Ibuprofen S -

The synthesis of (S)-ibuprofen (S)-34 utilizing allylic alkylation was undertaken to determine the stereochemical course of this process. The reaction of the enantiomeri-cally enriched allylic carbonate (S)-32 (95% ee) with the requisite aryl zinc bromide (Scheme 10.7) [32], under optimized reaction conditions, furnished the 3-aryl propenyl derivative (R)-33 in 90% yield (2° 1°=10 1) with inversion of configuration (100% cee). The synthesis of (S)-ibuprofen (S)-34 was then completed through the oxidative cleavage of the aUcene (R)-33 in 74% yield [33]. 

Nonsteroidal Antiinflammatory Drugs. Nonsteroidal antiinflammatory drugs (NSAIDs) include, among the numerous agents of this class, aspirin (acetylsalicylic acid), the arylacetic acids indomethacin and sulindac, and the arylpropionic acids, tS)-<8) and (/ )-(9) ibuprofen, (S)-(10) and (/ )-(11), flurbiprofen naproxen, and fenoprofen. See also Analgesics, Antipyretics, and Antiinflammatory Agents and Salicylic Acid and Related Compounds. 

Cheminor Drugs (part of Dr. Reddy s Group, Mumbai, India) have developed a process based on a chiral synthesis to (S)-ibuprofen. (S)-Ibuprofen is 160 times more active than the (R) form, so with an enantiomerically pure drug the dosage could be cut in half. As the human body has been reported to racemize (R)-ibuprofen partially into the (S) form and as (R)-ibuprofen is not harmful, nearly all the ibuprofen taken becomes active. The process discovered by Cheminor is therefore unlikely to have commercial significance. 

Figure 2. Solubility conditions of the raw material ( o (i)-cw-chrysanthemic acid ( )-ibuprofen S-(+)-2-benzylamino-l -butanol x / -(+)-1-phenylethylamine Perfilt)...

These ketones are important intermediates in the synthesis of fragrances of the musk type, of UV absorbents and of pharmaceuticals such as paracetamol, ibuprofen, S-naproxen. Thus, in the processes of ibuprofen synthesis (9), the first classical step is the acetylation of isobutylbenzene with acetic anhydride in presence of HF (Hoechst process) or of A1C13 (Boots process) ... 

With the variety of transformations that can be promoted by organopalladium reagents, it is unfortunate that palladium is such a rare metal. Biochemical processes might be much more exotic if palladium had been more abundant in the earth s crust at the origin of life (although selenium, which is an essential trace nutrient, is only approximately five times as concentrated as palladium in the earth s crust). The discovery of high turnover number catalysts has allowed several palladium-catalyzed reactions to be used in fine chemical and pharmaceutical synthesis. Naproxen (29) can be made using a Heck reaction. Ibuprofen s (30) synthesis... 

The relative concentration of the pharmacologically active S enantiomer of ibuprofen (S R ratio) increases with prolongation of the gastrointestinal transit time of racemic formulations due to a corresponding increase in chiral inversion of the R to S enantiomer in the gut (25). Administration of S-ibuprofen, therefore, reduces the formulation-dependent variability in the concentration of the active enantiomer in the body. 

Sandyk R. Phenytoin toxicity induced by interaction with ibuprofen. S Afr Med J 1982 62(17) 592. 

The syntheses of ibuprofen, (S)-metolachlor, and (-)-menthol represent only three of the numerous uses of soluble transition metal complexes to catalyze, often stereoselectively, key steps in the production of biologically important compounds in the laboratory or on an industrial scale. Discussions in Chapter 12, especially with regard to asymmetric conditions, will explore more fully the use of these catalysts in the synthesis of other organic compounds. 

