51146-56-6

Usage

Uses

Used in Pharmaceutical Industry:
(S)-(+)-Ibuprofen is used as a nonsteroidal anti-inflammatory drug (NSAID) for its potent anti-inflammatory, analgesic, and antipyretic properties. It is particularly effective in treating conditions such as rheumatoid arthritis, osteoarthritis, and other inflammatory disorders.
Used in Medical Treatment:
(S)-(+)-Ibuprofen is used as a therapeutic agent for the management of pain, inflammation, and fever. Its preferential usage over the racemic mixture of ibuprofen leads to a reduced dosage level and an improved side effect profile, making it a more effective treatment option for patients.
Used in Research and Development:
(S)-(+)-Ibuprofen serves as an important enantiomer in the study of stereoselectivity in drug action and metabolism. Its distinct biochemical actions compared to the R-isomer make it a valuable compound for research in drug development, understanding the mechanisms of action, and optimizing therapeutic outcomes.

Originator

Gebro Broschek (Austria)

Biological Activity

Non-steroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase 1 and cyclooxygenase 2 (IC 50 values are 12 and 80 μ M respectively). Active isomer of ibuprofen.

Clinical Use

NSAID and analgesic

Drug interactions

Potentially hazardous interactions with other drugsACE 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 ritonavirCiclosporin: may potentiate nephrotoxicityCytotoxics: reduced excretion of methotrexate; increased risk of bleeding with erlotinibDiuretics: increased risk of nephrotoxicity; antagonism of diuretic effect; hyperkalaemia with potassium-sparing diuretics.Lithium: excretion decreased.Pentoxifylline: increased risk of bleeding.Tacrolimus: increased risk of nephrotoxicity

Metabolism

Dexibuprofen is the S(+)-enantiomer of ibuprofen. After metabolic transformation in the liver (hydroxylation and carboxylation), the pharmacologically inactive metabolites are completely excreted, mainly by the kidneys (90%), but also in the bile.

Purification Methods

Crystallise the (+) and (-) acids from EtOH or aqueous EtOH. The racemate which crystallises from pet ether with m 75-77o is sparingly soluble in H2O and has IR (film) 1705 (C=O), 2300—3700 (OH broad)cm-1. It is used as a non-steroidal anti-inflammatory. [Shiori et al. J Org Chem 43 2936 1978, Kaiser et al. J Pharm Sci 65 269 1976, J Pharm Sci 81 221 1992, Freer Acta Cryst (C) 49 1378 1993 for the (S+)-enantiomer.]

InChI:InChI=1/C13H18O2/c1-9(2)8-11-4-6-12(7-5-11)10(3)13(14)15/h4-7,9-10H,8H2,1-3H3,(H,14,15)/t10-/m0/s1

Upstream product

• 113544-36-8 (S)-2-(4-Isobutyl-phenyl)-propionic acid (3aR,5R,6S,6aR)-5-(1,2-dihydroxy-ethyl)-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-6-yl ester 
• 123054-48-8 2-(4-Isobutyl-phenyl)-propionic acid (R)-cyclohexyl-methoxycarbonyl-methyl ester 
• 123054-51-3 (S)-2-[2-(4-Isobutyl-phenyl)-propionyloxy]-succinic acid dimethyl ester 
• 123054-44-4 (R)-2-(4-isobutylphenyl)propionic acid 4,4-dimethyl-2-oxo-tetrahydrofuran-3-yl ester 
• 6448-14-2 2-(4-isobutylphenyl)acrylic acid 
• 538-93-2 1-phenyl-2-methylpropane 
• 66423-08-3 (S)-2-(methylsulfonyloxy)propionic acid 
• 71381-91-4 (+/-)-2-(4-isobutylphenyl)propanoyl chloride 
• 362470-66-4 (S)-1-carbamoylmethyl-4,4-dimethyl-2-oxopyrrolidinyl (S)-2-(4-isobutylphenyl)propionate 
• 51407-46-6 2-(4-isobutylphenyl)propionaldehyde 
• 134309-32-3 R-(+)-1-[4-isobutylphenyl]-chloroethane 
• 41283-72-1 ibuprofen ethyl ester 
• 64-18-6 formic acid 
• 132464-91-6 4'-isobutyl phenylacetylene 

