is transformed into p-Aminophenol by catalytic hydrogenation with Pd/C as catalyst. P-acetaminophen is synthesized acetylation by one-step acylation without separation and the yield is 64.3%. The reaction is as followed:
2. Using paranitrophenol as raw material
With paracetamol as raw material and Pd/C as catalyst, paracetamol is synthesized by hydroacylation on one-step method. The optimum solvent is acetic acid of which the dosage is 2 to 5 times of paranitrophenol and the yield of paracetamol is up to 95%. When Pd-La/C is used as catalyst instead, the yield can reach 97%. The reaction is as followed:
?
3. Using p-aminophenol as raw material
Under these conditions of using p-aminophenol and acetic anhydride as raw materials, zinc powder as the antioxidant, activated carbon as the decolorizing agent and dilute acetic acid as the reaction medium, paracetamol is synthesized by microwave irradiation technology and the yield is up to81.2%. The reaction is as followed:
4. Using p-Hydroxyacetophenone as raw material
First oximate p-Hydroxyacetophenone and then rearrange it to obtain paracetamol by means of Beckmann. Under this method, the yield of 4-hydroxyacetophenone oxime obtained by oximating p-Hydroxyacetophenone is 93.5%. Then we use Hβ molecular sieve as catalyst and acetone as the solvent to obtain acetaminophen by rearrangement and the yield is 81.2 %. In the rearrangement reaction, acetone is used as the solvent and Al-MCM-41 molecular sieve is used as the catalyst. The yield is the highest when the content of phosphoric acid in the catalyst is 30%. The reaction is as followed:
?
5. Using? phenol as raw material
Phenol is used as the raw material and synthesizes paracetamol after acetylation, Fries rearrangement, oxime and Beckmann rearrangement. The yields are 82%, 68.6%, 50.5%,
respectively. The reaction is as followed:
Usage and Dosage
Usage
This product is antipyretic and analgesic whose international nonproprietary name is Paracetamol. It is the most common non anti-inflammatory analgesia-antipyretic drugs without anti inflammatory and anti rheumatism action. Its antipyretic effect is similar to aspirin, but analgesic effect is weak. It is the best of breed of acetanilid drugs. The product is especially suitable for patients who cannot use carboxylic acids drugs. It is used for cold and toothache. Acetaminophen is also used as organic synthesis intermediates, stabilizer of hydrogen peroxide, photographic chemicals.
Dosage???
1. Oral (1) Paracetamol tablets or paracetamol capsules: adults take 300～600mg at a time and 3～4 times a day according to the need. The daily dosage should not be greater than 2g. Defervescence treatment is generally less than 3 days and the administration of pain relief lasts less than 10 days. Children take 10～15mg/kg every 4～ 6 hours. The dosage of children under the age of 12 does not exceed 5 times a day, a five-day course at most. This product should not be taken for a long time.
2. Dispersible tablets: When take tablets, disperse them in warm water dispersion. The commonly used amount of children is 10～15mg/kg every 4～ 6 hours. The dosage of children under the age of 12 does not exceed 5 times a day, a five-day course at most. Children under 3 years old cut back on the amount.
Application in Particular Diseases
In Osteoarthritis：
Acetaminophen is recommended by the ACR as first-line drug therapy for pain management of OA. The dose is 325 to 650 mg every 4 to 6 hours on a scheduled basis (maximum dose 4 g/day; maximum 2 g/day if chronic alcohol intake or underlying liver disease). Comparable relief of mild to moderate OA pain has been demonstrated for acetaminophen (2.6 to 4 g/ day) compared with aspirin (650 mg four times daily), ibuprofen (1,200 or 2,400 mg daily), and naproxen (750 mg daily). However, some patients respond better to NSAIDs.
Acetaminophen is usually well tolerated, but potentially fatal hepatotoxicity with overdose is well documented. It should be used with caution in patients with liver disease and those who chronically abuse alcohol. Chronic alcohol users (three or more drinks daily) should be warned about an increased risk of liver damage or GI bleeding with acetaminophen. Other individuals do not appear to be at increased risk for GI bleeding. Renal toxicity occurs less frequently than with NSAIDs.
Adverse reaction
1. Allergic reactions: This product has less and slight side effects a dose treatment except for occasional rashes, hives and other allergic reactions. Methemoglobinemia may occur in a few cases.
2. Hepatorenal damage: A large number of long-term use,? hepatorenal damages and thrombocytopenia may occur, even jaundice, oliguria, acute severe hepatitis, which could lead to coma, and death. Using at high dosage may cause nausea, vomiting, stomach pain, stomach cramps, diarrhea, anorexia, sweating, etc.
3. For children under the age of 3, the development of liver and kidney function is not mature with poor detoxification and excretory function, so they should try to avoid using this product. In addition, patients with liver and kidney insufficiency and pregnant women should use cautiously. The long-term drug users should regularly check renal function and hemogram.
Taboo
It is contraindicated in patients allergic to the product and patients with severe liver and kidney function deficiency.
Notes
Allergies are disabled. Patients who are allergic to aspirin do not have allergic reactions generally. However, it has been reported that a small number of patients with asthma caused by aspirin-sensitivity can have an episode of bronchospasm after taking drugs.
This product may increase the risk of liver toxicity when patients suffer from alcohol poisoning, liver disease or viral hepatitis, so it should be used with caution. Patients with renal insufficiency take a lot of products regularly, leading to increasing risk of renal toxicity, so they should be careful. It is contraindicated in patients with severe liver and kidney function deficiency.
