Naproxen Chemical Properties

Melting point:

152-154 °C (lit.)

alpha 

D +66° (in chloroform)

Boiling point:

332.25°C (rough estimate)

Density 

1.1450 (rough estimate)

refractive index 

67.5 ° (C=1, CHCl3)

Flash point:

9℃

storage temp. 

2-8°C

solubility 

Practically insoluble in water, soluble in ethanol (96 per cent) and in methanol.

form 

powder

pka

pKa 4.28± 0.02(H2O,t =25,I=0.01) (Uncertain)

color 

White to Almost white

optical activity

[α]25/D +66°, c = 1 in chloroform

Water Solubility 

Insoluble in water.

Merck 

14,6417

BRN 

3591067

BCS Class

2

LogP

3.18

CAS DataBase Reference

22204-53-1(CAS DataBase Reference)

NIST Chemistry Reference

Naproxen(22204-53-1)

EPA Substance Registry System

2-Naphthaleneacetic acid, 6-methoxy-.alpha.-methyl-, (.alpha.S)- (22204-53-1)

Safety Information

Hazard Codes 

Xn,T,F

Risk Statements 

22-39/23/24/25-23/24/25-11-36/37/38

Safety Statements 

36/37-45-16-7-26

RIDADR 

UN 2811 6.1/PG 3

WGK Germany 

3

RTECS 

UF5275000

HazardClass 

6.1(b)

PackingGroup 

III

HS Code 

29189900

Hazardous Substances Data

22204-53-1(Hazardous Substances Data)

Toxicity

LD50 in mice (mg/kg): 435 i.v.; 1234 orally; in rats (mg/kg): 575 i.p.; 534 orally (Roszkowski)

MSDS

• Language:English Provider:(+)-2-(6-Methoxy-2-naphthyl)-propionic acid
• Language:English Provider:SigmaAldrich
• Language:English Provider:ALFA

Naproxen Usage And Synthesis

Non-steroidal anti-inflammatory drugs

Naproxen is a non-steroidal anti-inflammatory drug ,it is a PG synthase inhibitor, which can inhibit prostaglandin synthetase, it has significant analgesic and antipyretic effects, oral absorption is rapid and complete, 2 to 4 hours after a dose ,plasma concentration reaches the peak, in the blood , more than 99% is bound to plasma proteins, t1/2 is 13 to 14 hours, about 95% is discharged from the urine with the prototype and metabolites.it is clinically used For the treatment of rheumatic and rheumatoid arthritis , osteoarthritis, ankylosing spondylitis, gout, arthritis, tenosynovitis.it can also be used to alleviate pain caused by musculoskeletal sprains, contusions,damages and dysmenorrhea . But it should be noted that like other non-steroidal anti-inflammatory drugs, the same serious gastrointestinal adverse reactions could occur at any time while taking naproxen during treatment, so the active gastroduodenal ulcer patients are hanged, other gastrointestinal tract disease patients should take this drug under close medical supervision.
The above information is edited by the Chemicalbook of Tian Ye.

Chemical Properties

White crystal or crystalline powder. Melting point 155.3 ℃. Soluble in acetone, soluble in methanol, ethanol, acetic acid, insoluble in benzene, practically insoluble in water. In case of light,it is color-graded, odorless, tasteless.

Uses

It is a non-steroidal anti-inflammatory drug for the relief of fever and inflammation and pain associated with arthritis or other symptoms , it has anti-inflammatory, antipyretic and analgesic effects. Naproxen plays a role by inhibiting the cyclooxygenase, which generates prostaglandin and is one kind of enzymes related to inflammatory mediators . It is recommended to take the drug during meals to reduce stomach irritation.

Used in Particular Diseases

Acute Gouty Arthritis:
Dosage and Frequency: 500 mg twice daily for 3 days, then 250–500 mg daily for 4–7 days

production method

by methylation, acetylation With 2-naphthol , 6-methoxy-2-acetonaphthone is produced, then it is condensed with acid ester, then generate the product through isomerization, hydrolysis, oxidation, and split and other reactions.

Category

Toxic substances

Toxicity grading

Highly toxic

Acute toxicity

Oral-rat LD50 248 mg/kg; Oral-Mouse LD50: 360 mg/kg

Flammability and hazard characteristics

Combustible; combustion produces toxic and acrid smoke.

Storage Characteristics

Ventilated, low-temperature ,dry storeroom, it should be stored and transported from food raw materials separately.

