5104-49-4 Usage
Anti-inflammatory analgesics
Flibanserin , also known as flurbiprofen, flurbiprofen, is a potent Phenylalanine anti-inflammatory and antipyretic analgesics,it can inhibit prostaglandin synthesizing cyclooxygenase to have analgesic, anti-inflammatory and antipyretic effects. Its anti-inflammatory and analgesic effects are 250 times and 50 times of aspirin (also known as acetylsalicylic acid) . The oral absorption is rapid , peak plasma concentration achieves after 1.5 hours , half-life is 3.5 hours, it has wide tissue distribution, PPB is 99.4%, it can compete with drugs having a high plasma protein binding rate to bind plasma protein .it Metabolizes in the liver and becomes flurbiprofen hydroxy and its aldehyde acid conjugates. T1/2 is 3.5 h. Urine and fecal excretion,account for approximately 60% and 40% respectively . Age has no effect on drug metabolism. It is Mainly used for rheumatoid arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis. It is also used in preventing aphakic cystoid patchy edema After surgical removal of the lens, inhibiting pupillary constrictionsurgery, treatment of inflammation after cataract and trabeculoplasty argon laser eye surgery. It Also applies to pain caused by some other reasons such as trauma, sprains, surgery.
Toxicity
Non-steroidal anti-inflammatory drug (NSAID) has anti-inflammatory, analgesic and antipyretic effects, toxicity ascending ranking is nabumetone, salsalate, sulindac, diclofenac, ibuprofen, one fabric ibuprofen, aspirin, naproxen, tolmetin, flurbiprofen, piroxicam, a phenoxy ibuprofen, indomethacin, mefenamic acid chlorine. Traditional NSAID medications may be the preferred aspirin, if children in the course of treatment can not tolerate its adverse reactions, use of other non-steroidal anti-inflammatory drugs is taken. a selective COX-2 inhibitor Has been developed, which will replace all traditional NSAID. Selective COX-2 inhibitors which has been listed are nimesulide (Nimeng Shu), rofecoxib (Vioxx), celecoxib (Celebrex), etodolac (Rodin), meloxicam. A recent large-scale, international, multi-center, randomized, double-blind technology, prospective study has shown that selective COX-2 inhibitors have few side effects on the gastrointestinal tract, kidneys, having no significant effect on platelet function,it can be used as drug of choice for early combination therapy of JRA children replacing aspirin .
The above information is edited by the lookchem of Tian Ye.
Adverse reactions
The most common adverse reactions are indigestion, stomach discomfort, occasional headache, skin rash. Peptic ulcer, bronchial asthma patients and pregnant women, lactating women should not take.
Other adverse reactions are nausea, diarrhea, abdominal pain, blurred vision, urinary tract infection symptoms, dermatitis. Few have elevated liver transaminases, continuing medication, may develop, or remain unchanged or disappear. Mild tingling and burning sensations and (or) visual disturbances when it is dropped into the eye.because it leads to platelet aggregation and prolongs bleeding time, it is reported that the application of the drug in the eye surgery increases intraocular hemorrhage tendency.in Animal experiments, Flibanserin 50~100 mg/kg, medication for three months, can cause renal papillary necrosis. For Humans,it also has this effect.
Chemical Properties
Different sources of media describe the Chemical Properties of 5104-49-4 differently. You can refer to the following data:
1. White fine crystalline powder. Melting point 110111 ℃. Soluble in alcohol, ether, acetone, chlorine protection, chloroform and other organic solvents, almost insoluble in water, with a pungent odor.
2. White to Off-White Crystalline Solid
Uses
Different sources of media describe the Uses of 5104-49-4 differently. You can refer to the following data:
1. This product is anti-inflammatory drug for chronic arthritis and pain, inflammation of Deformation joint disease , and pain after surgery and tooth extraction. Mouse oral LD50 of 140mg/kg, rats 640-800mg/kg.
2. A cyclooxygenase inhibitor
3. An anti-inflammatory used as an analgesic.
4. antiinflammatory, analgesic
production method
It is obtained by 2-fluoro-linked acetophenone through oxidation, esterification, transesterification, hydrolysis, decarboxylation reaction.
Description
Flurbiprofen synthesis was originally reported in 1974. During a study of the pharmacological
properties of a large number of substituted phenylalkanoic acids, including ibuprofen and ibufenac, the most potent
were found to be substituted 2-(4-biphenyl)propionic acids. Further toxicological and pharmacological studies
indicated that flurbiprofen possessed the most favorable therapeutic profile, so it was selected for further clinical
development. It was not marketed until 1987, when it was introduced as the sodium salt as Ocufen, the first topical
NSAID indicated for ophthalmic use in the United States. The indication for Ocufen is the same as that for
Profenal—that is, to inhibit intraoperative miosis induced by prostaglandins in cataract surgery.