Downstream Products

• 81576-55-8 (S)-(+)-methyl 2-(4-isobutylphenyl)propionate 
• 114937-30-3 (2S)-2-<4-(2-Methylpropyl)phenyl>propan-1-ol 
• 115588-20-0 (2S)-2-(4-isobutylphenyl)-propionyl chloride 
• 851913-34-3 N-ibuprofyl-6-aminohexanoic acid methyl ester 
• 851913-12-7 pentafluorophenyl (S)-2-(4-isobutylphenyl)propionate 
• 1033293-24-1 S-salbutamol*S-ibuprofen 
• 272458-63-6 (S)-ethyl 2-(4-isobutylphenyl)propanoate 
• 1146411-22-4 C₁₅H₂₃NO₂ 
• 190605-07-3 (1R,2S,2''S,5R)-2-(4-isobutylphenyl)propionic acid 2-isopropyl-5-methylcyclohexyl ester 
• 1046119-52-1 C₂₁H₂₆O₂ 
• 163158-04-1 (S,S)-2-(4-isobutylphenyl)propionic anhydride 
• 1202064-16-1 C₁₈H₂₄O₃ 
• 1265905-04-1 (2S)-N-methoxy-N-methyl-2-[4-(2-methylpropyl)phenyl]propanamide 
• 1402082-56-7 N-[(2S)-2-(4-isobutylphenyl)propionyl]-(2S)-2-methyl-1,2,3,4-tetrahydroquinoline 

Relevant academic research and scientific papers

High pressure CO2-controlled reactors: Enzymatic chiral resolution in emulsions

In this work we have reported the formulation of a CO2-based micelle stabilized by nontoxic TMN series surfactants. Enantioselection of racemic ibuprofen catalyzed by Candida antarctica lipase B (CALB) was used as a model reaction. The effect of reactive parameters, such as temperature, pH, pressure, and water content on reactive environment and conversion has been discussed. For the resolution of racemic ibuprofen in CO2-based micelles, the enzymatic activity reached a high level at 45 °C, with pressure 250 bar, pH 7.4, and water to surfactant ratio W0 25. In addition, the relatively long-chain length in TMN-10 could help the esterification and trans-esterification processes, which resulted in an efficient reaction rate in a CO2-based micelle system. Enzymatic catalysis has been conducted in a CO2-based system rather than in the conventional media to make the enzyme reaction greener. The better resolution efficiency in high pressure CO2-based micelles could be achieved within a relatively short period of time compared with other traditional reactive systems. The Royal Society of Chemistry 2014.

Esterification of (RS)-Ibuprofen by native and commercial lipases in a two-phase system containing ionic liquids

Four commercially available lipases and two native lipases from Aspergillus niger AC-54 and Aspergillus terreus AC-430 were used for the resolution of (RS)-Ibuprofen in systems containing the ionic liquids [BMIM][PF6] and [BMIM][BF4]. The lipases showed higher conversion in a two-phase system using [BMIM][PF6] and isooctane compared to that in pure isooctane. Although the best enzyme was a commercially available lipase from Candida rugosa (E = 8.5), another native lipase, produced in our laboratory, from A. niger gave better enantioselectivity (E = 4.6) than the other lipases tested (E = 1.9-3.3.). After thorough optimization of several reaction conditions (type and ratios of isooctane/ionic liquid, amount of enzyme, and reaction time), the E-value of A. niger lipase (15% w/v) could be duplicated (E = 9.2) in a solvent system composed of [BMIM][PF6] and isooctane (1:1) after 96 h of reaction.