Extinguishing agent

Water, dry powder, foam,sand

Description

Naproxen is synthesized from 2-methoxynaphthalene and the (+)-isomer obtained by resolution with cinchonidine (61). It was introduced in the United States in 1976 and, as a generic drug, has consistently been among the more popular NSAIDs. It is marketed as the S-(+)-enantiomer, but interestingly, the sodium salt of the (–)-isomer also is on the market as Anaprox. As an inhibitor of prostaglandin biosynthesis, it is 12 times more potent than aspirin, 10 times more potent than phenylbutazone, three to four times more potent than ibuprofen, and four times times more potent than fenoprofen, but it is approximately 300 times less potent than indomethacin.

Chemical Properties

white to light yellow crystal powde

Originator

Naprosyn,Syntex,UK,1973

Uses

Being analogous to other drugs of this series, naproxene exhibits analgesic, fever-reducing, and long-lasting anti-inflammatory action. It causes reduction and removal of painful symptoms including joint pain, stiffness, and swelling in the joints. It is used in the same indications as ibuprofen.

Uses

(S)-(+)-2-(6-Methoxy-2-naphthyl)propionic acid is a non-selective cyclooxygenase (COX-1 and COX-2) inhibitor.

Uses

An anti-inflammatory, analgesic, antipyretic. A non-steroidal anti-inflammatory

Definition

ChEBI: A methoxynaphthalene that is 2-methoxynaphthalene substituted by a carboxy ethyl group at position 6. Naproxen is a non-steroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such a osteoarthritis, kidney stones, rheumatoid arthritis, psoriatic arthritis, gout, ankylosing spondylitis, menstrual cramps, tendinitis, bursitis, and for the treatment of primary dysmenorrhea. It works by inhibiting both the COX-1 and COX-2 enzymes.

Indications

Naproxen (Naprosyn) also has pharmacological properties and clinical uses similar to those of ibuprofen. It exhibits approximately equal selectivity for COX-1 and COX-2 and is better tolerated than certain NSAIDs, such as indomethacin. Adverse reactions related to the GI tract occur in about 14% of all patients, and severe GI bleeding has been reported. CNS complaints (headache, dizziness, drowsiness), dermatological effects (pruritus, skin eruptions, echinoses), tinnitus, edema, and dyspnea also occur.

Manufacturing Process

According to US Patent 3,658,858, a solution of 24 grams of 2-bromo-6- methoxynaphthalene in 300 ml of tetrahydrofuran is slowly added to 2.5 grams of magnesium turnings and 100 ml of tetrahydrofuran at reflux temperature. After the addition is complete, 20 grams of cadium chloride is added, and the resultant mixture is refluxed for 10 minutes to yield a solution of di-(6-methoxy-2-naphthyl)cadmium (which can be separated by conventional chromatography, although separation is unnecessary).
A solution of 18 grams of ethyl 2-bromopropionate in 20 ml of tetrahydrofuran is then added to the cooled reaction mixture. After 24 hours at 20°C, the product is hydrolyzed by adding 200 ml of 5 weight percent methanolic sodium hydroxide followed by heating to reflux for 1 hour. The reaction mixture is then diluted with excess 1 N sulfuric acid and extracted with ether. The ether phase is separated, evaporated to dryness and the residue is recrystallized from acetone-hexane to yield 2-(6-methoxy-2- naphthyl)propionic acid.

brand name

Naprosyn (Roche), Anaprox (Syntex, Canada, USA), Apranax (Roche, France), Bonyl (Ercopharm, Denmark), Miranax (Syntex, Finland), Novo-Naprox (Novorpharm, Canada), Proxen (Hoffmann La Roche, Germany).

Therapeutic Function

Antiinflammatory

Synthesis Reference(s)

Tetrahedron, 49, p. 8433, 1993 DOI: 10.1016/S0040-4020(01)81926-8

General Description

Naproxen (Naprosyn, Anaprox), marketed as the (S)-enantiomer,is well absorbed after oral administration, givingpeak plasma levels in 2 to 4 hours and a half-life of 13 hours.Naproxen is highly protein bound and displaces most protein-bound drugs. It is recommended for use in RA, OA, acute gouty inflammation, and in primary dysmenorrhea. Itshows good analgesic activity (i.e., 400 mg is comparable to75–150 mg of oral meperidine and superior to 65 mg ofpropoxyphene and 325 mg of aspirin plus 30 mg of codeine).It is also available OTC as 200-mg tablets (Aleve).

