31879-05-7

Usage

Uses

Used in Pharmaceutical Industry:
Fenoprofen is used as an anti-inflammatory agent for the management of mild to moderate pain and inflammation associated with disorders such as arthritis. It is pharmacologically similar to aspirin but causes less gastrointestinal bleeding.
Used in Rheumatology:
Fenoprofen is used as a treatment for the symptoms of rheumatoid arthritis (RA) and osteoarthritis (OA). It is recommended for RA and OA at an oral dose of 300 to 600 mg for 3 or 4 times per day, but not exceeding 3 g/d to avoid any serious side effects.
However, it is important to note that fenoprofen exhibits a number of undesirable side effects and has been most closely associated with a rare acute interstitial nephritis in a comparison study of all NSAIDs.
For mild to moderate pain relief, the recommended dosage is 200 mg given every 4 to 6 hours, as needed.
Brand Names:
Fenoprofen is available under the brand names Nalfon (Dista) and Nalfon (Pedinol).

Used in Particular Diseases

Acute Gouty Arthritis: Dosage and Frequency:?300–600 mg three to four times daily

Originator

Fenopron,Dista,UK,1974

Indications

Fenoprofen (Nalfon) is chemically and pharmacologically similar to ibuprofen and is used in the treatment of rheumatoid arthritis, osteoarthritis, and mild to moderate pain. GI effects such as dyspepsia and pain are most common, although dizziness, pruritus, and palpitations may occur. GI bleeding, sometimes severe, has been reported, and interstitial nephritis has been rarely associated with this drug. Concomitant administration of aspirin decreases the biological half-life of fenoprofen by increasing the metabolic clearance of hydroxylated fenoprofen. Chronic administration of phenobarbital also decreases the drug’s half-life.

Manufacturing Process

3-Phenoxyacetophenone: A mixture consisting of 908 grams (6.68 mols) of m-hydroxyacetophenone, 4,500 grams (28.6 mols) of bromobenzene, 996 grams (7.2 mols) of anhydrous potassium carbonate, and 300 grams of copper bronze was heated under reflux with stirring until water evolution was complete, using a Dean-Stark water separator. The mixture was then stirred and refluxed for 24 hours. After cooling to room temperature, the reaction was diluted with an equal volume of CHCl3 and filtered. The filtrate was washed with 5% HCl, then with 5% NaOH, with water, dried over Na2SO4 and evaporated in vacuo. The residual oil was distilled through a 15 cm Vigreux column, yielding 918 grams of 3-phenoxy-acetophenone, BP 120° to 121°C (0.09 mm).α-Methyl-3-Phenoxybenzyl Alcohol: A stirred solution of 700 grams of mphenoxyacetophenone in 3,000 ml anhydrous methanol was cooled to 0°C in an ice-acetone bath. Sodium borohydride, 136 grams (3.6 mols) was added to this solution in small portions at such a rate that the temperature never rose above 10°C. After borohydride addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 18 hours. It was then stirred and refluxed for 8 hours. About 400 ml of methanol was distilled out and the remaining solution was evaporated to about one-third its original volume in vacuo and poured into ice water. This mixture was extracted twice with ether, acidified with 6 N HCl, and again extracted with ether. The ether extracts were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residual oil was distilled through a 15 cm Vigreux column, yielding 666 grams of α-methyl-3- phenoxybenzyl alcohol, BP 132° to 134°C (0.35 mm), nD 25 = 1.5809.α-Methyl-3-Phenoxybenzyl Bromide: A stirred solution of 1,357 grams of α- methyl-3-phenoxybenzyl alcohol in 5,000 ml anhydrous CCl4 (predriedover molecular sieve) was cooled to 0°C. To this was added 1,760 grams PBr3,stirring and cooling being maintained at such a rate that the temperature remained at 0° to 5°C, during the addition. The reaction mixture was then allowed to warm to room temperature and was stirred at room temperature overnight (ca 12 hours). The reaction mixture was then poured into ice water and the organic phase separated. The aqueous phase was extracted with CCl4 and the combined extracts were washed three times with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to yield 1,702 grams of α-methyl-3-phenoxybenzyl bromide as a heavy viscous oil, nD 25=1.5993.2-(3-Phenoxyphenyl)Propionitrile: A well-stirred suspension of 316 grams of 98% sodium cyanide in 5,000 ml of anhydrous dimethyl sulfoxide (previously dried over molecular sieve) was warmed to 55° to 60°C and maintained at this temperature while 1,702 grams of α-methyl-3-phenoxybenzyl bromide was slowly added. After the bromide addition was completed, the temperature was raised to 75°C and the mixture stirred at this temperature for 1.5 hours. The mixture was then allowed to cool to room temperature and was stirred overnight at room temperature and then poured into ice water. The resulting aqueous suspension was extracted twice with ethyl acetate, and then with ether. The organic extract was washed twice with a sodium chloride solution, once with water, and dried over anhydrous sodium sulfate. Evaporation of the solvent in vacuo left an oily residue which was distilled through a 15 cm Vigreux column to yield 1,136 grams of 2-(3-phenoxyphenyl)propionitrile, BP 141° to 148°C (0.1 mm), nD 25 = 1.5678.2-(3-Phenoxyphenyl)Propionic Acid: A mixture of 223 grams of 2-(3- phenoxyphenyl)propionitrile and 400 grams of sodium hydroxide in 1,600 ml of 50% ethanol was refluxed with stirring for 72 hours. After cooling to room temperature, the reaction mixture was poured into ice water. The resulting solution was washed with ether, acidifed with concentrated HCl, and extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo. The residual oil was distilled to yield 203.5 grams (84%) of 2-(3-phenoxyphenyl)propionic acid as a viscous oil; BP 168° to 171°C (0.11 mm), nD 25 = 1.5742.