When taking the drug for pain, it is not allowed to take for more than 40 consecutive days. Antipyretic treatments shall not exceed 3 days, unless doctors tell you otherwise. After taking this product, patients should immediately stop taking medicine when symptoms of erythema or edema occur. This product is only a drug for symptomatic treatment, it is necessary to take other treatments to relieve reasons of pain or fever at the same time when taken.
This product can be passed through the placenta and secreted in milk, so pregnant women and lactating women are not recommended to use. For children under the age of 3, the development of liver and kidney function is not mature with poor detoxification and excretory function, so they should try to avoid using this product. Because the development of liver and kidney function declines, t1/2 of elderly patients may increase leading to adverse reactions easily. Patients should take with caution or take a smaller amount of use appropriately.
The interferences of diagnosis: ① Glucose measurement, falsely low values are measured by glucose oxidase/peroxidase methods, but no effect occurs when measured by hexokinase /6-dehydrogenase methods; ② Assays for uric acid of serum, falsely high values are measured by phosphotungstic acid method; ③ Determination of urinary 5-hydroxyindoleacetic acid (5-HIAA), falsely positive results are obtained in a screening test with nitroso naphthol reagent, but quantitative test is not affected; ④Liver function tests, prothrombin time, serum bilirubin, lactic dehydrogenase and serum aminotransferase can be increased due to high doses or long-term use.
In case of large dosage, promote vomiting timely and give antagonists named N-acetylcysteine (140mg/kg orally given at the beginning, then 70mg/kg, take 1 times every 4h, 17 times; it can be given intravenously when serious, the drug can be dissolved in 5% 200 ml glucose injection and used through intravenous drip) or take methionine orally, which has a protective effect on the liver. Do not give activated carbon, because it can affect the absorption of drugs. The antagonist should be applied as soon as possible because the effect is satisfactory in 12 h but the effect is worse over 24 h. In the treatment, it is best to monitor the blood concentration and give other therapies, such as hemodialysis or hemofiltration.
Drug interactions
Different sources of media describe the Drug interactions of 103-90-2 differently. You can refer to the following data:
1. For patients with chronic alcohol ingestion or other liver enzyme inducers, especially barbiturates or anticonvulsants, when taking long-term or a large-scale use of this product, they may have a higher risk of liver toxicity.When combined with chloramphenicol, this product can prolong the latter t1/2 and enhance its toxicity.When combined with anticoagulant drugs, this product can increase the anti-blood-clotting effect. So it is necessary to adjust the dosage of anticoagulant drugs.When combining long-term large quantities of Acetaminophen with aspirin or other non-steroidal anti-inflammatory drugs, it will increase the risk of renal toxicity.When combined with the antiviral drug, zidovudine, it can increase the toxicity. We ought to avoid using at the same time.
2. Potentially hazardous interactions with other drugs
None known
Administration nursing care point
Nurse according to the general principles of analgesia-antipyretic drugs.
The caregiver should exhort the patient to pay attention to the following things during medication period: ①No drinking, drinking may aggravate the liver toxicity of this product; ②Drink plenty of water to reduce the concentration of drug in renal tubules and reduce the occurrence of “analgesic nephropathy”; ③When taking chewing chips, chew them up; ④No unauthorized use other NSAIDS or compound preparation containing NSAIDS at the same time to avoid increasing the renal toxicity.
In a poisoning caused by this product, we should give patients oral antagonists, acetylcysteine (Tan Yijing) as soon as possible, not oral activated carbon, because the latter can affect the absorption of antagonists. Initial dose of acetylcysteine is 140 mg/kg, add 70 mg/kg every 4 h, 17 times totally. Intake: configure acetylcysteine into a 5% solution or add in triple drinks and take after shaking well to avoid fetid odors and irritations. For the occurrence of vomiting within 1 h after medication, resupply, if necessary, take nasal or rectal administration. In severe cases, the drug can be dissolved in 5% 200 ml glucose injection and used through intravenous drip. The antagonist should be applied as soon as possible because the effect is satisfactory in 12 h but the effect is worse over 24 h. In the treatment, it is best to monitor the blood concentration and give other therapies, such as hemodialysis or hemofiltration.
Usage
Organic synthesis intermediates, stabilizer of hydrogen peroxide, photographic chemicals, non anti-inflammatory analgesia-antipyretic drugs.
Production
Produced by acetylation of p-aminophenol.
Method 1: add p-aminophenol into dilute acetic acid, then add glacial acetic acid, heat up to 150℃and react for 7h, add acetic anhydride and react for 2h, check the end point and cool to 25℃ after the acceptance, shake it and filter, water until no acetic acid flavor exists, dry to get crude products.
Method 2: distill p-aminophenol, acetic acid and acid industrial containing more than 50% acid together, the speed of distilling dilute acid for is 1/10 of the total distillate in one hour, check the residue of p-aminophenol less than 2.5% aminophenol by sampling inspection when inner temperature rises up to 130℃, add dilute acid (content of more than 50%), cool to get crystallization. After shaking and filter, first use a small amount of dilute acid to wash, and then use a large number of water till filtrate is near colourless to get crude products. The yield of method 1 is 90%, but the yield of method 2 is 90-95%. Refining methods: add the crude product when the water is heated to near boiling. Heat up to the total dissolution, add activated carbon soaked in water, use dilute acetic acid to adjust till pH=4.2-4.6, boil for 10min. Filter press, add a small amount of sodium bisulfite into the filtrate. Cool to below 20℃, separate crystals out. After shaking and filter, wash and dry to get active ingredients, paracetamol finished products.
