Naproxen, manufacture

S)-Naproxen, 18, and S-ibuprofen, 19, are important and widely used analgesics with annual sales of about US 1.4 billion and a production volume of about 8000 tons. A technical feasible use of R,R-tartaric acid as chiral auxiliary was demonstrated in the Zambon Process for S-naproxen manufacture [3]. The diastereoselective bromination is followed by bromine hydrogenolysis and hydrolysis to produce S-naproxen in 75 percent overall yield. 

However, already in an early clinical trial, rofecoxib was found to produce four times the number of myocardial infarctions than its comparator drug, naproxen. A subsequent trial of rofecoxib compared to placebo in colorectal cancer prevention demonstrated, after 18 months of study, that a greater number of myocardial infarctions occulted in the rofecoxib group. In 2004 the manufacturers of rofecoxib withdrew the diug from the market. A similar study of celecoxib compared to placebo in cancer prevention, showed that celecoxib also increased the risk of cardiovascular embolisms [3]. 

Monsanto [117] has developed a way to electrosynthesize by reductive carboxylation the optically active precursor to Naproxen, (S)-2-(6 -methoxy-2 -naphthyl)propionic acid, a drug used to treat arthritis. A more economical route was needed since the US patent expires in 1993 while the market is growing. The electrochemical process is said to cut manufacturing costs by over 50%. Since it uses CO 2 instead of the hazardous HCN used in conventional synthesis, it is also safer. 

Naproxen was introduced to the market by Syntex in 1976 as a nonsteroidal antiinflammatory drug (NS AID) in an optically pure form. The original manufacturing process (Scheme 6.1) before product launch started from P-naphthol (1), which was brominated in methylene chloride to produce 1,6-dibromonaphthol (2). The labile bromine at the 1-position was removed with bisulfite to give... 

Manufacture of optically pure (5)-(+)-ibuprofen (13), an NSAID similar to naproxen, is another example demonstrating the role of resolution in production of chiral fine chemicals, although from a somewhat different angle. Unlike naproxen, ibuprofen (14) was introduced to the market as a racemate almost 30 years ago.30 31 At the time of the introduction, it was thought that both R- and 5-isomers of ibuprofen had the same in vivo activity.32 It has been demonstrated that the R-isomer is converted to the 5-isomer in vivo29 by a unique enzyme system called invertase.34 Based on these data, ibuprofen has since been marketed as a racemate and has achieved sales of more than a billion... 

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... 

S)-Naproxen (36), a potent nonsteroidal antiinflammatory drug (NSAID), is a best-selling agent for arthritis and represents a billion dollar a year market.50 Extensive research is aimed at the formation of the active 5-enantiomer because the /f-isomer is a potent liver teratogen. An asymmetric reduction has been proposed for the manufacture of 36 but has yet to be put into practice. Monsanto has reported that a 4-step manufacture process was in development for naproxen (Scheme 12.10).51... 

The ultimate goal in most industrial research is to develop economically attractive processes or products. The technology of asymmetric hydrogenation of 2-arylacrylic acids is probably most useful for the production of naproxen and S-ibuprofen. Naproxen is currently one of the top ten prescription drugs in the world S-ibuprofen is the active isomer in the popular anti-inflammatory drug ibuprofen. Figures 5 and 6 summarize two commercially feasible processes for the manufacturing of these products. 

NS AIDs ANTIGOUT DRUGS-PROBENECID T levels of indometacin, ketorolac and possibly dexketoprolien, ketoprofen, naproxen, tenoxicam and tiaprofenic acid Probenecid competitively inhibits renal metabolism of these NSAIDs Watch for signs of toxicity of these NSAIDs. Consider using an alternative NSAID. The manufacturers of ketorolac advise avoiding co-adminis-tration of ketorolac and probenecid... 

An example of a formulation generated by this system, for the non-steroidal anti-inflammatory drug naproxen, is given in Table 6. This example, as well as others, was considered acceptable by experienced formulators for manufacture and initial stability evaluation. 

