22494-42-4 Usage
Description
Diflunisal, also known as Dolobid, is a non-steroidal anti-inflammatory drug (NSAID) that is more potent and longer-acting than aspirin. It is characterized by its hydrophobic, 2,4-difluorophenyl group attached to the 5-position of the salicyclic acid. Diflunisal is highly protein-bound and has a unique pharmacokinetic profile due to its enterohepatic circulation and reabsorption. It is rapidly and completely absorbed upon oral administration, with a peak plasma level achieved within 2 to 3 hours. Diflunisal is a white solid and is marketed under the brand name Dolobid by Merck.
Uses
1. Used in Pharmaceutical Industry:
Diflunisal is used as a prostaglandin synthetase inhibitor for its analgesic, fever-reducing, and anti-inflammatory actions. It is particularly effective in providing longand short-lasting symptomatic relief of low to moderate pain in osteoarthritis and rheumatoid arthritis.
2. Used in Pain Management:
Diflunisal is used as an analgesic agent for treating mild to moderate postoperative pain.
3. Used in Alzheimer's Studies:
Diflunisal is used as an anti-inflammatory agent in Alzheimer's studies, where it helps in autolytic regulation of human kallikrein-related peptidase 6.
4. Used in General Medicine:
Diflunisal is used as a non-selective cyclo-oxygenase inhibitor, antipyretic, analgesic, and anti-inflammatory for various medical conditions requiring pain relief and inflammation reduction.
Please note that the provided materials do not mention the use of Glycerol, so the usage of Glycerol cannot be listed based on the given information.
Outline
Diflunisal, a nonsteroidal anti-inflammatory analgesic, is the most promising alternative to aspirin.It is used clinically for the treatment of rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, sprain, strain and analgesia. Researches have indicated that diflunisal and ibuprofen are effective in the treatment of rheumatoid arthritis and degenerative arthritis. It has also been observed that diflunisal is superior to ibuprofen in improving the grip strength and relieving joint pain and tenderness of rheumatoid arthritis and degenerative arthritis in patients with rheumatoid arthritis. At the same time, diflunisal can decrease and alleviate the rheumatoid factor titre in patients with rheumatoid arthritis and stiffness,The analgesic effect of diflunisal is 7.5 to 13 times as high as aspirin.Its antipyretic effect is 1.4 times as high as aspirin, and its therapeutic effect is about 3 times as strong as aspirin. Therefore, it is suitable for treating rheumatoid arthritis, osteoarthritis, muscle sprain, strain, meniscus surgery, orthopedic and oral surgery, and primary pain caused by dysmenorrhea. It is worthy of clinical application.Diflunisal is selected from more than 500 salicylic acid derivatives by American company Merck Sharp & Do hme using the flunisal as the leading compound in 1975. It was launched in 1975. Now it is one of the Merck Co's annual sales of over 100 million US dollars. And it has been listed in more than 70 countries, such as Britain, the United States, Japan, Italy, France and other countries. It has also been recorded by the United States Pharmacopoeia and the British Pharmacopoeia. In China, the tablets and capsules of diflunisal have been approved for production.
Pharmacokinetics
This product is well absorbed in oral administration, and the blood concentration 2 ~ 3H after taking will reach the peak.The half-life is proportional to the dosage, about 8 to 12h, and the binding rate of plasma protein is 90%. Oral administration of 125mg should be 3 ～ 4d and 500mg should be 7 to 9d. .The elimination of half-life of 125mg is 7 to 8h, and 500mg is 15h.Its binding rate with plasma protein in normal human body is up to 98% ~ 99%.The content of breast milk in lactating women is 2% ~ 7% of the blood concentration.It is not metabolized into salicylic acid in the body.80% to 95% of the drugs will be discharged from the urine in the form of 2 soluble glucoside complexes within 72-96h.
Pharmacokinetics
Diflunisal is more
potent than aspirin but produces fewer side effects and has a biological half-life three to four times greater than that
of aspirin. It is rapidly and completely absorbed on oral administration, with peak plasma levels being achieved within
2 to 3 hours of administration. It is highly bound (99%) to plasma proteins after absorption. Its elimination half-life is
8 to 12 hours, and it is excreted into urine primarily as glucuronide conjugates. The most frequently reported side
effects include disturbances of the GI system (e.g., nausea, dyspepsia, and diarrhea), dermatological reactions, and
CNS effects (e.g., dizziness and headache).