Therapeutic Function

Antiinflammatory

Clinical Use

Clinical use NSAID and analgesic

Synthesis

Fenoprofen, 2-(3-phenoxyphenyl)propionic acid (3.2.32), is synthesized from 3-hydroxyacetophenone, which is esterfied by bromobenzene in the presence of potassium carbonate and copper filings, forming 3-phenoxyacetophenone (3.2.28). The carbonyl group of the resulting product is reduced by sodium borohydride and the resulting alcohol (3.2.29) is brominated by phosphorous tribromide. The reaction of the resulting bromo derivative (3.2.20) with sodium cyanide gives 2-(3-phenoxyphenyl)propionitrile (3.2.31), which is hydrolyzed into the desired fenoprofen (3.2.32) [102,103].

Drug interactions

Potentially hazardous interactions with other drugs ACE inhibitors and angiotensin-II antagonists: increased risk of hyperkalaemia and nephrotoxicity; reduced hypotensive effect. 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. Pentoxifylline: increased risk of bleeding. Tacrolimus: increased risk of nephrotoxicity

Metabolism

Molecular weight (daltons) 558.6 (as calcium salt) % Protein binding >99 % Excreted unchanged in urine 2-5 Volume of distribution (L/kg) 0.10 Half-life - normal/ESRF (hrs) 3 / Unchanged

InChI:InChI=1/2C15H14O3.Ca/c2*1-11(15(16)17)12-6-5-9-14(10-12)18-13-7-3-2-4-8-13;/h2*2-11H,1H3,(H,16,17);/q;;-1/p-2

Upstream product

• 124-38-9 carbon dioxide 
• 80379-89-1 1-(m-phenoxyphenyl)-1-chloroethane 
• 66202-87-7 methyl 2-(3-phenoxybenzene)propionate 
• 31469-22-4 1,1-bis(trimethylsilyloxy)prop-1-ene 
• 64782-40-7 α-methylthio-α-(m-phenoxyphenyl)propionic acid 
• 7440-66-6 zinc 
• 32929-75-2 2-(3-phenoxy-phenyl)-propan-1-ol 
• 78427-95-9 1-ethyl-3-phenoxybenzene 
• 591-50-4 iodobenzene 
• 620-17-7 3-ethylphenol 
• 243861-00-9 (1S,2R,3S)-1,2-Dihydroxy-3-(3-phenoxyphenyl)-1-phenylbutane 
• 29679-58-1 Fenoprofen 
• 62784-66-1 bis(1-naphthyl)methanol 
• 1226783-62-5 (2S)-2-(3-phenoxy-phenyl)-propan-1-ol 