Originator
Froben, Boots,UK ,1977
Indications
Flurbiprofen (Ansaid) is indicated for the treatment
of rheumatoid arthritis and osteoarthritis. Its half-life,
longer than that of many of the NSAIDs, allows for
twice daily dosing.The most common adverse effects of
flurbiprofen are similar to those of the other acidic
NSAIDs. Flurbiprofen inhibits both COX isoforms
about equally.
Manufacturing Process
A mixture of 3-acetyl-2-fluorobiphenyl, MP 95°C to 96°C, (73.5 g) [prepared from 4.bromo-3-nitroacetophenone (Oelschlage, Ann., 1961, 641, 81) via-4acetyl-2-nitrobiphenyl, MP 106°C to 108°C (Ullman reaction), 4-acetyl-2aminobiphenyl, MP 124°C to 125°C (reduction), and finally the Schiemann reaction], sulfur (17.4 g) and morpholine (87 ml) was refluxed for 16.5 hr, and then the resulting thiomorpholide was hydrolyzed by refluxing with glacial acetic acid (340 ml) concentrated sulfuric acid (54 ml) and water (78 ml) for 24 hr. The cooled solution was diluted with water, and the precipitated crude 2-fluoro-4-biphenylylacetic acid was collected. (A sample was purified by recrystallization to give MP 143°C to 144.5°C; Found (%): C, 73.2; H, 4.8. C14H11FO2 requires C, 73.1; H, 4.8.)A sodium carbonate solution of the crude acetic acid was washed with ether and then acidified with hydrochloric acid; the required acid was isolated via an ether extraction and was esterified by refluxing for 6 hr with ethanol (370 ml) and concentrated sulfuric acid (15 ml). Excess alcohol was distilled, the residue diluted with water and the required ester isolated in ether. Distillation finally gave ethyl 2-fluoro-4-biphenylacetate, BP 134°C to 136°C/0.25 mm.This ester (70g) and diethyl carbonate (250 mg) were stirred at 90°C to 100°C while a solution of sodium ethoxide [from sodium (7.8 g) and ethanol (154 ml)] was added over 1 hr. During addition, ethanol was allowed to distill and after addition distillation was continued until the column heat temperature reached 124°C. After cooling the solution to 90°C, dimethyl sulfate (33 ml) was followed by a further 85 ml of diethyl carbonate. This solution was stirred and refluxed for 1 hr and then, when ice cool, was diluted with water and acetic acid (10 ml). The malonate was isolated in ether and fractionally distilled to yield a fraction boiling at 148°C to 153°C/0.075 mm, identified as the alpha-methyl malonate. This was hydrolyzed by refluxing for 1 hr at 2.5 N sodium hydroxide (350 ml) and alcohol (175 ml), excess alcohol was distilled and the residual suspension of sodium salt was acidified with hydrochloric acidto give a precipitate of the alpha-methyl malonic acid. This was decarboxylated by heating at 180°C to 200°C for 30 minutes and recrystallized from petroleum ether (BP 80°C to 100°C) to give 2-(2-fluoro-4biphenylyl)propionic acid, MP 110°C to 111°C
Brand name
Ansaid (Pharmacia & Upjohn).
Therapeutic Function
Antiinflammatory
General Description
Flurbiprofen (Ansaid, Ocufen, Froben), is another drug inthis class indicated for both acute and long-term managementof RA and OA but with a more complex mechanism ofaction. Unlike the other drugs in this class, it does not undergochiral inversion (i.e., the conversion of the “inactive”[R]-enantiomer to the active, [S]-enantiomer). Similar to aspirinand other salicylates, both flurbiprofen enantiomersblock COX-2 induction as well as inhibiting the nuclearfactor-κB-mediated polymorphonuclear leukocyte apoptosissignaling; therefore, both enantiomers are believed to contributeequally to its overall anti-inflammatory action.(R)-flurbiprofen is actually a strong clinical candidate forthe treatment of Alzheimer disease, because it has beenshown to reduce Aβ42 production by human cells.
Biological Activity
Potent inhibitor of cyclooxygenase (IC 50 values are 0.1 and 0.4 μ M for inhibition of human COX-1 and COX-2 respectively). Analgesic, anti-inflammatory and antipyretic in vivo . Inhibits tumor cell growth in vitro and in vivo . Also inhibits fibroblast proliferation in vitro .