Pharmacokinetics

Naproxen is almost completely absorbed following oral administration. Peak plasma levels are achieved within 2 to 4 hours following administration. Like most of the acidic NSAIDs (pKa = 4.2), it is highly bound (99.6%) to plasma proteins. Approximately 70% of an administered dose is eliminated as either unchanged drug (60%) or as conjugates of unchanged drug (10%). The remainder is converted to the 6-O-desmethyl metabolite by both CYP3A4 and CYP1A2 and, further, to the glucuronide conjugate of the demethylated metabolite. The 6-O-desmethyl metabolite lacks anti-inflammatory activity. Like most of the arylalkanoic acids, the most common side effect associated with the use of naproxen is irritation to the GI tract. The most common other adverse reactions are associated with CNS disturbances (e.g., nausea and dizziness).

Clinical Use

Naproxen is indicated for the treatment of rheumatoid arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tendinitis, bursitis, acute gout, and primary dysmenorrhea and for the relief of mild to moderate pain.

Side effects

Common side effects of Naproxen may include indigestion, heartburn, stomach pain, nausea, headache, dizziness, drowsiness, bruising, itching, rash, swelling, or ringing in the ears. Seek immediate medical attention if you have any of the following serious drug reactions. For example: shortness of breath, swelling or rapid weight gain, rash, signs of stomach bleeding (bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds), liver problems (nausea, upper stomach pain, itching, feeling tired, flu-like symptoms, loss of appetite, dark urine, clay-coloured stools, jaundice), kidney problems (little or no urination, pain or difficulty in urinating, swelling of the feet or ankles, feeling tired or shortness of breath), low red blood cells (anaemia), etc. In addition, in rare cases, a severe allergic reaction to naproxen may occur. You may also suffer from stomach ulcers and other adverse reactions when taking it for a long time.

Synthesis

Synthesis of Naproxene: Friedel - Crafts acylation (aluminum chloride - nitrobenzene) of β-naphthol methyl ether affords 2-acetyl-6- methoxynaphthalene, which, when treated with either dimethylsulfonium or dimethylsulfoxonium methylide, gives 2-(6-methoxynaphthalen-2-yl)propylene oxide. Treatment of the latter with boron trifluoride etherate in tetrahydrofuran gives 2-(6-methoxynaphthalen- 2-yl)propionaldehyde, which is oxidized using Jones reagent (4 M chromic acid) to yield the racemic 2-(6-methoxynaphthalen-2- yl)propionic acid. Resolution and isolation of the dextrorotatory enantiomer is accomplished via its cinchonidine salt.
2-(6-methoxy-2-naphthyl)-propionic acid (3.2.15) can be synthesized by the methods of synthesis described for ibuprofen as well as by the methods of fenoprofen (3.2.21) and ketoprofen (3.2.27) synthesis that will be described below from 2-acetyl or 2-chloromethyl-6-methoxynaphthaline [99–101].

Veterinary Drugs and Treatments

The manufacturer lists the following indications: “…for the relief of inflammation and associated pain and lameness exhibited with myositis and other soft tissue diseases of the musculoskeletal system of the horse.” (Package Insert; Equiproxen?—Syntex). It has also been used as an antiinflammatory/analgesic in dogs for the treatment of osteoarthritis and other musculoskeletal inflammatory diseases (see adverse reactions below).

Drug interactions

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

Metabolism

Naproxen is extensively metabolised in the liver to 6-0-desmethyl naproxen. Both naproxen and 6-0-desmethyl naproxen are further metabolised to their respective acylglucuronide conjugated metabolites. About 95% of a dose is excreted in urine as naproxen and 6-O-desmethylnaproxen and their conjugates. Less than 5% of a dose appears in the faeces.

References

[1] barnett j, chow j, ives d, et al. purification, characterization and selective inhibition of human prostaglandin g/h synthase 1 and 2 expressed in the baculovirus system[j]. biochimica et biophysica acta (bba)-protein structure and molecular enzymology, 1994, 1209(1): 130-139.
[2] laneuville o, breuer d k, dewitt d l, et al. differential inhibition of human prostaglandin endoperoxide h synthases-1 and-2 by nonsteroidal anti-inflammatory drugs[j]. journal of pharmacology and experimental therapeutics, 1994, 271(2): 927-934.
[3] dubois r n, abramson s b, crofford l, et al. cyclooxygenase in biology and disease[j]. the faseb journal, 1998, 12(12): 1063-1073.
[4] agdeppa e d, kepe v, petri a, et al. in vitro detection of (s)-naproxen and ibuprofen binding to plaques in the alzheimer’s brain using the positron emission tomography molecular imaging probe 2-(1-{6-[(2-[18 f] fluoroethyl)(methyl) amino]-2-naphthyl} ethylidene) malononitrile[j]. neuroscience, 2003, 117(3): 723-730.

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