Profens ibuprofen

Sz z, G. Budvdri-Bdrany, Z. Lore, A. Radeczky, G. Shalaby, A. HPLC of antiphlogistic acids on silica dynamically modified with cetylpyridinium chloride. J.Liq.Chromatogr., 1993,16, 2335—2345 [feno-profen, ibuprofen, ketoprofen, naproxen, nicotinic acid, nifluminic add, salicylic add]... 

FIGURE 2.20 Schematic presentation of the hydrogen-bonded cyclic dimers of enantiomeric antipodes of 2-phenylpropionic acid, Ibuprofen, and Naproxen (the latter two compounds are drugs from the group of profens). 

The procedure shows that it is feasible to combine racemization with the kinetic resolution process (hence the DKR) of R,S)- ethoxyethyl ibuprofen ester. The chemical synthesis of the ester can be applied to any esters, as it is a common procedure. The immobilized lipase preparation procedure can also be used with any enzymes or support of choice. However, the enzyme loading will need to be optimized first. The procedures for the enzymatic kinetic resolution and DKR will need to be adjusted accordingly with different esters. Through this method, the enantiopurity of (5)-ibuprofen was found to be 99.4 % and the conversion was 85 %. It was demonstrated through our work that the synthesis of (5)-ibuprofen via DKR is highly dependent on the suitability of the reaction medium between enzymatic kinetic resolution and the racemization process. This is because the compatibility between both processes is crucial for the success of the DKR. The choice of base catalyst will vary from one reaction to another, but the basic procedures used in this work can be applied. DKRs of other profens have been reported by Lin and Tsai and Chen et al. ... 

Ibuprofen has good analgesic and anti-inflammatory action. Ibuprofen is made at approximately 16 million Ib/yr in the U.S. Its price is higher than aspirin or acetaminophen and is usually around 9.30/lb. Its common name does tell us something about its structure. There are a number of profens, ... 

The effect of various SFC parameters on chiral resolution were also studied. Modifiers can provide control over both retention and selectivity and, therefore, certain modifiers were used to optimize the separation in sub-FC and SFC. The effect of the enantioselectivity of carbon dioxide on acidic drugs (benzoxaprofen, temazepam, and mephobarbital), profen, and barbiturate derivatives was carried out on Chiralcel OJ, with acetonitrile or methanol as organic modifier [140]. Acetonitrile proved to be a good alternative to methanol, especially for the profen compounds that were not well resolved when methanol was used. Wilson [143] studied the effects of methanol, ethanol, and 2-propanol as organic modifiers on the chiral resolution of ibuprofen on Chiralpak AD CSPs. Methanol was found to be the best organic modifier. 

The asymmetric hydroformylation of vinyl arenes can provide a route to the preparation of the profen class of drugs. Naproxen and ibuprofen, two examples in the profen class, are NSAIDs on the market.50... 

Ibuprofen, cicloprofen, 1-phenylethanol, 1,1 -binaphthyl-2,2 -dihydrogen-phosphate, flurbiprofen, car-profen, etodolac, warfarin, hexobarbital Chirasil-Dex coated column, 0.2 pm... 

Selective nitrilases have also been developed for the enantiopure preparation of ibuprofen [106]. In a kinetic resolution with Acinetobacter sp. AK226 (S)-ibu-profen could be prepared in good optical purity (Scheme 6.35). 

Although nitrile hydratases tend not to be stereoselective, examples of enantioselective enzymes are known [103, 106, 107, 114]. Of particular interest is the possibility to selectively hydrolyse 2-phenylproprionitriles, the core structure for ibuprofen and many other profens [103, 107, 114, 115]. This enables the enantioselective synthesis of the amides of ketoprofen and naproxen (Scheme 6.39). 

The profens are non-steroidal anti-inflammatory agents based on arylpropionic acids the best known is ibuprofen. The BHC company (Boots-Hoechst-Celanese) developed a commercial route to ibuprofen which involves a... 

The carbonylation reaction is the final part of a three step route to ibuprofen (shown in Figure 6a) which has superseded a less efficient six-step pathway from isobutylbenzene (Box 6). A related profen, naproxen is made by a hydroxycarbonylation route (Figure 6b). 

Aryl propionic acid nonsteroidal antiinflammatory drugs. The compounds from this class of agents that have been stereochemically resolved include ibuprofen, flurbiprofen, naproxen, benoxaprofen, pirprofen, su-profen, fenoprofen, indoprofen, and ketoprofen (94). 

To explore the frequency of continuous use of over-the-counter drugs and the potential for harmful interactions between OTC drugs and prescribed drugs, a population-based interview survey was conducted in 10 477 subjects (231). Daily use of over-the-counter drugs was reported by 7% of the subjects and 4% of those who used over-the-counter drugs had taken combinations with potential for clinically significant interactions. Interactions were most common for NSAIDs such as ketoprofen (15% of keto-profen users), ibuprofen (10%), and aspirin (6%). Unfortunately, this study did not provide information on whether the potential interactions led to actual clinical problems. 