Other methods of production are as followed:
(1) p-nitrophenol is reduced by zinc in acetic acid, and acetaminophen is obtained by acetylation at the same time;
(2) put the hydrazone generated from p-hydroxyacetophenone in acid solution containing sulfuric acid, and then add sodium nitrite to get acetaminophen by renversement.
Description
Different sources of media describe the Description of 103-90-2 differently. You can refer to the following data:
1. Acetaminophen differs from the nonsteroidal anti-inflammatory agents described in that it
is devoid of anti-inflammatory and antirheumatic properties. It was recently shown that
acetaminophen, like aspirin, inhibits cyclooxygenase action in the brain and is even
stronger than aspirin. On the other hand, the mechanism of analgesic action of acetaminophen is not fully clear, since it acts poorly on peripheral cyclooxygenase.
2. Acetaminophen is an analgesic and antipyretic compound. Unlike many NSAIDs, which inhibit both COX-1 and COX-2, early studies suggested that acetaminophen is a poor inhibitor of both isoforms. However, it does inhibit COX-2 by 83% and COX-1 by 56% in human blood ex vivo, albeit at a high 1,000 mg dose, with IC50 values of 25.8 and 113.7 μM, respectively. Acetaminophen is enzymatically and non-enzymatically converted to several reactive metabolites that contribute to adverse or indirect effects, including liver injury. At toxic doses, the acetaminophen metabolite N-acetyl-4-benzoquinone imine (NAPQI; ) depletes glutathione reserves in the liver, leading to an accumulation of NAPQI and subsequent hepatocyte necrosis. Acetaminophen decreases glutathione levels and reduces glutathione peroxidase activity in mice when administered at a dose of 250 mg/kg and induces ferroptotic cell death in primary mouse hepatocytes, an effect that can be blocked by the ferroptosis inhibitor ferrostatin-1 . Acetaminophen has analgesic and antipyretic properties in animal models.
Chemical Properties
White Solid
Originator
Trigesic ,Squibb ,US ,1950
Uses
Different sources of media describe the Uses of 103-90-2 differently. You can refer to the following data:
1. Analgesic; antipyretic
2. antiinfectant
3. dispersing agent in liquid scintillation counting
4. manufacture of azo dyes, photographic chemicals.
5. Acetaminophen is widely used as an analgesic and fever-reducing agent. Acetaminophen is
designed for moderate analgesia. It is also effective like aspirin and is used in analgesia for
headaches (from weak to moderate pain), myalgia, arthralgia, chronic pain, for oncological and
post-operational pain, etc.
Indications
Acetaminophen (Tylenol) is an effective antipyretic and
analgesic that is well tolerated at therapeutic doses. It
has only weak antiinflammatory activity; thus, it is not
useful in the treatment of rheumatoid arthritis and
other inflammatory conditions.
Manufacturing Process
About 250 ml of a reaction mixture obtained by the electrolytic reduction of
nitrobenzene in sulfuric acid solution and containing about 23 grams of paminophenol
by assay is neutralized while at a temperature of 60°C to 65°C,
to a pH of 4.5 with calcium carbonate. The calcium sulfate precipitate which
forms is filtered off, the precipitate washed with hot water at about 65°C and
the filtrate and wash water then combined. The solution is then extracted
twice with 25 ml portions of benzene and the aqueous phase is treated with
0.5 part by weight, for each part of p-aminophenol present, of activated
carbon and the latter filtered off. The activated carbon is regenerated by
treatment with hot dilute caustic followed by a hot dilute acid wash, and
reused a minimum of three times.
To the filtrate obtained, there are then added about 0.2 gram of sodium
hydrosulfite or sodium sulfite and 15.0 grams of anhydrous sodium acetate in
about 27 grams of acetic anhydride at 40°C. The reaction mixture formed is
cooled to 8°C to 10°C with stirring and held at this temperature for 60
minutes. A crystalline precipitate of about 27 grams of N-acetyl-paminophenol
is obtained melting at 169-171°C. This is equivalent to a yield of
85%.
In lieu of utilizing calcium carbonate as the neutralizing agent, calcium
hydroxide, barium hydroxide, barium chloride or other alkaline earth metal
salt or hydroxide forming an insoluble sulfate may be employed.
Brand name
Acephen (G & W);
Infants’ Feverall (Actavis); Injectapap (Ortho-McNeil);
Neopap (Polymedica); Tylenol (McNeil);Anacin;Crocin.
Therapeutic Function
Analgesic, Antipyretic
World Health Organization (WHO)
Paracetamol, a widely used analgesic and antipyretic is known, in
case of overdose, to cause liver damage, frequently with fatal outcome. In
recommended dosages this risk does not occur. Paracetamol is listed in the WHO
Model List of Essential Drugs.
Synthesis Reference(s)
The Journal of Organic Chemistry, 27, p. 1092, 1962 DOI: 10.1021/jo01050a543Tetrahedron Letters, 22, p. 1257, 1981 DOI: 10.1016/S0040-4039(01)90289-8
General Description
Odorless white crystalline solid. Bitter taste. pH (saturated aqueous solution) about 6.
Air & Water Reactions
Slightly soluble in water.
Reactivity Profile
Acetaminophen is sensitive to light. Incompatible with strong oxidizers.
Fire Hazard
Flash point data for Acetaminophen are not available; however, Acetaminophen is probably combustible.
Flammability and Explosibility
Nonflammable
Biological Activity
Cyclooxygenase inhibitor; may be selective for COX-3 (IC 50 values are 460, > 1000 and > 1000 μ M for canine COX-3, and murine COX-1 and COX-2 respectively). Widely used analgesic and antipyretic agent.