Clinical application
This product can inhibit the synthesis of prostaglandin with analgesic, anti-inflammatory and antipyretic effects. It is used to relieve the moderate pain in bone and rheumatoid arthritis.It is also used to relieve pain and joint, muscle sprain and cancer pain after meniscus and orthopedic surgery. The drug will take effect 1h after taking and the effect lasts for 8 ~ 12h.It can also be used to treat osteoarthritis and rheumatoid arthritis etc.
Precaution
The combined use with hydrochlorothiazine, indomethacin, and paracetamol can increase the plasma concentration of these drugs.?
Long-term application can cause renal function damage and drug accumulation, so the patients with renal insufficiency should be careful in application with reduced doses.
This drug is forbidden for patients with cardiac insufficiency, hypertension, edema, peptic ulcer and bleeding as well as for pregnant women and breast-feeding women.
It is forbidden for those who are allergic to this product and acetyl salicylic acid.
Used with anticoagulants, it can prolong the time of coagulation
Adverse reaction
Digestive system: anorexia, nausea, abdominal pain, abdominal distention, diarrhea, and constipation.
Nervous system: vertigo, headache, fatigue, insomnia, lethargy, etc.
Others: rare rash, edema, rhinitis, tinnitus, transient visual impairment, etc.
Originator
Dolobid,Morson,UK,1978
Manufacturing Process
A mixture of 10 g of 4-(2',4'-difluorophenyl)-phenol and 27.2 g of potassium
carbonate is exposed to carbon dioxide at 1,300 psi and 175°C. The dark
mass obtained from this carbonation is then dissolved in 300 ml of water and
200 ml of methylene chloride and the two layers separated. The water layer is
then extracted with 100 ml of methylene chloride and then acidified with 2.5
N hydrochloric acid. This mixture is then filtered and the cake dried in vacuo
to yield 5.32 g of the crude product. The crude product is then recrystallized
from benzene-methanol. An additional crystallization of this semipure material
from benzene-methanol yields analytically pure 2-hydroxy-5-(2',4'-
difluorophenyl)-benzoic acid (MP 210-211°C).
Therapeutic Function
Analgesic, Antiinflammatory
Clinical Use
Diflunisal (pKa 3.3) was introduced in the United States in 1982 and has gained considerable acceptance as an
analgetic and as a treatment of rheumatoid arthritis and osteoarthritis. Diflunisal is metabolized primarily to ether and
ester glucuronide conjugates.
Safety Profile
Poison by ingestion,
subcutaneous, and intraperitoneal routes.
Human systemic effects by ingestion: tolerance, and cholestatic jaundce (due to
the stoppage of the flow of bile),
agranulocytosis, increased body temperature.
An experimental teratogen. Other
experimental reproductive effects. An
analgesic and anti-inflammatory agent.
When heated to decomposition it emits
toxic fumes of F-. See also FLUORIDES.
Synthesis
Diflunisal, 2′,4′-difluoro-4-hydroxy-3-byphenylcarboxylic acid (3.2.5), is
synthesized from a diazonium salt, which is synthesized from 2,4-difluoroaniline and
isoamyl nitrite, and anisole in the presence of copper (I) salts by the classic scheme of
making diaryls. The resulting 4-(2,4-difluorophenyl)anisole (3.2.3) is demethylated by
hydrogen iodide into 4-(2,4-difluorophenyl)-phenol (3.2.4). This product is reacted with
carbon dioxide in the presence of a base according to the Kolbe–Schmitt phenol carboxylation method, giving diflunisal (3.2.5) [64–67].
Check Digit Verification of cas no
The CAS Registry Mumber 22494-42-4 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 2,2,4,9 and 4 respectively; the second part has 2 digits, 4 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 22494-42:
(7*2)+(6*2)+(5*4)+(4*9)+(3*4)+(2*4)+(1*2)=104
104 % 10 = 4
So 22494-42-4 is a valid CAS Registry Number.
