Naproxen process, reaction

The effects of added C02 on mass transfer properties and solubility were assessed in some detail for the catalytic asymmetric hydrogenation of 2-(6 -meth-oxy-2 -naphthyl) acrylic acid to (Sj-naproxen using Ru-(S)-BINAP-type catalysts in methanolic solution. The catalytic studies showed that a higher reaction rate was observed under a total C02/H2 pressure of ca. 100 bar (pH2 = 50bar) than under a pressure of 50 bar H2 alone. Upon further increase of the C02 pressure, the catalyst could be precipitated and solvent and product were removed, at least partly by supercritical extraction. Unfortunately, attempts to re-use the catalyst were hampered by its deactivation during the recycling process [11]. 

The intercalation of these species has been studied using time-resolved EDXRD. For intercalation into the LiAl - Cl system, a kinetic analysis of the data for naproxen (Nx), diclofenac (Df) and 4-biphenylacetic acid (4-Bpaa) suggests that the reactions are 2D diffusion controlled processes following instantaneous nucleation. In a number of cases, the importance of nucleation decreases at higher temperatures (T > 60 °C), with a corresponding reduction in the value of n from 1 to 0.5. This latter value corresponds to a situation where nucleation plays no part in controlling the reaction rate. The data in Fig. 22 relate to the intercalation of Nx. 

Other drugs are metabolised by Phase II synthetic reactions, catalysed typically by non-microsomal enzymes. Processes include acetylation, sulphation, glycine conjugation and methylation. Phase II reactions may be affected less frequently by ageing. Thus according to some studies, the elimination of isoniazid, rifampicin (rifampin), paracetamol (acetaminophen), valproic acid, salicylate, indomethacin, lorazepam, oxazepam, and temazepam is not altered with age. However, other studies have demonstrated a reduction in metabolism of lorazepam, paracetamol (acetaminophen), ketoprofen, naproxen, morphine, free valproic acid, and salicylate, indicating that the effect of age on conjugation reactions is variable. 

Other asymmetric synthetic processes used for the manufacturing of (S)-(+)-naproxen can also be applied to the production of (S)-(+)-ibuprofen these include the Rh-phosphite catalyzed hydro-formylation,37 hydrocyanation,25 and hydrocarboxylation reactions.24... 

The homogeneous catalytic asymmetric hydrogenations of 2-arylacrylic acids have been studied. Both rhodium and ruthenium catalysts have been examined. The reaction temperatures and hydrogen pressures have profound effects on the optical yields of the the products. The presence of a tertiary amine such as triethylamine also significantly increases the product enantiomer excess. Commercially feasible processes for the production of naproxen and S-ibuprofen have been developed based on these reactions. 

Aromatic ketones are important intermediates in the production of fine chemicals and pharmaceuticals1,2. Thus, the anti-rheumatic Naproxen is produced by the Friedel-Crafts acetylation of 2-methoxynaphthalene into 2-acetyl-6-methoxynaphthalene and subsequent Willgerodt-Kindler reaction. Commercial acylation processes involve over-stoechiometric amounts of metal chlorides (e g. AICI3) as catalysts and acid chlorides as acylating agents, which results in a substantial formation of by-products and in corrosion problems. This is why the substitution of these corrosive catalysts by solid acid catalysts and of acid chlorides by anhydrides or acids is particularly desirable. 

Over HBEA zeolites, acetylation of 2-methoxynaphthalene with acetic anhydride leads mainly to l-acetyl-2-methoxynaphthalene. However, the desired product, i.e. 2-acetyl-6-methoxynaphthalene, precursor of Naproxen is obtained at long reaction time by an intermolecular irreversible isomerization process. A very selective production of II (83%) can be obtained by acetylation of 2-methoxynaphthalene over a commercial HBEA zeolite (Si/Al = 15) at 170°C, with nitrobenzene as a solvent. With dealuminated HBEA samples (framework Si/Al ratio between 20 and 40), better results could be expected. Furthermore, preliminary experiments showed that this selective synthesis of 2-methoxynaphthalene can be carried out in a flow reactor system. 

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... 

In the excited singlet state the ionization potential of the molecule is reduced, and the excited electron is more easily removed compared to the ground state. This process of photoionization is also more likely to occur if higher energy UV radiation is used (i.e., wavelengths less than 300 nm) and if the drug molecule is in its anionic state. An example is naproxen in aqueous solution at pH 7, where the process of decarboxylation occurs and a neutral radical is formed (11), Reaction 7 ... 