Mechanism of action
The mechanism of action of paracetamol is not well understood, but it may
act in a similar fashion to NSAIDs, with inhibition of cyclo-oxygenase
enzymes COX-1 and COX-2 to reduce the phenoxyl radical
formation required for COX-1 and 2 activity and prostaglandin synthesis. I t
has selectivity for inhibition of prostaglandin synthesis with low
concentrations of peroxidases and arachidonic acid, but limited effect at
higher concentrations and, therefore, has limited anti-inflammatory effects.
Unlike opioids, paracetamol has no well-defined endogenous binding sites.
I n some circumstances, it may exhibit a preferential effect on COX-2
inhibition. There is growing evidence of a central antinociceptive effect of
paracetamol. It has also been found to prevent prostaglandin production at
the cellular transcriptional concentration, independent of COX activity.
Clinical Use
Acetaminophen is weakly acidic (pKa = 9.51) and synthesized by the acetylation of p-aminophenol. It is weakly bound
to plasma proteins (18–25%). Acetaminophen is indicated for use as an antipyretic/analgetic, particularly in those
individuals displaying an allergy or sensitivity to aspirin. It does not possess anti-inflammatory activity, but it will
produce analgesia in a wide variety of arthritic and musculoskeletal disorders. It is available in various formulations,
including suppositories, tablets, capsules, granules, and solutions. The usual adult dose is 325 to 650 mg every 4 to
6 hours. Doses of greater than 2.6 g/day are not recommended for long-term therapy because of potential
hepatotoxicity issues. Acetaminophen, unlike aspirin, is stable in aqueous solution, making liquid formulations readily
available, a particular advantage in pediatric cases.
Synthesis
Acetaminophen, p-acetaminophenol (3.2.80), is synthesized by reacting
p-aminophenol with acetic anhydride [76,77].
Environmental Fate
Although a major part of the ingested dose of acetaminophen is
detoxified, a very small proportion is metabolized via the
cytochrome P450-mixed function oxidase pathway to a highly
reactive n-acetyl-p-benzoquinoneimine (NAPQI). The toxic
intermediate NAPQI is normally detoxified by endogenous
glutathione to cysteine and mercapturic acid conjugates and
excreted in the urine. Recent studies have shown that hepatic
P450s, CYP2E1, and to a lesser extent CYP1A2 are responsible
for conversion of acetaminophen to NAPQI. In acetaminophen
overdose, the amount of NAPQI increases and depletes
endogenous glutathione stores. Time course studies have
shown that covalent binding of reactive NAPQI and subsequent
toxicity occur only after cellular glutathione stores are
reduced by 70% or more of normal. Mitochondrial dysfunction
and damage can be seen as early as 15 min after a toxic dose in
mice, suggesting that this may be a critical to cellular necrosis.
The NAPQI is then thought to covalently bind to critical
cellular macromolecules in hepatocytes and cause cell death.
Recent proteomic studies have identified at least 20 known
proteins that are covalently modified by the reactive acetaminophen
metabolite. The resulting acetaminophen-cysteine
(APAP-CYS) protein adducts can be quantified via a highpressure
liquid chromatography coupled with electrochemical
detection (HPLC-EC). Hepatic necrosis and inflammation
develop as a consequence of hepatocellular death, which
results in development of clinical and laboratory findings
consistent with liver failure. A similar mechanism is postulated
for the renal damage that occurs in some patients following
acetaminophen toxicity.
Metabolic pathway
Acetaminophen (APAP) is metabolized by mice, and
nine metabolites are identified in the urine. The main
metabolites are APAP-glucuronide and 3-cysteinyl-
APAP. Hydroquinone metabolites of S-(2,5-
dihydroxyphenyl)cysteine and S-(2,5-dihydroxyphenyl)-
N-acetylcysteine result from the benzoquinone
metabolite of APAP.
Metabolism
acetaminophen is undergoes rapid first-pass metabolism in the GI tract primarily by conjugation reactions, with the
O-sulfate conjugate being the primary metabolite in children and the O-glucuronide being the primary metabolite in
adults. A minor, but significant, product of both acetaminophen and phenacetin is the N-hydroxyamide produced by a
CYP2E1 and CYP3A4.
Purification Methods
Recrystallise Paracetamol from water or EtOH. The 3,5-dinitrobenzamide complex gives orange crystals from hot H2O and has m 171.5o. [Beilstein 13 H 460, 13 I 159, 13 II 243, 13 III 1056, 13 IV 1091.]
Check Digit Verification of cas no
The CAS Registry Mumber 103-90-2 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 1,0 and 3 respectively; the second part has 2 digits, 9 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 103-90:
(5*1)+(4*0)+(3*3)+(2*9)+(1*0)=32
32 % 10 = 2
So 103-90-2 is a valid CAS Registry Number.
InChI:InChI=1/C8H9NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5,11H,1H3,(H,9,10)/i2D,3D,4D,5D
103-90-2Relevant articles and documents
Enhanced catalytic activity of natural hematite-supported ppm levels of Pd in nitroarenes reduction
Gholinejad, Mohammad,Shojafar, Mohammad,Sansano, José M.
, p. 2033 - 2043 (2020)
In this work, Pd NPs supported on amine-modified natural hematite have been prepared and characterized. Using this simple catalyst, nitroaromatic compounds as a major cause of industrial pollution were reduced to corresponding amines with ppm levels of Pd in the presence of designer surfactant TPGS-750-M and NaBH4 at room temperature in aqueous media. Synergistic effect between hematite and Pd is responsible for the observed enhanced catalytic activity. This catalyst was recycled for at least four times with a small decrease in the activity.
