22494-42-4

Basic information

• Product Name: Diflunisal
• Synonyms: DIFLUSINAL;LABOTEST-BB LT00771921;2',4'-DIFLUORO-4-HYDROXY[1,1'-BIPHENYL]-3-CARBOXYLIC ACID;2',4'-DIFLUORO-4-HYDROXY-BIPHENYL-3-CARBOXYLIC ACID;5-[2,4-DIFLUOROPHENYL]SALICYLIC ACID;[1,1'-Biphenyl]-3-carboxylic acid, 2',4'-difluoro-4-hydroxy-;1’-biphenyl)-3-carboxylicacid,2’,4’-difluoro-4-hydroxy-(;1’-biphenyl]-3-carboxylicacid,2’,4’-difluoro-4-hydroxy-[
• CAS NO: 22494-42-4
• Molecular Formula: C₁₃H₈F₂O₃
• Molecular Weight: 250.2
• EINECS: 245-034-9
• Product Categories: Fluorobenzene;Aromatics;Fluorescent Labels & Indicators;Intermediates & Fine Chemicals;Pharmaceuticals;DOLOBID
• Mol File: 22494-42-4.mol

Chemical Properties

• Melting Point: 207-209?C
• Boiling Point: 386.9 °C at 760 mmHg
• Flash Point: 187.8 °C
• Appearance: White solid
• Density: 1.3505 (estimate)
• Vapor Pressure: 2.75E-07mmHg at 25°C
• Refractive Index: 1.601
• Storage Temp.: Refrigerator
• Solubility: Practically insoluble in water, soluble in ethanol (96 per cent). It dissolves in dilute solutions of alkali hydroxides.
• PKA: pKa 3.3 (H2O I=0.1) (Uncertain)
• Water Solubility: 6.186mg/L(24.99 oC)
• CAS DataBase Reference: Diflunisal(CAS DataBase Reference)
• NIST Chemistry Reference: Diflunisal(22494-42-4)
• EPA Substance Registry System: Diflunisal(22494-42-4)

Safety Data

• Hazard Codes: Xn,Xi
• Statements: 22-36/37/38-63
• Safety Statements: 22-26-36
• WGK Germany: 3
• RTECS: DV2030000
• Hazardous Substances Data: 22494-42-4(Hazardous Substances Data)

Usage

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.

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].

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)

Upstream product

• 124-38-9 carbon dioxide 
• 367-25-9 2,4-difluorophenylamine 
• 100-66-3 methoxybenzene 
• 71-43-2 benzene 
• 89-55-4 5-bromosalicyclic acid 
• 144025-03-6 2,4-difluorophenylboronic acid 
• 497-19-8 sodium carbonate 
• 2263-65-2 3-carboxy-4-hydroxybenzenediazonium tetrafluoroborate 
• 55544-00-8 methyl 2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylate 
• 529-28-2 4-iodoanisol 
• 148854-10-8 (2,4-difluorophenyl)trimethylsilane 
• 119-30-2 2-hydroxy-5-iodobenzoic acid 
• 40757-09-3 methyl 2-methoxy-5-iodobenzoate 
• 866625-02-7 5-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzoic acid methyl ester 

Downstream Products

• 58446-30-3 Diflunisal acyl glucuronide 
• 22510-33-4 2-hydroxy-5-(4'-fluorophenyl)benzoic acid 
• 662157-81-5 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid hydrazide 
• 662157-83-7 2',4'-Difluoro-4-hydroxy-biphenyl-3-carboxylic acid [1-phenyl-meth-(E)-ylidene]-hydrazide 
• 662157-89-3 2',4'-Difluoro-4-hydroxy-biphenyl-3-carboxylic acid [1-(4-fluoro-phenyl)-meth-(E)-ylidene]-hydrazide 
• 662157-87-1 2',4'-Difluoro-4-hydroxy-biphenyl-3-carboxylic acid [1-(2-fluoro-phenyl)-meth-(E)-ylidene]-hydrazide 
• 662157-88-2 2',4'-Difluoro-4-hydroxy-biphenyl-3-carboxylic acid [1-(3-fluoro-phenyl)-meth-(E)-ylidene]-hydrazide 
• 662157-85-9 2',4'-Difluoro-4-hydroxy-biphenyl-3-carboxylic acid [1-(4-chloro-phenyl)-meth-(E)-ylidene]-hydrazide 
• 662157-92-8 2',4'-Difluoro-4-hydroxy-biphenyl-3-carboxylic acid [1-p-tolyl-meth-(E)-ylidene]-hydrazide 

Relevant articles and documents

Functionally substituted isoxazoles and isothiazoles: Synthesis, palladium(II) complexes and their catalytic activity

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.