Enzymatic reduction, oxidation, ligase, or lyase reactions, especially, provide us with numerous examples in which prochiral precursor molecules are stereo-selectively functionalized. Ajinomoto s S-tyrosinase-catalyzed L-dopa process [112], the formation of L-camitine from butyro- or crotonobetaine invented by Lonza [113], and the IBIS naproxen route oxidizing an isopropylnaphthalene to an (S)-2-arylpropionic acid are representative, classic examples for many successful applications of enzymatic asymmetric synthesis on an industrial scale. A selection of recent industrial contributions in this field are summarized below. 

One of the few available examples is represented by the synthesis of cilastatine by a chiral Cu complex promoted cyclopropanation reaction developed by Sumitomo Chemical Co. [78]. Another is the catalytic asymmetric hydrocyanation of vinylarenes developed at DuPont [79]. In this process (Fig. 27) sugar-derived phosphinites are used in combination with a Ni catalyst to prepare enantiomerically enriched precursors of the NSAID naproxen. 

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. 

An interesting solution was provided by a process developed by the Zambon company. [197] Friedel-Crafts acylation of 2-methoxynaphthalene is followed by a ketaUsation with diethyl (RJl)-tartrate and a double bromination, at C-1 and in the side-chain, yielding a 92 8 mixture of diastereomers. After hydrolysis of the tartrate, the reaction mixture is heated to 90 °C in water. Thereby, under kinetic resolution and by a [l,2]-aryl migration with complete inversion at the stereogenic centre, bromonaproxen is formed, which is finally converted by reductive dehalogenation into enantiomericaUy pure (S)-naproxen. 

The hydrocarboxylation of vinylarenes has also been studied extensively as a simple, clean route to the ot-aryl carboxylic acids that are common non-steroidal anti-inflamatory medicines, such as ibuprofen and naproxen. " By this process, a vinylarene undergoes hydrocarboxylation to form the branched a-aryl carboxylic acid. A series of patents and papers describe this hydrocarboxylation process " and the related hydroesteri-fication. Like the hydrosilylations and hydrocyanations presented in Qiapter 16 and the hydroformylations described in this chapter, the regioselectivity for reactions of vinylarenes contrasts with that for reactions of alkenes. The reactions of vinylarenes form branched hydrocarboxylation products. 

The selectivity for formation of the branched isomer and the activity for formation of the carboxylic acid or ester when the catalyst is generated from monodentate ligands, such as PPhj and neomenthyldiphenylphosphine, " is exceptionally high, as shown in Equation 17.34. The use of these ligands led to the development of a particularly efficient method to prepare naproxen by the Albemarle company shown in Equation 17.35. Naproxen was synthesized from 2-bromo-6-methoxynapthalene by a sequence of a Heck reaction (Chapter 19) to form the vinylnapthalene, followed by palladium-catalyzed hydrocarboxylation. Unfortunately, changes in business focus have reduced the use of this process. 

The final common class of coupling reactions to form C-C bonds described here is the coupling of an aryl halide with an olefin to cleave the C-H bond of the olefin and replace it with an aryl group. This reaction, which is shown generically in Equation 19.18, was first reported by Mizoroki the synthetic utility of this process and e most useful conditions for this process at the time were reported by Heck. ° This process is often called the "Heck reaction," or more appropriately the "Mizoroki-Heck reaction." " The Heck reaction is most commonly conducted with electron-deficient olefins, such as styrene or acrylate derivatives. The electronic properties of these substrates tend to favor formation of the conjugated products. The reaction can also be conducted effectively with ethylene a Heck reaction between 6-methoxy-2-bromonaphthalene and ethylene is one step of a short, catalytic commercial synthesis of naproxen. In contrast, intermolecular reactions of internal olefins typically form mixtures of regioisomeric products. Intramolecular Mizoroki-Heck reactions with intemal olefins are more common. Mizoroki-Heck reactions of aliphatic electrophiles have been reported, but remain rare. Applications of the Mizoroki-Heck reaction have been reviewed. ... 

This reaction was used in the highly successful commercial production of the drug l-DOPA by hydrogenation of the alkene 9. l-DOPA is effective against Parkinson s disease. Another commercial process is the asymmetric synthesis of the pain reliever, naproxen. ... 

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