-
Rosenmund et al.
, p. 324,327 (1953)
-
Regioselective preparation of 5-hydroxypropranolol and 4′-hydroxydiclofenac with a fungal peroxygenase
Kinne, Matthias,Poraj-Kobielska, Marzena,Aranda, Elisabet,Ullrich, Rene,Hammel, Kenneth E.,Scheibner, Katrin,Hofrichter, Martin
, p. 3085 - 3087 (2009)
An extracellular peroxygenase of Agrocybe aegerita catalyzed the H2O2-dependent hydroxylation of the multi-function beta-adrenergic blocker propranolol (1-naphthalen-1-yloxy-3-(propan-2-ylamino)propan-2-ol) and the non-steroidal anti-inflammatory drug diclofenac (2-[2-[(2,6-dichlorophenyl)amino]phenyl]acetic acid) to give the human drug metabolites 5-hydroxypropranolol (5-OHP) and 4′-hydroxydiclofenac (4′-OHD). The reactions proceeded regioselectively with high isomeric purity and gave the desired 5-OHP and 4′-OHD in yields up to 20% and 65%, respectively. 18O-labeling experiments showed that the phenolic hydroxyl groups in 5-OHP and 4′-OHD originated from H2O2, which establishes that the reaction is mechanistically a peroxygenation. Our results raise the possibility that fungal peroxygenases may be useful for versatile, cost-effective, and scalable syntheses of drug metabolites.
Spectrophotometric Determination of Aspirin by Transacetylation of 4-Aminophenol
Verma, Krishna K.,Jain, Archana
, p. 821 - 824 (1986)
Aspirin transacetylates 4-aminophenol, yielding acetaminophen (N-acetyl-4-aminophenol), which can be determined by its oxidation to an orange-yellow product either by iodylbenzene in acetone when the absorbance is measured at 430 nm or by photometric titration with 2-iodylbenzoate in acetone-water medium at 444 nm.Salicylic acid, salicylamide, oxyphenbutazone, caffeine, and sodium hydrogen carbonate do not interfere.Drug mixtures of acetaminophen and aspirin have been analyzed by determining acetaminophen alone directly with iodyl reagents and then determining acetaminophen plus aspirin after 4-aminophenol reaction; aspirin is found b y difference
Assessment of cytochrome P450 (1A2, 2B6, 2C9 and 3A4) induction in cryopreserved human hepatocytes cultured in 48-well plates using the cocktail strategy
Gerin, Brigitte,Dell'aiera, Sylvie,Richert, Lysiane,Smith, Steven,Chanteux, Hugues
, p. 320 - 335 (2013)
1. A fast, straightforward and cost-effective assay was validated for the assessment of CYP induction in cryopreserved human hepatocytes cultured in 48-well plates. The cocktail strategy (in situ incubation) was used to assess the induction of CYP1A2, CYP2B6, CYP2C9 and CYP3A4 by using the recommended probe substrate, i.e. phenacetin, bupropion, diclofenac and midazolam, respectively. 2. Cryopreserved human hepatocytes were treated for 72 h with prototypical reference inducers, β-naphthoflavone (25 μM), phenobarbital (500 μM) and rifampicin (10 μM) as positive controls for CYP induction. The use of a cocktail strategy has been validated and compared to the classical approach (single incubation). The need of using phase II inhibitor (salicylamide) in CYP induction assay was also investigated. 3. By using three different batches of cryopreserved human hepatocytes and our conditions of incubations, we showed that there was no relevant drug-drug interaction using the cocktail strategy. The same conclusions were observed when a broad range of enzyme activity has to be assessed (wide range of reference inducers, i.e. EC50-Emax experiment). In addition, the interassay reproducibility assessment showed that the day-to-day variability was minimal. 4. In summary, the study showed that the conditions used (probe substrates, concentration of probe substrate and time of incubation) for the cocktail approach were appropriate for investigations of CYP induction potential of new chemical entities. In addition, it was also clear that the use of salicylamide in the incubation media was not mandatory and could generate drug-drug interactions. For this reason, we recommend to not use salicylamide in CYP induction assay.
Identification of human cytochrome P450s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data
Li, Xue-Qing,Bjoerkman, Anders,Andersson, Tommy B.,Gustafsson, Lars L.,Masimirembwa, Collen
, p. 429 - 442 (2003)
Objective: Knowledge about the metabolism of anti-parasitic drugs (APDs) will be helpful in ongoing efforts to optimise dosage recommendations in clinical practise. This study was performed to further identify the cytochrome P450 (CYP) enzymes that metabolise major APDs and evaluate the possibility of predicting in vivo drug clearances from in vitro data. Methods: In vitro systems, rat and human liver microsomes (RLM, HLM) and recombinant cytochrome P450 (rCYP), were used to determine the intrinsic clearance (CLint) and identify responsible CYPs and their relative contribution in the metabolism of 15 commonly used APDs. Results and discussion: CLint determined in RLM and HLM showed low (r2=0.50) but significant (Pint values were scaled to predict in vivo hepatic clearance (CLH) using the 'venous equilibrium model'. The number of compounds with in vivo human CL data after intravenous administration was low (n=8), and the range of CL values covered by these compounds was not appropriate for a reasonable quantitative in vitro-in vivo correlation analysis. Using the CLH predicted from the in vitro data, the compounds could be classified into three different categories: high-clearance drugs (> 70% liver blood flow; amodiaquine, praziquantel, albendazole, thiabendazole), low-clearance drugs (int drug categories. The identified CYPs for some of the drugs provide a basis for how these drugs are expected to behave pharmacokinetically and help in predicting drug-drug interactions in vivo.