Enantioselective analysis of ibuprofen enantiomers in mice plasma and tissues by high-performance liquid chromatography with fluorescence detection: Application to a pharmacokinetic study

A direct fluorometric high-performance liquid chromatography (HPLC) method was developed and validated for the analysis of ibuprofen enantiomers in mouse plasma (100?μl) and tissues (brain, liver, kidneys) using liquid–liquid extraction and 4-tertbutylphenoxyacetic acid as an internal standard. Separation of enantiomers was accomplished in a Chiracel OJ-H chiral column based on cellulose tris(4-methylbenzoate) coated on 5?μm silica-gel, 250 x 4.6?mm at 22?°C with a mobile phase composed of n-hexane, 2-propanol, and trifluoroacetic acid that were delivered in gradient elution at a flow rate of 1?ml min?1. A fluorometric detector was set at: λexcit. = 220?nm and λemis. = 290?nm. Method validation included the evaluation of the selectivity, linearity, lower limit of quantification (LLOQ), within-run and between-run precision and accuracy. The LLOQ for the two enantiomers was 0.125 μg ml?1 in plasma, 0.09?μg g?1 in brain, and 0.25?μg g?1 in for liver and kidney homogenates. The calibration curves showed good linearity in the ranges of each enantiomers: from 0.125 to 35?μg ml?1 for plasma, 0.09–1.44?μg g?1 for brain, and 0.25–20?μg g?1 for liver and kidney homogenates. The method was successfully applied to a pharmacokinetic study of ibuprofen enantiomers in mice treated i.v. with 10?mg kg?1 of racemate.

Highly effective and recyclable dendritic BINAP ligands for asymmetric hydrogenation

A series of dendritic BINAP ligands have been synthesised and their ruthenium complexes used as catalysts in asymmetric hydrogenation.

Enzymatic hydrolytic resolution of racemic ibuprofen ethyl ester using an ionic liquid as cosolvent

The aim of this study was to develop an ionic liquid (IL) system for the enzymatic resolution of racemic ibuprofen ethyl ester to produce (S)-ibuprofen. Nineteen ILs were selected for use in buffer systems to investigate the effects of ILs as cosolvents for the production of (S)-ibuprofen using thermostable esterase (EST10) from Thermotoga maritima. Analysis of the catalytic efficiency and conformation of EST10 showed that [OmPy][BF4] was the best medium for the EST10-catalyzed production of (S)-ibuprofen. The maximum degree of conversion degree (47.4%), enantiomeric excess of (S)-ibuprofen (96.6%) and enantiomeric ratio of EST10 (177.0) were achieved with an EST10 concentration of 15 mg/mL, racemic ibuprofen ethyl ester concentration of 150 mM, at 75°C, with a reaction time of 10 h. The reaction time needed to achieve the highest yield of (S)-ibuprofen was decreased from 24 h to 10 h. These results are relevant to the proposed application of ILs as solvents for the EST10-catalyzed production of (S)-ibuprofen.

Encapsulation of biologicals within silicate, siloxane, and hybrid sol- gel polymers: An efficient and generic approach

The sol-gel encapsulation of labile biological materials with catalytic and recognition functions within robust polymer matrices remains a challenging task, despite the considerable research that has been focused on this field. Herein, we describe a new class of precursors, based around polyol silicates and polyol siloxanes, especially those derived from glycerol, that addresses problems faced with traditional bioencapsulation protocols. Poly(glyceryl silicate) (PGS) was prepared and employed for sol- gel bioentrapment, in an approach distinguished by a high biocompatibility and mild encapsulation conditions, and which enables the reproducible and efficient confinement of proteins and cells inside silica. The methodology was extended to metallosilicate, alkylsiloxane, functionalized siloxane, and composite sol-gels, thereby allowing the fabrication of a physicochemically diverse range of bio-doped polymers. The hybrid materials display activities approaching those of the free biologicals, together with the high stabilities and robustness that characterize sol-gel bioceramics. Indeed, the bioencapsulates performed better than those fabricated from tetramethoxysilane, poly(methyl silicate) or alcohol-free poly(silicic acid), even when the latter were doped with glycerol. The activity enhancements appear to derive at least in part from the unusual microstructure of PGS sol- gels, in particular their high porosity, although the underlying mechanisms are unclear. Differences in precursor hydrolysis/condensation; development of gel structure, biological-matrix interactions, precursor toxicity, and pore collapse probably all contribute to the observed efficiency of the PGS materials. The performances of the encapsulates are compared with conventional sol-biogels and other immobilizates, in representative biocatalyst, biosensor, and biodiagnostic applications.