InChI:InChI=1/C13H8F2O3/c14-10-3-1-8(6-11(10)15)7-2-4-12(16)9(5-7)13(17)18/h1-6,16H,(H,17,18)
22494-42-4Relevant articles and documents
Functionally substituted isoxazoles and isothiazoles: Synthesis, palladium(II) complexes and their catalytic activity
Bumagin,Zelenkovskii,Kletskov,Petkevich,Dikusar,Potkin
, p. 68 - 81 (2016)
Functionally substituted 5-(p-tolyl)isoxazoles and 4,5-dichloroisothiazoles, whose molecules contain azomethine, amino, carboxyl, and ester moieties in various combinations in the aromatic ring in the position 3 of heterocycle, were synthesized. Synthesis of complexes of Pd(II) with carboxyl derivative of 1,2-azoles was performed. They show high catalytic activity in the Suzuki reaction in aqueous media.
3,5-[5-Arylisoxazol-3-yl(4,5-dichloroisothiazol-3-yl)]-substituted 1,2,4- and 1,3,4-oxadiazoles: synthesis, palladium complexes, and catalysis of Suzuki reactions in aqueous media
Bumagin, Nikolay A.,Petkevich, Sergey K.,Kletskov, Alexey V.,Potkin, Vladimir I.
, p. 1340 - 1349 (2017)
[Figure not available: see fulltext.] A reaction sequence involving transformations of 5-(4-methylphenyl)isoxazole and 4,5-dichloroisothiazole derivatives containing an amidoxime group at position 3 allowed to synthesize the respective 3,5-isoxazolyl(isothiazolyl)-substituted 1,2,4-oxadiazoles. Selective recyclization of 4,5-dichloro-3-(1Н-tetrazol-5-yl)isothiazole and 5-(4-methylphenyl)-3-(1Н-tetrazol-5-yl)isoxazole gave 2,5-isoxazolyl-(isothiazolyl)-substituted 1,3,4-oxadiazoles. The obtained compounds combining three azole heterocycles in one molecule formed palladium complexes that showed high catalytic activity in Suzuki reactions in aqueous and aqueous alcohol media. The bimetallic reusable Pd/Fe catalyst obtained from palladium polyazole complex retained high catalytic activity after five uses.
Mimics of Pincer Ligands: An Accessible Phosphine-Free N-(Pyrimidin-2-yl)-1,2-azole-3-carboxamide Framework for Binuclear Pd(II) Complexes and High-Turnover Catalysis in Water
Bumagin, Nikolay A.,Dikusar, Evgenij A.,Ivashkevich, Ludmila S.,Kletskov, Alexey V.,Kolesnik, Iryna A.,Lyakhov, Alexander S.,Petkevich, Sergey K.,Potkin, Vladimir I.
supporting information, (2020/08/12)
We report for the first time cyclic phosphine-free "head to tail"N,N,N pincer-like (pincer complexes mimicking) N-(pyrimidin-2-yl)-1,2-azole-3-carboxamide Pd(II) complexes with deprotonated amide groups as high-turnover catalysts (TON up to 106, TOF up to 1.2 × 107 h-1) for cross-coupling reactions on the background of up to quantitative yields under Green Chemistry conditions. The potency of the described catalyst family representatives was demonstrated in Suzuki-Miyaura, Mizoroki-Heck, and Sonogashira reactions on industrially practical examples. Corresponding ligands could be synthesized based on readily available reagents through simple chemical transformations. Within the complex structures, a highly unusual 1,3,5,7-tetraza-2,6-dipalladocane frame could be observed.
Green synthesis of biphenyl carboxylic acids via Suzuki–Miyaura cross-coupling catalyzed by a water-soluble fullerene-supported PdCl2 nanocatalyst
Liu, Wanyun,Zhou, Xiuming,Huo, Ping,Li, Jingbo,Mei, Guangquan
, p. 50 - 52 (2019/06/21)
A green synthesis of variously substituted biphenyl carboxylic acids was achieved through Suzuki–Miyaura cross-coupling of a bromobenzoic acid with an aryl boronic acid using a water-soluble fullerene-supported PdCl2 nanocatalyst (C60-TEGs/ PdCl2). Yields of more than 90% were obtained at room temperature in 4 h using 0.05 mol% catalyst and 2 equiv. K2CO3.