Ytterbium triflate mediated selective deprotection of acetates
Sharma,Ilangovan
, p. 1963 - 1965 (1999)
Ytterbium triflate mediated selective deprotection of acetates in isopropyl alcohol at reflux temperature is reported. Unlike hafnium triflate, under the present reaction conditions aryl acetates also undergo deacetylation instead of Fries migration.
Mechanism of Decomposition of N-Hydroxyacetaminophen, a Postulated Toxic Metabolite of Acetaminophen
Gemborys, Mark W.,Mudge, Gilbert H.
, p. 304 - 308 (1980)
The decomposition of N-hydroxyacetaminophen (N-acetyl-N-hydroxy-p-aminophenol, 2) a postulated toxic metabolite of acetaminophen (N-acetyl-p-aminophenol, 1) in aqueous solution is quantitatively accounted for by the appearance of equimolar amounts of p-nitrosophenol and acetaminophen.The rate of decomposition depends on initial concentration and varies with pH.Antioxidants decrease the rate of decomposition and change the products.In the presence of cysteine, N-acetyl-3-(S-cysteine)-p-aminophenol, an in vivo metabolite of acetaminophen, is a product of decomposition.
Retrorsine, but not monocrotaline, is a mechanism-based inactivator of P450 3A4
Dai, Jieyu,Zhang, Fan,Zheng, Jiang
, p. 49 - 56 (2010)
Retrorsine (RTS) and monocrotaline (MCT) cause severe toxicities via P450-mediated metabolic activation. The screening of mechanism-based inhibitors showed RTS inactivated 3A4 in the presence of NADPH. Unlike RTS, MCT failed to inhibit P450 3A4 and other enzymes tested. Further studies showed the loss of P450 3A4 activity occurred in a time- and concentration-dependent way, which was not recovered after dialysis. Dextromethorphan, a P450 3A4 substrate, protected the enzyme from the inactivation. Exogenous nucleophile glutathione (GSH) and reactive oxygen species scavengers catalase and superoxide dismutase did not protect P450 3A4 from the inactivation. GSH trapping experiments showed both P450 3A4 and 2C19 converted RTS and MCT to the corresponding electrophilic metabolites which could be trapped by GSH to form 7-GSH-DHP conjugate. We conclude that RTS and MCT are metabolically activated by P450 3A4 and 2C19, and that RTS, but not MCT, is a mechanism-based inactivator of P450 3A4.
Amidation of phenol derivatives: A direct synthesis of paracetamol (acetaminophen) from hydroquinone
Joncour, Roxan,Duguet, Nicolas,Metay, Estelle,Ferreira, Amadeo,Lemaire, Marc
, p. 2997 - 3002 (2014)
A direct synthesis of paracetamol (acetaminophen) from hydroquinone has been developed using ammonium acetate as an amidating agent. The reaction proceeds in acetic acid at elevated temperatures without any metallic catalyst. Under these conditions, paracetamol was obtained with high yield and selectivity (>95%). The reaction has also been carried out on the multi-gram scale (44 g of hydroquinone) and a potential process has been proposed based on the recycling of the solvent and by-products. This amidation protocol has also been extended to other phenol derivatives. This journal is the Partner Organisations 2014.
A Realistic Model for Heme-containing Catalases and Peroxidases: the X-Ray Structural Characterisation of a Non-porphyrin Iron(III) Macrocyclic Complex, and the Mechanism of Its Peroxidation of Aromatic Substrates
Cairns, Colin J.,Heckman, Roger A.,Melnyk, Alexandra C.,Davis, William M.,Busch, Daryle H.
, p. 2505 - 2510 (1987)
In acidic buffered aqueous solution the complex dichloroheptadeca-1(17),13,15-triene>iron(III) tetrafluoroborate, BF4, exhibits both catalase- and peroxidase-like activity.The predominant cation in aqueous buffered solution at pH 4.65 is the mixed species 2+.The catalase- and peroxidase-like activity is proposed to occur via a high oxidation state intermediate rather than through involvement of free hydroxyl radicals.Quantitative compliance with the algebraic forms of theoretical rate laws fails to distinguish between these possibilities.However, the kinetics of dioxygen evolution in the presence of hydroxyl radical traps leads to the elimination of the hydroxyl radical model.In addition, the peroxidase-like reactivity of substituted benzenes toward the 2+-H2O2 model system parallels that expected for an electrophilic oxidant, and not that of free OH radicals.Parallel experiments with Fenton's reagent support this view.An X-ray structural determination on the dichloro complex indicates that the macrocycle adopts a folded conformation allowing the two chloride ligands to occupy cis positions in the co-ordination sphere.This stereochemistry is proposed to be retained in aqueous solution, and may allow bidentate co-ordination of hydrogen peroxide,a structural feature that may be critical to the catalase- and peroxidase-like activity.The iron(III) complex crystallises in the orthorhombic system, a=10.046(2), b=13.322(2), c=15.262(3) Angstroem, space group Pnma, with four molecules per unit cell.Final residuals had values of 0.042 and 0.043, for R and R', respectively, upon convergence for 1525 observed reflections.Both the cationic, macrocyclic complex and the BF4 anion display crystallographically imposed mirror symmetry.The iron(III) ion displays an approximately octahedral geometry, with co-ordination angles ranging from 77 to 95 deg.An analysis of associated torsion angles suggests that the folded conformation of the macrocycle is almost strain free.