Electron-Poor, Fluoro-Containing Arylboronic Acids as Efficient Coupling Partners for Bis(1,5-cyclooctadiene)nickel(0)/Tricyclohexylphosphine-Catalyzed Cross-Coupling Reactions of Aryl Arenesulfonates

The use of electron-poor, fluoro-containing arylboronic acids as general coupling partners for nickel(0)/tricyclohexylphosphine-catalyzed cross-coupling of aryl arenesulfonates is described. Electron-poor fluoro-containing arylboronic acids were found to react faster than electron-rich/neutral arylboronic acids, with (4-methoxyphenyl)(4-methylbenzenesulfonato-κO)bis(tricyclohexylphosphine)nickel. Bis(1,5-cyclooctadiene)nickel(0)/tricyclohexylphosphine, (4-methoxyphenyl)(4-methylbenzenesulfonato-κO)bis(tricyclohexylphosphine)nickel and bis(tricyclohexylphosphine)nickel(II) bromide were all found to be efficient catalysts/catalyst precursors. (Figure presented.) .

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

[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.

Nickel- and Palladium-Catalyzed Cross-Coupling of Stibines with Organic Halides: Site-Selective Sequential Reactions with Polyhalogenated Arenes

Herein, we disclose a general and efficient method for the synthesis of Sb-aryl and Sb-alkyl stibines by the nickel-catalyzed cross-coupling of halostibines with organic halides. The synthesized Sb-aryl stibines couple with aryl halides to give biaryls efficiently via palladium catalysis. Sequential reactions of stibines with polyhalogenated arenes bearing active C–I/C–Br sites and inactive C–Cl sites successfully proceeded, resulting in the formation of a variety of complex molecules with good site selectivity. Drugs such as diflunisal and fenbufen, as well as a fenofibrate derivative, were synthesized on gram scales in good yields, together with the high recovery of chlorostibine. Furthermore, catalytic mechanisms are proposed based on the results of control experiments.

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

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

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.

Iron-Catalyzed Room Temperature Cross-Couplings of Bromophenols with Aryl Grignard Reagents

Herein we report a room temperature Fe-catalyzed coupling reaction of various bromophenols with aryl Grignard reagents, which exhibits a wide substrate scope and high functional group tolerance. For the first time, the combination of simple Fe(acac)3/PBu3/Ti(OEt)4 has been used as an effective catalyst for the biaryl couplings of bromophenols or their Na or K salts with debromination and etherification side reactions being well suppressed. Various biphenols including natural product garcibiphenyl C as well as pharmaceutical diflunisal and its ethyl ester were facilely synthesized using the present protocol. (Figure presented.).

Method for synthetizing diflunisal and derivative thereof through one-step method

The invention discloses a method for synthetizing diflunisal and a derivative thereof through a one-step method. The method comprises the steps: under joint catalysis of an iron salt, a ligand and titanate, 2,4-difluorophenylmagnesium halide and 5-halogenated salicylic acid or a 5-halogenated salicylic acid derivative are mixed, heated and coupled in a solvent, and the diflunisal and the derivative thereof are obtained. The method has the advantages that (1) high-priced palladium or high-toxicity nickel does not need to be adopted as catalytic metal, only low-toxicity, high-yield and inexpensive iron salts and titanate need to be used, thus the cost is low, and environmental friendliness is achieved; (2) a zinc salt does not need to be used, or step preparation of a boron reagent is not needed, a Grignard reagent is directly used, the preparation steps are few, and raw material and energy consumption is low; and (3) operation is easy and convenient, conditions are mild, amplification is easy, and the method is suitable for industrial production.

Diflunisal-adjoined cobalt(iii)-polypyridyl complexes as anti-cancer stem cell agents

We report a novel series of cobalt(iii)-polypridyl complexes, 4-6, that can selectively release diflunisal, a nonsteroidal anti-inflammatory drug, under reducing conditions. Remarkably, the 1,10-phenanthroline-bearing complex 5 displays selective potency towards hard-to-kill cancer stem cells (CSCs) (IC50 = 2.1 ± 0.1 μM) over bulk cancer (IC50 = 3.9 ± 0.2 μM) and normal cells (IC50 = 21.2 ± 1.3 μM). This complex induces CSC apoptosis by DNA damage and cyclooxygenase-2 inhibition.

Oxidative [3+3] Annulation of Atropaldehyde Acetals with 1,3-Bisnucleophiles: An Efficient Method of Constructing Six-Membered Aromatic Rings, Including Salicylates and Carbazoles

An oxidative [3+3] annulation of atropaldehyde acetals with various 1,3-bisnucleophiles was developed using either N-bromosuccinimide or copper(II) bromide as oxidizing reagent and Br?nsted or Lewis acids as catalyst. The [3+3] annulations can be considered mechanistically as oxidizing reagent-induced acid-acid-catalyzed domino reactions established through the concept of auto-tandem catalysis. Alkyl acetoacetates, α-(indol-2-yl)acetate, anilines, 1-methyl-1H-pyrazol-3-amine, ethyl 5-amino-1H-pyrazole-3-carboxylate, and 3-amino-1H-indazole can all be used as 1,3-bisnucleophiles in this type of transformation. The established reactions can very efficiently construct six-membered aromatic rings, including salicylates and carbazoles. A four-step method of synthesizing the anti-inflammatory agent diflunisal was also developed based on the oxidative [3+3] annulation reaction, and the yield was high. (Figure presented.).