Downstream Products

• 32853-04-6 N-methyl-2-(3-phenoxyphenyl)propionamide 
• 32853-02-4 N-cyclopropylmethyl-2-(3-phenoxyphenyl)propionamide 
• 33028-97-6 (S)-fenoprofen 
• 31879-05-7 (R)-fenoprofen 
• 37785-47-0 (S)-2-(4-Hydroxy-3-phenoxy-phenyl)-propionic acid 
• 37785-47-0 (R)-2-(4-Hydroxy-3-phenoxy-phenyl)-propionic acid 
• 32949-85-2 Acetic acid 2-(3-phenoxy-phenyl)-propyl ester 
• 32929-78-5 2-(3-Phenoxyphenyl)propyl propionate 
• 32949-84-1 Methyl-carbamic acid 2-(3-phenoxy-phenyl)-propyl ester 
• 32853-01-3 Dimethyl-[2-(3-phenoxy-phenyl)-propyl]-amine 
• 1252576-27-4 (R)-fenoprofen di(9-phenanthryl)methyl ester 
• 32853-00-2 N,n-dimethyl-2-(3-phenoxyphenyl)propionamide 

Relevant academic research and scientific papers

Deracemization through photochemical E/Z isomerization of enamines

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

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.

Visible-light photoredox-catalyzed selective carboxylation of C(sp3)?F bonds with CO2

It is highly attractive and challenging to utilize carbon dioxide (CO2), because of its inertness, as a nontoxic and sustainable C1 source in the synthesis of valuable compounds. Here, we report a novel selective carboxylation of C(sp3)?F bonds with CO2 via visible-light photoredox catalysis. A variety of mono-, di-, and trifluoroalkylarenes as well as α,α-difluorocarboxylic esters and amides undergo such reactions to give important aryl acetic acids and α-fluorocarboxylic acids, including several drugs and analogs, under mild conditions. Notably, mechanistic studies and DFT calculations demonstrate the dual role of CO2 as an electron carrier and electrophile during this transformation. The fluorinated substrates would undergo single-electron reduction by electron-rich CO2 radical anions, which are generated in situ from CO2 via sequential hydride-transfer reduction and hydrogen-atom-transfer processes. We anticipate our finding to be a starting point for more challenging CO2 utilization with inert substrates, including lignin and other biomass.

Palladium-Catalyzed Asymmetric Markovnikov Hydroxycarbonylation and Hydroalkoxycarbonylation of Vinyl Arenes: Synthesis of 2-Arylpropanoic Acids

Asymmetric hydroxycarbonylation is one of the most fundamental yet challenging methods for the synthesis of carboxylic acids. Herein, we reported the development of a palladium-catalyzed highly enantioselective Markovnikov hydroxycarbonylation of vinyl arenes with CO and water. A monodentate phosphoramidite ligand L6 plays vital role in the reaction. The reaction tolerates a range of functional groups, and provides a facile and atom-economical approach to an array of 2-arylpropanoic acids including several commonly used non-steroidal anti-inflammatory drugs. The catalytic system has also enabled an asymmetric Markovnikov hydroalkoxycarbonylation of vinyl arenes with alcohols to afford 2-arylpropanates. Mechanistic investigations suggested that the hydropalladation is irreversible and is the regio- and enantiodetermining step, while hydrolysis/alcoholysis is probably the rate-limiting step.

Exploration of New Biomass-Derived Solvents: Application to Carboxylation Reactions

A range of hitherto unexplored biomass-derived chemicals have been evaluated as new sustainable solvents for a large variety of CO2-based carboxylation reactions. Known biomass-derived solvents (biosolvents) are also included in the study and the results are compared with commonly used solvents for the reactions. Biosolvents can be efficiently applied in a variety of carboxylation reactions, such as Cu-catalyzed carboxylation of organoboranes and organoboronates, metal-catalyzed hydrocarboxylation, borocarboxylation, and other related reactions. For many of these reactions, the use of biosolvents provides comparable or better yields than the commonly used solvents. The best biosolvents identified are the so far unexplored candidates isosorbide dimethyl ether, acetaldehyde diethyl acetal, rose oxide, and eucalyptol, alongside the known biosolvent 2-methyltetrahydrofuran. This strategy was used for the synthesis of the commercial drugs Fenoprofen and Flurbiprofen.