Oxygen activation by the iron(II)-2-mercaptobenzoic acid complex. A model for microsomal mixed function oxygenases.
Ullrich
, p. 699 - 704 (1969)
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Aluminium chloride hexahydrate (AlCl3.6H2o): An efficient, facile, mild, and highly chemoselective catalytic deprotection of tert-butyldimethylsilyl (tbs) ethers
Gonzalez-Calderon, Davir,Benitez-Puebla, Luis J.,Gonzalez-Gonzalez, Carlos A.,Garcia-Eleno, Marco A.,Fuentes-Benitez, Aydee,Cuevas-Yanez, Erick,Corona-Becerril, David,Gonzalez-Romero, Carlos
, p. 1258 - 1265 (2014)
tert-Butyldimethylsilyl (TBS) phenyl / alkyl ethers were cleaved to the corresponding efficiently parent hydroxyl compounds in good yields using catalytic amounts of AlCl3.6H2O by conventional or microwave-assisted heating in methanol or isopropanol solution. Intramolecular and competitive experiments demonstrated the chemoselective deprotection of TBS ethers in the presence of triisopropylsilyl and tert-butyldiphenylsilyl ethers.
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Freifelder
, p. 1092 (1962)
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Feldstein et al.
, p. 1656 (1961)
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Synthesis and evaluation in vitro of 4-acetamidophenyl phosphate
Taniguchi,Nakano
, p. 577 - 580 (1981)
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Large scale Biginelli reaction via water-based biphasic media: A green chemistry strategy
Bose, Ajay K.,Manhas, Maghar S.,Pednekar, Suhas,Ganguly, Subhendu N.,Dang, Hoang,He, William,Mandadi, Arun
, p. 1901 - 1903 (2005)
An important stage in process development is kilo scale preparation of the target compound. For this reason, a procedure involving water-based biphasic reaction media has been developed for conducting some exothermic reactions on a large scale. This protocol is illustrated by the energy-efficient and rapid preparation of dihydropyrimidinones by a solvent-free, green chemistry procedure applied to the Biginelli reaction using p-toluenesulfonic acid as catalyst. 2005 Elsevier Ltd.
Preparation of an organic–inorganic hybrid based on synergy of Br?nsted and Lewis acid centres as heterogeneous magnetic nanocatalyst for ultrafast synthesis of acetaminophen
Kooti,Nasiri
, (2018)
A heterogeneous nanocatalyst based on a Cu(II) complex containing phosphotungstic acid and N/O-donor ligands supported on cobalt ferrite nanoparticles was successfully prepared. The synthesized nanocatalyst was characterized using various techniques. The magnetic nanocatalyst was examined as an efficient and synergistic catalyst for ultrafast synthesis of acetaminophen at room temperature and under solventless conditions. The examined synergistic nanocatalyst, which has both Lewis and Br?nsted acidic sites, could be easily separated from the reaction system and reused several times without significant loss of its activity. The synthesized acetaminophen was also fully characterized.
Human cytochromes p450 mediating phenacetin 0-deethylation in vitro: Validation of the high affinity component as an index of CYP1A2 activity
Venkatakrishnan, Karthik
, p. 1502 - 1507 (1998)
Phenacetin 0-deethylation, widely used as an index reaction for cytochrome P450 1A2 (CYP1A2) activity, displays biphasic kinetics in human liver microsomes. CYP1A2 has been identified as contributing to the high affinity component, but is not verified as the sole contributor to the high affinity phase. In addition, the human CYP isoforms accounting for the low affinity phase have not been identified. We have used heterologously expressed human CYP isoforms to identify, kinetically characterize, and predict the relative contribution of the major human liver CYP isoforms mediating phenacetin 0-deethylation. CYP1A2 (Km 31 /J.M) is the only high affinity phenacetin 0-deethylase in human liver microsomes, while CYPs 2A6 (Km 4098 pM), 2C9 (Km 566 μM), 2C19 (Km 656 μM), 2D6 (Km 1021 μM), and 2E1 (Km 1257 μM) all contribute to the low affinity phase of the reaction. Considering the relative abundance of the various CYPs in human liver, CYP1A2 accounts for 86% of net reaction velocity at a substrate concentration of 100 fM, while CYP2C9 becomes the primary phenacetin 0-deethylase at substrate concentrations of 865 /M and higher and accounts for 31% of the net Vmsst of the reaction. Predictions from kinetic studies on heterologously expressed CYPs are consistent with chemical inhibition studies on human liver microsomes with sulfaphenazole and a-naphthoflavone that suggest a greater role for CYP2C9, and a smaller role for CYP1A2, at higher substrate concentrations. Thus CYP1A2 is the only high affinity human liver phenacetin 0-deethylase, thereby validating the use of the high affinity component as an index of CYP1A2 activity in human liver microsomes.
N-hydroxylation of p-acetophenetidide as a factor in nephrotoxicity.
Calder,Creek,Williams,Funder,Green,Ham,Tange
, p. 499 - 502 (1973)
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Functionalized nanomagnetic graphene by ion liquid containing phosphomolybdic acid for facile and fast synthesis of paracetamol and aspirin
Nasiri, Elahe,Kooshki, Feridoon,Kooti, Mohammad,Rezaeinasab, Rezvan
, (2021)
A nanocomposite has been synthesized by supporting of polyaniline-modified polyoxometalate-paired poly(ionic liquid) on the surface of magnetic graphene and characterized by various techniques. The fabricated nanocomposite was found to be a versatile catalyst for the synthesis of paracetamol and aspirin drugs showing high activity and selectivity. The observed high catalytic activity of the newly synthesized catalyst, in the preparation of these two important drugs, can be attributed to the presence of graphene, which provides high surface area for the supporting of polyaniline–polyoxometalate pair and also to the strong acidity of the solid acid. This catalytic system has several advantages, such as simple experimental process, easy separation of the product, solvent-free condition, efficient isolation, and recovery of the magnetic catalyst as well as high reusability.