For adsorption of impurities, the suiTounding phase of interest is typically the liquid phase. The adsorption isotherm can be built by determining the impurity levels in the solution before and after adding the solid (as adsorbent). Based upon the change of impurity levels in the solution, the adsorption isotherm can then be determined. Figiue 2-24 shows a Langmuir-type adsorption isotherm of R-ibuprofen S-lysinate on S-ibuprofen S-lysinate crystals in an ethanol/water solvent mixture. As shown in the figure, a trace amount of impurities can be adsorbed onto the crystal surface even when the impurity concentration in the solution is well below its solubility limit. 

Goals . Resolve S-ibuprofen-S-lysine from a pair of diastereomeric salts of R-ibuprofen-S-lysine and S-ibuprofen-S-lysine... 

Resolution via crystallization is an important method for the synthesis of pure optical isomers on an industrial scale. In the development of a process for the resolution of racemic ibuprofen, S-lysine is used as the resolving agent to accomplish this task. As shown in Fig. 7-22, R/S-ibuprofen reacts with S-lysine to form a pair of diastereomeric salts of R-ibuprofen-S-lysine and S-ibuprofen-S-lysine, and S-ibuprofen-S-lysine is separated via stereospecific crystallization. 

Table 7-2 Solubility of the R/S-Ibuprofen-S-Line in an Ethanol/Water 97/3 Solvent Mixture (23°C)...

A solution of R/S ibuprofen S-lysine diastereomers was found to sustain a high degree of supersaturation. The experimental observation showed that a supersaturated diastereomeric solution with a... 

Ibuprofen [(S+) and (R-) 4-isobutyl-a-methylphenylacetic acid, Brufen, Nurofen, Motrui]... 

S)-p-lsobutylhydratropic acid L-lysine salt monohydrate. Ibuprofen S-form L-lysine salt ML-223 MK-223 Doctrin. S-Form of ibuprofen L-lysine salt. Cyclooxygenase Inhibitor. Analgesic antiinflammatory. Merck Co.Inc. 

Fig. 6.3.1 Production of S-ibuprofen (S-Ibu) by kinetic resolution of the ester racemate (R-S IbuME) with lipase (L) in organic medium in a membrane bioreactor (1), with product separation (2) and racemization (3) of the unreacted R-ibuprofen methyl ester (R-IbuME)...

Figure 7 Ibuprofen, a prototype category II racemic drug with chiral inversion. Mean (w = 4) plasma concentration-time curves of R-ibuprofen, S-ibuprofen, and enantiomeric S/R ratios after oral administration of racemic ibuprofen given as an immediate-release (upper panel three 200 mg doses 6 hours apart) and controlled-release formulation (lower panel two 300 mg doses 12 hours apart). The arrows on the time axes indicate the time of drug administration. (From Ref. 26, with permission.)... 

Besides the more common reactions such as hydrogenation, isomerization, alkylation, and the Diels-Alder reaction. Sharpless epoxidation and dihydroxylation by asymmetrical catalysis are rapidly emerging as reactions with immense industrial potential. Table 9.7 lists some important syntheses based on asymmetric catalysis. These include processes for the pharmaceutical drugs (S)-naproxen, (S)-ibuprofen, (,S)-propranolol, L-dopa, and cilastatin, a fragrance chemical, L-menthol, and an insecticide (/ )-disparlure. Deltamethrin, an insecticide, is another very good example of industrial asymmetric synthesis. The total synthetic scheme is also given for each product. In general, the asymmetric step is the key step in the total synthesis, but this is not always so, as in the production of ibuprofen. Many of the processes listed in the table are in industrial production. 

Wikipedia Ibuprofen S. S. Adams, /. Clin. Pharmacol. 32 (1992) 317 http //www.telegraph.co.uk/health/3351540/Dr-Ste wart-Adams-I-tested-ibu-profen-on-my-hangover.html. 

After fine-tuning the nucleophile and the BTM catalyst, this method was eventually used in the KR of ibuprofen (s = 34), ketoprofen (s = 14), fenoprofen (s = 17), flurbiprofen (s = 15), and naproxen (s = 61), five chiral non-steroidal antiinflammatory drugs (Figure 41.5). 

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