Alpha-alkylphenylacetic acid compound with high optical activity as well as preparation method and application thereof

The invention discloses an alpha-alkylphenylacetic acid compound with high optical activity as well as a preparation method and application of the alpha-alkylphenylacetic acid compound. The preparation method comprises the following steps: mixing an aryl alkyl substituted malonic acid monoester substrate and a sulfonamide organic catalyst derived from chiral cyclohexylenediamine according to a molar ratio of 1: (0.01-0.30) in an organic solvent, and reacting for 2-48 hours at the temperature of 20-50 DEG C to obtain the alpha-alkylphenylacetic acid compound. The alpha-alkylphenylacetic acid compound can be used for preparing non-steroidal anti-inflammatory drugs, analgesics and central nervous excitants. The preparation method has the advantages of simple operation, mild conditions, almostno by-product, easily available catalyst and high enantioselectivity, and the reaction product can be used for synthesizing medical intermediates with important biological activity through simple conversion.

Deracemizing α-Branched Carboxylic Acids by Catalytic Asymmetric Protonation of Bis-Silyl Ketene Acetals with Water or Methanol

We report a highly enantioselective catalytic protonation of bis-silyl ketene acetals. Our method delivers α-branched carboxylic acids, including nonsteroidal anti-inflammatory arylpropionic acids such as Ibuprofen, in high enantiomeric purity and high yields. The process can be incorporated in an overall deracemization of α-branched carboxylic acids, involving a double deprotonation and silylation followed by the catalytic asymmetric protonation.

Synthesis of pharmaceutical drugs from cardanol derived from cashew nut shell liquid

Cardanol from cashew nut shell liquid extracted from cashew nut shells was successfully converted into various useful pharmaceutical drugs, such as norfenefrine, rac-phenylephrine, etilefrine and fenoprofene. 3-Vinylphenol, the key intermediate for the synthesis of these drugs, was synthesised from cardanol by ethenolysis to 3-non-8-enylphenol followed by isomerising ethenolysis. The metathesis reaction worked very well using DCM, but the greener solvent, 2-methyl tetrahydrofuran, also gave very similar results. Hydroxyamination of 3-vinylphenol with an iron porphyrin catalyst afforded norfenefrine in over 70% yield. Methylation and ethylation of norfenefrine afforded rac-phenylephrine and etilefrine respectively. A sequence of C-O coupling, isomerising metathesis and selective methoxycarbonylation afforded fenoprofene in good yield. A comparison of the routes described in this paper with some standard literature syntheses of 3-vinylphenol and of the drug molecules shows significant environmental advantages in terms of precursors, yields, number of steps, conditions and the use of catalysts. The Atom Economy of our processes is generally similar or significantly superior to those of the literature processes mainly because the side products produced during synthesis of 3-vinylphenol (1-octeme, 1,4-cyclohexadiene and propene) are easily separable and of commercial value, especially as they are bio-derived. The E Factor for the production of 2-vinylphenol by our process is also very low compared with those of previously reported syntheses.

Palladium-Catalyzed α-Arylation of Carboxylic Acids and Secondary Amides via a Traceless Protecting Strategy

A novel traceless protecting strategy is presented for the long-standing challenge of conducting the palladium-catalyzed α-arylation of carboxylic aids and secondary amides with aryl halides. Both of the presented coupling processes occur with a variety of carboxylic acids and amides and with a variety of aryl bromides containing a broad range of functional groups, including base-sensitive functionality like acyl, alkoxycarbonyl, nitro, cyano, and even hydroxyl groups. Five commercial drugs were prepared through this method in one step in 81-96% yield. Gram-scale synthesis of medication Naproxen and Flurbiprofen with low palladium loading further highlights the practical value of this method.

Photocarboxylation of Benzylic C-H Bonds

The carboxylation of sp3-hybridized C-H bonds with CO2 is a challenging transformation. Herein, we report a visible-light-mediated carboxylation of benzylic C-H bonds with CO2 into 2-arylpropionic acids under metal-free conditions. Photo-oxidized triisopropylsilanethiol was used as the hydrogen atom transfer catalyst to afford a benzylic radical that accepts an electron from the reduced form of 2,3,4,6-tetra(9H-carbazol-9-yl)-5-(1-phenylethyl)benzonitrile generated in situ. The resulting benzylic carbanion reacts with CO2 to generate the corresponding carboxylic acid after protonation. The reaction proceeded without the addition of any sacrificial electron donor, electron acceptor or stoichiometric additives. Moderate to good yields of the desired products were obtained in a broad substrate scope. Several drugs were successfully synthesized using the novel strategy.