Pharmacokinetics
Flurbiprofen is well absorbed after oral administration, with peak plasma levels being attained within 1.5 hours. Food
alters the rate of absorption but not the extent of its bioavailability. It is extensively bound to plasma proteins (99%).and has a plasma half-life of 2 to 4 hours. Metabolism is extensive, with 60 to 70% of flurbiprofen and its metabolites
being excreted as sulfate and glucuronide conjugates. Flurbiprofen shows some interesting metabolic patterns, with
40 to 47% as the 4′-hydroxy metabolite, 5% as the 3′,4′-dihydroxy metabolite, 20 to 30% as the 3′-hydroxy-
4′-methoxy metabolite, and the remaining 20 to 25% of the drug being excreted unchanged. None of these
metabolites demonstrates significant anti-inflammatory activity.
Clinical Use
Flurbiprofen is indicated as an oral formulation for the acute or long-term treatment of rheumatoid arthritis and
osteoarthritis and as an ophthalmic solution for the inhibition of intraoperative miosis.
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 with other
NSAIDs or aspirin; avoid concomitant use with
ketorolac (increased 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 heparin, dabigatran and edoxaban -
avoid long term use with edoxaban.
Antidepressants: increased risk of bleeding with
SSRIs or venlafaxine.
Antidiabetics: effects of sulphonylureas enhanced.
Antiepileptics: possibly enhanced effect of phenytoin.
Antivirals: concentration possibly increased by
ritonavir; increased risk of haematological toxicity
with zidovudine.
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 reduced (risk of lithium toxicity).
Pentoxifylline: increased risk of bleeding.
Tacrolimus: increased risk of nephrotoxicity
Metabolism
Flurbiprofen is metabolised mainly by hydroxylation (via the
cytochrome P450 isoenzyme CYP2C9) and conjugation
in the liver and excreted in the urine. The rate of urinary
excretion of flurbiprofen and its two major metabolites
([2-(2-fluoro-4′-hydroxy-4-biphenylyl) propionic acid] and
[2-(2-fluoro-3′-hydroxy-4′-methoxy-4-biphenylyl) propionic
acid]) in both free and conjugated states is similar for both
the oral and rectal routes of administration.
Check Digit Verification of cas no
The CAS Registry Mumber 5104-49-4 includes 7 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 4 digits, 5,1,0 and 4 respectively; the second part has 2 digits, 4 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 5104-49:
(6*5)+(5*1)+(4*0)+(3*4)+(2*4)+(1*9)=64
64 % 10 = 4
So 5104-49-4 is a valid CAS Registry Number.
InChI:InChI=1/C12H4F14/c13-7(9(15,16)17,10(18,19)20)5-1-2-6(4-3-5)8(14,11(21,22)23)12(24,25)26/h1-4H
5104-49-4Relevant articles and documents
Biotransformation with whole microbial systems in a continuous flow reactor: Resolution of (RS)-flurbiprofen using Aspergillus oryzae by direct esterification with ethanol in organic solvent
Tamborini, Lucia,Romano, Diego,Pinto, Andrea,Contente, Martina,Iannuzzi, Maria C.,Conti, Paola,Molinari, Francesco
, p. 6090 - 6093 (2013)
Cell-bound lipases of dry mycelium of Aspergillus oryzae were used in organic solvent for the resolution of racemic flurbiprofen by direct esterification with ethanol in a flow-chemistry reactor. Under flow conditions a significant reduction of the reaction time and an increase of the enantioselectivity were achieved compared to the batch mode. Moreover, the process was implemented by adding an in-line purification step integrated with the racemization of the unreacted flurbiprofen directly into a polymer-supported resin.
Method for determination of optical purity of 2-arylpropanoic acids using urea derivatives based on a 1,1′-binaphthalene skeleton as chiral NMR solvating agents: Advantages and limitations thereof
Cu?ínová, Petra,Hájek, Peter,Jank?, Kristyna,Holakovsky, Roman
, p. 410 - 417 (2019)
Five optically active urea derivatives (1-5) were used as NMR solvating agents for analysis of the optical purity of different 2-arylpropanoic acids commonly used as nonsteroidal anti-inflammatory drugs. These novel chiral solvating agents were more efficient at discriminating the respective enantiomers of targets than the chiral solvating agents known so far, without the need to add a base for achieving the signal splitting. The advantages and limits of the use of these novel chiral solvating agents were studied.
