Ketoprofen, synthesis

Naproxene Naproxene, 2-(6-methoxy-2-naphthyl)-propionic acid (3.2.15) can be synthesized by the methods of synthesis described for ibuprofen as well as by the methods of fenoprofen (3.2.21) and ketoprofen (3.2.27) synthesis that will be described below from 2-acetyl or 2-chloromethyl-6-methoxynaphthaline [99-101]. 

Common NSAIDs include aspirin, ibuprofen, indomethacin, naproxen, and ketoprofen. Even though anti-inflammatories generally target cyclooxygenase, there are apparent differences in the details of how they relieve pain. For example, aspirin acts by primarily inhibiting the COX-dependent synthesis of eicosanoids, which are end products of metabolism of essential fatty acids including prostaglandin... 

Similarly, glutaryl acylase was used as a biocatalyst in the synthesis of amides of glutaric acid derivatives using the acyl donor as the liquid phase in which the undissolved nucleophile was suspended [33]. In another example, immobilized lipase was used in a medium composed solely of substrate to resolve racemic ketoprofen esters via hydrolysis [36]. 

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). 

Owens J G, Kamerling S G, Stanton S R et al 1996 Effects of pretreatment with ketoprofen and phenylbutazone on experimentally induces synovitis in horses. American Journal of Veterinary Research 57 866-874 Palmoski M J, Brandt K D 1983 Benoxaprofen stimulates proteoglycan synthesis in normal canine knee cartilage in vitro Arthritis and Rheumatism 26 771-774 Pasargiklian M, Bianco S 1986 Perspectives in the treatment of reversible ainway obstruction. Respiration 50(suppl 2) 131-136... 

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). 

Immobilized forms or reticulated crystals of Candida antarctica lipase are effective biocatalysts for the synthesis of pure enantiomers utilized as anti-inflammatory agents. For example, one route for produetion of the 5-isomers of 2-aryl propionic acids (ibuprofen, naproxen, ketoprofen, and flurbprofen) involves enantioselective hydrolysis of the corresponding raeemie esters. Arroyo has indicated that an immobilized form of C. antarctica lipase (fraetion B) is used to mediate the selective acetylation of a diol to form the 5-enantiomer of a monoaeetate (Fig. 5), which is further proeessed to obtain an antifungal agent. ... 

Rhone-Poulenc developed ketoprofen [66]. A few synthetic routes have been reported that involving multi-step syntheses [67, 68]. Ketoprofen is produced by similar reaction sequences that were described for naproxen [69]. Transition metal-catalyzed reactions including carbonylations, hydroformylations, and hydrogenations have been applied to the synthesis of ketoprofen. 3-Vinylbenzophenone (4) was obtained from 3-bromo-benzophenone (3) by a Heck reaction. Palladium-catalyzed carbonylation of 4 provided the isopropyl-a-(3-benzoylphenyl)propionate in 95% yield. Ketoprofen was then obtained in 90% yield by hydrolysis of the isopropyl ester [69]. 

Pirkle, W.H. Welch, C.J. Lamm, B. Design, synthesis, and evaluation of an improved enantioselective naproxen selector. J.Org.Chem., 1992, 57, 3854-3860 [chiral also carprofen, cicloprofen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, pirprofen, tiaprofenic acid]... 

Various NSAIDs, such as ibuprofen, indomethacin, ketoprofen, phenylbutazone, piroxicam, and oxyphenbutazone, can decrease renal creatinine and lithium clearance by their common inhibitory action on prostaglandin synthesis. Aspirin (acetylsalicylic acid) and sulindac have not been found to increase lithium plasma steady-state concentrations. ... 

Extramitochondrial fatty acid CoA ligases are destined for lipid synthesis [40]. Ibuprofen is a substrate for this enzyme, and it has therefore been demonstrated that a number of 2-APAs, including ketoprofen, ibuprofen, and fenoprofen, can be stereoselectively incorporated into lipid tissues... 

McMillan and Allen have accomplished the enantioselective a-arylation of aldehydes using diaryliodonium salts and a combination of copper and organic amine catalysts. This asymmetric protocol has been applied to the rapid synthesis of (5 -ketoprofen, a commercially successful oral and topical analgesic [920],... 

An example of an industrial Heck reaction of an aryl bromide is the announced synthesis of Naproxen by Albermarle. Toward that end, 2-bromo-6-methoxynaphthalene is reacted with ethylene in the presence of a homogeneous palladium catalyst. Apparently, as a ligand a sterically hindered basic phosphine is used. Known Pd-catalyzed hydro-carboxylation of 2-methoxy-6-vinylnaphthalene and subsequent resolution give access to Naproxen (Scheme 3). In addition, it was shown that Ketoprofen can be produced by a similar reaction sequence. 

Two products obtained by this reaction, (m-carboxymethylphenyl)-propionitrile and methyl 2-(6-methoxy-2-naphthyl)propionate (entries 9 and 11, Table I), are intermediates for the preparation of the analgesics Ketoprofen and Naproxen (Figure 2), respectively. In particular, the synthesis of Ketoprofen by DMC has been also scaled up in a pilot plant by Tessenderlo Chemie in Belgium (19). 

Yamauchi Y, Sakai K, Fukuhara T, HaraS, Senboku H (2009) Synthesis of 2-aryl-2,3,3,3-tetrafluoropropanoic acids, tetrafluorinated fenoprofen and ketoprofen by electrochemical carboxylation of pentafluor-oethylarenes. Synthesis 3375-3377... 

Wang H-Y, Zhou Y-J, Wang Z, Wang N, Li K, YuX-Q (2011) Enzyme-catalyzed synthesis of a novel thermosensitive polyester with pendant ketoprofen. Macromol Biosci 11 595-599... 

When used with diphenyliodonium salts in the presence of a metal and an organocatalyst the enantioselective introduction of a phenyl group at the a-position of aldehydes can be accompUshed [42]. This transformation can be extended to a more general concept of enantioselective a-arylation of aldehydes by deployment of different substituted diaryl-iodonium salts. In these reactions CuBr was used as Lewis acid (Scheme 4.12). Based on these findings the authors were able to develop a rapid asymmetric synthesis of the anti-inflammatory drug (S)-ketoprofen. 

SCHEME 14.27. One pot Suzuki carbonylation-hydroxycarbonylation synthesis of ketoprofen... 

Neumann H, Brennfuhrer A, Beller M. An efficient and practical sequential one-pot synthesis of suprofen, ketoprofen and other 2-arylpropionic acids. Adv. Synth. Catal. 2008 350 2437-2442. 

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