Various arylpropionic acids show similar specificity. For most, if not all, the (5) enantiomer is the pharmacologically active one, whereas the R) enantiomer is usually much less active, although the ratio of iS)/ R) activity varies from drug to drug (and species to species). Only one of these drugs, however, is administered as the separated (S) enantiomer (naproxen, Naprosyn ). Normally these drugs are considered safe, and one cannot readily differentiate between the relative activities of the (S) and (R) forms because the in vivo half-life is very short, typically one or two hours. In patients with impaired renal function, where clearance is much slower, however, problems can arise. From in vivo studies of ibuprofen, it was established that the (S)-(-l-) isomer was responsible for antiinflammatory activity. In vivo, however, the (/ )-(-) isomer may become active because there is stereoselective inversion from R) to (S) (but not from 5 to R) in vivo with a half-life of about two hours. This inversion apparently proceeds by stereoselective formation of the coenzyme A (CoA) ester of the (f )-(-)-arylpropionic acid, followed by epimerization and release of the (S)-(+)-enantiomer. This epimerization is observed in vivo before the oxidative metabolism. Such inversion from (R) to (S) in vivo is also known for fenoprofen and benoxa-profen, and is expected to occur for most of the drugs of this series. ... 

Because of an increasing demand for these products in the pharmaceutical industry, a number of companies have paid special interest to the synthesis of profenes [32] such as ibuprofen, naproxen, ketoprofen and others from 1-arylethanol derivatives. Catalysts used for this transformation are palladium-phosphine complexes in concentrated hydrochloric acid, and to a lesser extent nickel-phosphine complexes in the presence of alkyl iodides or rhodium salts (cf. Section 2.9). 

Because the aldehyde group is an extremely versatile functionality, AH constitutes a useful entree into chiral biologically active compounds such as the nonsteroidal antiinflammatory drug (S)-naproxen (32), commonly called Aleve. Section 9-7-1 highlighted a racemic hydrofomylation that was a key step in the synthesis of ibu-profen. naproxen is quite similar to ibuprofen in structure, but the toxic nature of racemic Naproxen in the body demands that it be synthesized and administered as the much less toxic (S)-enantiomer. Scheme 12.14 shows a possible route to 32, first involving AH of the vinyl naphthalene in the presence of BINAPHOS (34, Fig. 12-6) to create the chiral branched aldehyde and then subsequent oxidative conversion of the aldehyde to the carboxylic acid.83 AH of vinylnaphthalene (33)... 

NSAIDs have an overall favorable safety profile resulting in OTC availability in the United States of ibuprofen, naproxen, and keto-profen for short-term therapy. WWle potential adverse renal effects from OTC NSAIDs have been a concern, activity of vasodilatory prostaglandins is not necessary to maintain renal function in healthy individuals. NSAIDs are unlikely to impair renal function in the absence of renal ischemia or excess renal vasoconstrictor activity. Nevertheless, given the fact that 50 million U.S. citizens report NSAID use, it has been estimated that 500,000 to 2.5 million people will develop NSAID nephrotoxicity in this country annually. ... 

Simultaneous acetaminophen, acetanilide, N-acetylcysteine, N-acetylprocainamide, amo-barbital, aspirin, barbital, butabarbital, butalbit, caffeine, carbamazepine, cimetidine, codeine, cyheptamide, diazoxide, diflunisal, disopyramide, ethchlorvynol, ethosuximide, gentisic acid, glutethimide, heptabarbital, hexobarbital, ibuprofen, indomethacin, keto-profen, mefenamic acid, mephenytoin, mephobarbital, methaqualone, methsuximide, methyl salicylate, methypiylon, morphine, naproxen, nirvanol, oxphenylbutazone, pentobarbital, phenacetin, phenobarbital, phensuximide, phenylbutazone, phenytoin, primidone, procainamide, salicylamide, secobarbital, sulindac, thiopental, tolmetin, trimethoprim... 

Terfloth, G.J. Pirkle, W.H. Lynam, K.G. Nicolas, E.C. Broadly applicable polysiloxane-based chiral stationary phase for high-performance liquid chromatography and supercritical fluid chromatography. J.Chromatogr.A, 1995, 705, 185-194 [SEC HPLC also carprofen, cicloprofen, etodolac, feno-profen, flurbiprofen, ibuprofen, naproxen, pirprofen]... 

Nonsteroidal antiinflammatory drugs. Pirprofen, naproxen, ibuprofen, and keto-profen can occasionally cause microvesicular steatosis in humans (Bravo et al. 1997 Victorino et al. 1980 Danan et al. 1985 Dutertre et al. 1991). These NSAIDS have a 2-arylpropionate structure, with an asymmetric carbon, and exist as either the S(+)- or the R(—)-enantiomers. Only the S(+)-enantiomer inhibits prostaglandin synthesis, whereas only the R( )-enantiomer is converted into the acyl-CoA derivative. However, both the S(+)-enantiomer and the R( )-enantiomer of ibuprofen inhibit the p-oxidation of medium- and short-chain fatty acids (Freneaux et al. 1990). Pirprofen, tiaprofenic acid, and flurbiprofen also inhibit mitochondrial p-oxidation (Geneve et al. 1987a). 

Mayer, J.M. Testa, B. Roy-de Vos, M. Audergon, C. Etter, JC. Interactions between the in vitro metabolism of xenobiotics and fatty acids. The case of ibuprofen and other chiral profens. Arch. Toxicol. Suppl. 1995, 17, 499-513. 

Neuvonen PJ. The effect of magnesium hydroxide on the oral absorption of ibuprofen, keto-profen and diclofenac. BrJ Clin Pharmacol ( 99 ) 31,263-6. 

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