Direct enantioselective HPLC monitoring of lipase-catalyzed kinetic resolution of flurbiprofen
Ghanem, Ashraf
, p. 597 - 603 (2010)
The solvent versatility of Chiralpak IB, a 3,5-dimethylphenylcarbamate derivative of cellulose-based chiral stationary phase, is demonstrated in the direct enantioselective HPLC monitoring of lipase-catalyzed kinetic resolution of flurbiprofen in nonstandard HPLC organic solvents. Nonstandard HPLC organic solvents were used as the reaction media for the lipase-catalysis and in mean time as diluent to dissolve the difficult to dissolve enzyme substrate (the acid) and as eluent for the simultaneous enantioselective HPLC baseline separation of both substrate and product in one run without any further derivatization.
A Highly Enantioselective Alkene Methoxycarbonylation Enables a Concise Synthesis of (S)-Flurbiprofen
Harkness, Gavin J.,Clarke, Matthew L.
, p. 4859 - 4863 (2017)
A highly enantioselective synthesis of (S)-flurbiprofen methyl ester in two steps from commercially available 4-bromo-2-fluoro-1,1′-biphenyl is shown. [PdCl2((S)-xylyl-phanephos)] catalyst is used to accomplish both Grignard cross-coupling and the highly enantioselective intermolecular methoxycarbonylation reaction.
Different in vitro activity of flurbiprofen and its enantiomers on human articular cartilage
Panico,Cardile,Vittorio,Ronsisvalle,Scoto,Parenti,Gentile,Morrone,Nicolosi
, p. 1339 - 1344 (2003)
The 2-arylpropionic acid derivatives or 'profens' are an important group of non-steroidal anti-inflammatory drugs that have been used for the symptomatic treatment of various forms of arthritis. These compounds are chiral and the majority of them are stil
An efficient method for the synthesis of (S)-flurbiprofen by 1,2-rearrangement of the aryl group
Chen, Hua,Dai, Yuhao,Liu, Yu,Luo, Kaihong,Zhang, Yi
, (2022/03/15)
(S)-Flurbiprofen (1) is a nonsteroidal anti-inflammatory drug (NSAID) used to relieve pain and inflammation associated with osteoarthritis. Herein a new and practical method for the preparation of 1 from 4-bromo-2-fluorobiphenyl (2) is reported, which achieves a good overall yield (20%) and high enantioselectivity (96%). This method avoids the use of expensive catalysts and affords the possibility of large-scale manufacturing with simple operations.
Deracemization through photochemical E/Z isomerization of enamines
Huang, Mouxin,Luo, Sanzhong,Pan, Tianrun,Zhang, Long
, p. 869 - 874 (2022/03/07)
Catalytic deracemization of a-branched aldehydes is a direct strategy to construct enantiopure a-tertiary carbonyls, which are essential to pharmaceutical applications. Here, we report a photochemical E/Z isomerization strategy for the deracemization of a-branched aldehydes by using simple aminocatalysts and readily available photosensitizers. A variety of racemic a-branched aldehydes could be directly transformed into either enantiomer with high selectivity. Rapid photodynamic E/Z isomerization and highly stereospecific iminium/enamine tautomerization are two key factors that underlie the enantioenrichment. This study presents a distinctive photochemical E/Z isomerization strategy for externally tuning enamine catalysis.
Reshaping the active pocket of esterase Est816 for resolution of economically important racemates
Fan, Xinjiong,Fu, Yao,Liu, Xiaolong,Zhao, Meng
, p. 6126 - 6133 (2021/09/28)
Bacterial esterases are potential biocatalysts for the production of optically pure compounds. However, the substrate promiscuity and chiral selectivity of esterases usually have a negative correlation, which limits their commercial value. Herein, an efficient and versatile esterase (Est816) was identified as a promising catalyst for the hydrolysis of a wide range of economically important substrates with low enantioselectivity. We rationally designed several variants with up to 11-fold increased catalytic efficiency towards ethyl 2-arylpropionates, mostly retaining the initial substrate scope and enantioselectivity. These variants provided a dramatic increase in efficiency for biocatalytic applications. Based on the best variant Est816-M1, several variants with higher or inverted enantioselectivity were designed through careful analysis of the structural information and molecular docking. Two stereoselectively complementary mutants, Est816-M3 and Est816-M4, successfully overcame and even reversed the low enantioselectivity, and several 2-arylpropionic acid derivatives with highEvalues were obtained. Our results offer potential industrial biocatalysts for the preparation of structurally diverse chiral carboxylic acids and further lay the foundation for improving the catalytic efficiency and enantioselectivity of esterases.