The second study was a case-control study sponsored by Merck Co (the manufacturers of celecoxib), in which the risk of acute thromboembohc cardiovascular events among 16 937 patients aged 40-75 years with rheumatoid arthritis using naproxen was examined using the British General Practice Research Database (52). Each patient with a first... 

Naproxen was introduced to the market by Syntex in 1976 as a nonsteroidal antiinflammatory drug in an optically pure form. The original manufacturing process (Scheme 1) before product launch started from P-naphthol (1) which was brominated in methylene chloride to produce 1,6-dibromonaphthol (2). The labile bromine at the 1-position was removed with bisulfite to give 2-bromo-6-hydroxy-naphthalene that was then methylated with methyl chloride in water-isopropanol to obtain 2-bromo-6-methoxynaphthalene (3) in 85-90% yield from p-naphthol. The bromo compound was treated with magnesium followed by zinc chloride. The resultant naphthylzinc was coupled with ethyl bromopropionate to give naproxen ethyl ester that was hydrolyzed to afford the racemic acid 4. The final optically active naproxen (5) was obtained by a classic resolution process. The racemic acid 4 was treated with cinchonidine to fonn diastereomeric salts. The S -naproxen-cinchonidine salt was crystallized and then released with acid to give S -naproxen (5) in 95% of the theoretical yield (48% chemical yield) [8,9]. 

Acylation of 2-methoxynaphthalene with acetic anhydride was carried out using different solid acid catalysts such as zeolites, acid activated clays, ion exchange resins and sulphated zirconia. The products of the reaction are precursors of many organic and pharmaceutical intermediates. For example, the para isomer of the reaction product, 6-methoxy-2-naphthalene-a-methyl ketone is useful as a raw material for the manufacture of well-known anti-inflammatory dru called naproxen. The reaction products were isolated and confirmed by their melting points, H-NMR, gas chromatography, etc. 

The complete regioselectivity, the absence of byproducts, the ready availability at low cost of the ligand employed, and the chemical and stereochemical efficiency of this reaction make it a good candidate to become the first catalytic, stereoselective industrial manufacturing of naproxen, even if the use of HCN can be a drawback. In this context, it must be remembered that Union Carbide Co. has recently patented a route to (S)-ibuprofen based on a Rh(CO)2(acac)/chiral phosphite-catalyzed hydroformylation of 4-isoutylstyrene that occurs in 82% e.e. [63,80]. 

As of 1995 the manufacturer of ciprofloxacin had, on record, two confirmed spontaneous reports of convulsions in patients taking ciprofloxacin and an NSAID one with mefenamic acid and the other with naproxen. These appear to be the only medically validated reports of cipro-floxacinA SAID reactions by 1995. ... 

The manufacturers of clopidogrel warn about possible gastrointestinal bleeding if it is used with naproxen or other NSAIDs. There is also an increased risk of bleeding if ticlopidine is given with NSAIDs. 

The manufacture of fine chemicals, particularly drugs, fragrances, and flavors, is undergoing a major revolution now as a result of the capability of chemists to prepare these chemicals, mainly drugs, in their purest isomeric forms (as stereoisomers). This shift to pure forms has been described by Brown in the following words (1990) (see also Deutsch, 1991) A mixture of stereoisomers in a medicine will (now) need to be justified just the same way as any other mixture of compounds. Indeed, in the United States today (as in many other advanced countries), the use of pure enantiomeric forms is practically a requirement since extensive justification is needed to continue with racemates (FDA, 1992). As a consequence, the combined sales of the chiral top ten drugs (ammoxydllin, enalapril, ampicillin, captopril, pravastatine, diltiazem, ibuprofen, lovastatin, naproxen, and fluoxetine) in 1994 amounted to more than 16 billion dollars (Sheldon, 1996). (Of these, ibuprofen and fluoxetine are still sold as racemates.)... 

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