Microwave initiated reactions: Pechmann coumarin synthesis, Biginelli reaction, and acylation
Manhas, Maghar S.,Ganguly, Subhendu N.,Mukherjee, Somdatta,Jain, Amit K.,Bose, Ajay K.
, p. 2423 - 2425 (2006)
An energy-efficient protocol has been developed for solvent-free reactions that are mildly exothermic but not spontaneous. The exothermic reaction mixture-on several g-scale-is exposed for about 30 s to low power (about 200 W) microwaves and then the microwave oven is switched off. After this short burst of energy, the exothermic reaction gets initiated and proceeds on its own to completion. A number of coumarins were synthesized by the Pechmann reaction using this strategy.
Kinetics and inhibition by fluvoxamine of phenacetin O-deethylation in V79 cells expressing human CYP1A2
Gjervig Jensen,Enghusen Poulsen,Doehmer,Loft
, p. 286 - 288 (1995)
The kinetics of phenacetin O-deethylation and its inhibition by fluvoxamine was investigated in a V79 cell line (V79MZh1A2) transfected with human CYP1A2. In four sets of experiments the apparent Km values for phenacetin O-deethylation ranged from 35 to 95 μM and the Ki for fluvoxamine-mediated inhibition of the reaction ranged from 2.7 to 14.5 nM, i.e. comparable to values obtained in human liver microsomes. The kinetic performance of the V79MZh1A2 cell line demonstrates its usefulness as an analytical tool in a variety of toxicological and drug metabolism studies involving CYP1A2.
Acetylshikonin is a novel non-selective cytochrome P450 inhibitor
Shon, Jong Cheol,Phuc, Nguyen Minh,Kim, Won Cheol,Heo, Jae Kyung,Wu, Zhexue,Lee, Hyunyoung,Liu, Kwang-Hyeon
, p. 553 - 556 (2017)
Acetylshikonin is a biologically active compound with anti-cancer and anti-inflammatory activity, which is isolated from the roots of Lithospermum erythrorhizoma. An inhibitory effect of acetylshikonin against CYP2J2 activity was discovered recently. Based on this result, this study was expanded to evaluate the inhibitory effects of acetylshikonin against nine different cytochrome P450 (P450) isoforms in human liver microsomes (HLMs) using substrate cocktails incubation assay. Acetylshikonin showed a strong inhibitory effect against all P450s tested with IC50 values of 1.4–4.0 μ m. Pre-incubation of acetylshikonin with HLMs and NADPH did not alter the inhibition potency, indicating that acetylshikonin is not a mechanism-based inhibitor. SKF-525A, a widely used non-specific P450 inhibitor, had no inhibitory activity against CYP1A2, 2A6, 2E1 and 2J2, while it showed an inhibitory effect against CYP2B6, CYP2C19 and 2D6 with IC50 values of 2.5, 3.6 and 0.5 μ m, respectively. Our findings indicate that acetylshikonin may be a novel general P450 inhibitor, which could replace SKF-525A.
Pyridazine N-Oxides as Photoactivatable Surrogates for Reactive Oxygen Species
Basistyi, Vitalii S.,Frederich, James H.
supporting information, p. 1907 - 1912 (2022/03/27)
A method for the photoinduced evolution of atomic oxygen from pyridazine N-oxides was developed. This underexplored oxygen allotrope mediates arene C-H oxidation within complex, polyfunctional molecules. A water-soluble pyridazine N-oxide was also developed and shown to promote photoinduced DNA cleavage in aqueous solution. Taken together, these studies highlight the utility of pyridazine N-oxides as photoactivatable O(3P) precursors for applications in organic synthesis and chemical biology.
Antimalarial Benzimidazole Derivatives Incorporating Phenolic Mannich Base Side Chains Inhibit Microtubule and Hemozoin Formation: Structure-Activity Relationship and in Vivo Oral Efficacy Studies
Dziwornu, Godwin Akpeko,Coertzen, Dina,Leshabane, Meta,Korkor, Constance M.,Cloete, Cleavon K.,Njoroge, Mathew,Gibhard, Liezl,Lawrence, Nina,Reader, Janette,Van Der Watt, Mari?tte,Wittlin, Sergio,Birkholtz, Lyn-Marie,Chibale, Kelly
supporting information, p. 5198 - 5215 (2021/05/06)
A novel series of antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains at the C2 position, which possess dual asexual blood and sexual stage activities, is presented. Structure-activity relationship studies revealed that the 1-benzylbenzimidazole analogues possessed submicromolar asexual blood and sexual stage activities in contrast to the 1H-benzimidazole analogues, which were only active against asexual blood stage (ABS) parasites. Further, the former demonstrated microtubule inhibitory activity in ABS parasites but more significantly in stage II/III gametocytes. In addition to being bona fide inhibitors of hemozoin formation, the 1H-benzimidazole analogues also showed inhibitory effects on microtubules. In vivo efficacy studies in Plasmodium berghei-infected mice revealed that the frontrunner compound 41 exhibited high efficacy (98% reduction in parasitemia) when dosed orally at 4 × 50 mg/kg. Generally, the compounds were noncytotoxic to mammalian cells.