Resolution of (R,S)-ibuprofen catalyzed by immobilized Novozym40086 in organic phase

The enantioselective esterification of ibuprofen catalyzed by Novozym40086 was successfully conducted in organic solvent. Removing-water reagent was added into the reaction mixture to remove water produced in the esterification. The effects of temperature, n-hexanol concentration, ibuprofen concentration, and loading of enzymes were investigated. Under the condition of equilibrium, the thermodynamic equilibrium constant (K) of 7.697 and enantioselectivity (E) of 8.512 were obtained. The esterification reaction achieved its equilibrium in approximately 30?hours with conversion of 56% and eeS of 93.78%. The predicted values of X and eeS were 67.90% and 95.60%, respectively. The experimental value is approximately equal to the theoretical value, which indicates the feasibility of ideal models.

Enantioselective partitioning of racemic ibuprofen in a biphasic recognition chiral extraction system

Enantioselective partitioning of ibuprofen enantiomers in a biphasic recognition chiral extraction system was studied. A combination of hydrophobic L-isobutyl tartrate in organic phase and hydrophilic β-cyclodextrin derivative in aqueous phase is necessary to establish a biphasic recognition chiral extraction system. The studies performed involve an enantioselective extraction in a biphasic system, where ibuprofen enantiomers form four complexes with the β-cyclodextrin derivative in aqueous phase and the D(L)-isobutyl tartrate in organic phase, respectively. In these biphasic resolutions, the types and the concentrations of the extractants, pH and temperature all exert a considerable influence on the biphasic recognition process. Good enantioselectivities for ibuprofen enantiomers were obtained at pH≤2.5 and a ratio of 2:1 of [L-isobutyl tartrate] to [HP-β-CD]. Biphasic recognition chiral extraction is of strong chiral separation ability, and may be very helpful to optimize the extraction systems and realize the large-scale production of enantiomers.

Facile conversion of racemic ibuprofen to (S)-ibuprofen

The methyl ester of ibuprofen was quantitatively formed by Fischer esterification and converted into (S)-ibuprofen in 94% yield with an ee of 94% under dynamic kinetic resolution conditions at pH 9.8, using Candida rugosa lipase, and 20% DMSO. The (R)-methyl ibuprofen ester was observed to racemize by chiral HPLC without the Candida rugosa lipase present. The rates of in situ racemization and enzymatic hydrolysis for the dynamic kinetic resolution were determined to be 0.026 ± 0.004 and 0.053 ± 0.004 h-1, respectively. The rate of enzymatic hydrolysis when no DMSO was present was twice as fast but no racemization occurred. A facile purification of enriched (S)-ibuprofen was developed. Overall, 88% of racemic ibuprofen by weight was converted into (S)-ibuprofen with an ee of 99.7%.

New soluble bifunctional polymeric chiral ligands for enantioselectively catalytic reactions

Two new soluble bifunctional polymeric ligands (R,R)-4 and (R,R)-5 have been prepared via the direct condensation reaction of (R)-3,3′-diformyl-1,1′-bi-2-naphthol (R)-1 with (R)-5,5′-diamino BINAP (R)-2 and with (R)-5,5′-diamino BINAPO (R)-3, respectively. The different types of catalytic centers, BINOL and BINAP or BINAPO, were alternatively organized in a regular chiral polymer chain. Both polymeric ligands were found to be effective in the addition of diethylzinc to benzaldehyde either in the presence or in the absence of Ti(OPri)4 with different enantioselectivities. (R,R)-4/Ti(IV) catalyst, which showed similar efficiency to the parent catalyst BINOL/Ti(IV), was more enantioselective than (R,R)-5/Ti(IV). (R,R)-4 was also found to be highly effective in the Ru(II)-catalyzed asymmetric hydrogenation of 2-arylacrylic acids. The results demonstrated that the use of the co-polymer catalyst rather than a mixture of monomer catalysts not only simplified the recycling of the catalyst, but also improved the enantioselectivity and/or the activity in some cases.