In 1981, Shen (Shen T. Y., in: Wolff, M. F. (ed) Burger's Medicinal Chemistry, 4th edition, part III, Wiley, Interscience, New York, pp. 1205-1271) reviewed the medicinal aspects of the aryl-acetic acids and their 2-methyl analogues, especially the 2-aryl-propionic acids. In particular, it has been reported that the in vitro anti-inflammatory activity resides in the S-enantiomer which is an optically active enantiomer of the racemate (R,S)-2-aryl-propionic acid which is up to 150 times as active as its P-enantiomer as described by Adams et al. (S. Adams et al., J. Pharm. Pharmacol., 28, 1976, 256; A. J. Hutt and J. Caldwell, Chemical Pharmacokinetics 9, 1984, 371). Moreover, the chiral inversion by the metabolism in man of 2-aryl-propionic acids of the R-(-) enantiomer to the biologically active (S-(+) enantiomer, especially in case of ibuprofen (R,S)-2-(4-isobutylphenyl)-propionic acid), supports the pharmacologically active principle of the S-(+)-enantiomer which is also supported by the studies of the S-enantiomer of Naproxen (A. J. Hutt and J. Caldwell, J. Pharm. Pharmacol., 35, 1983, 693-694). In addition, there is no metabolic chiral inversion to the corresponding R-(-)-enantiomer of the S-(+) form in man, although some stereochemical inversion has been observed in rats occasionally, possibly due to unknown stereochemical interactions of the (S)-(+) and R-(-) enantiomers at the site of action.
Since the conversion of the R-(-)-2-aryl-propionic acids to the pharmacologically active S-(+)-enantiomer is a reaction of great medicinal impact, it is likely that certain benefits will be obtained by the use of the S-(+)-enantiomers of 2-aryl-alkanoic acids as compounds as opposed to the racemates. The use of the S-(+) enantiomers would permit reduction of the dose given, reduce the gastro-intestinal side effects, reduce the acute toxicity, remove variability in the rate and extent of inversion, and in addition will reduce any toxicity arising from non-specific reactions.
Therefore, there is need of a process capable of operating on an industrial scale in order to produce economically attractive yields of these S-(+) enantiomers of high optical purity &gt;98%, by applying a stereospecific chemical method. Optically pure enantiomers of 2-aryl-alkanoic acids, especially 2-aryl-propionic-acids which are approved for pharmaceutical use as a pure, optically active stereoisomer, e.g. S-(+)-(6-methoxy-2-naphthyl)-propionic acid (Naproxen) or S-(+) ibuprofen, can be obtained by using conventional ways of racemic separation by applying optically active bases, e.g. 2-phenyl-ethyl-amine, N-methyl-glucamine, cinchonidine, brucine or D-(-)-threo-1-p-nitrophenyl-2-amino-propane-1,3-diol or through biochemical racemate separation (P. Cesti and P. Piccardi, Eur. Pat. Appl. EP 195,717; 1986, J. S. Nicholson, and J. G. Tantum, U.S. Pat. No. 4,209,638, 1980), or by high performance liquid chromatographic techniques (see G. Blaschke, Angew. Chem. 92, 14-25, 1980). However, these methods of applying optically active bases or enzymes (pig liver esterase) have the drawback common to all these processes of high material costs, manufacturing labor and equipment for the recovery and racemization of the undesired optical stereoisomer not counting the energy necessary for redistillation of the solvents, low yields of crystalline compounds of high optical purity from the mother liquors. Thus the elimination of these resolution steps can result in substantial savings in material costs, manufacturing, labor and equipment.
Methods for synthesizing racemic 2-aryl-alkanoic acids, especially 2-aryl-propionic acids and in particular to R, S-ibuprofen are well known, see, for example, Tanonaka, T., et al., DE 3523082 A1, (1986), who uses microorganisms; JP-PSEN 40-7491 (1965); 47-18105, (1972); JP-OS 50-4040, (1975); DE 2404159 (1974); DE 1443429 (1968) by J. S. Nicholson and S. S. Adams; DE 2614306 by Bruzzese, T., et al., (1976); DE 2605650 by Gay, A., (1976): DE 2545154 by Heusser, J., (1976); and DE 2404160 by Kogure, E., et al., (1974).
Surprisingly, only & few methods for a stereospecific chemical synthesis for 2-aryl-alkanoic acids, especially 2-aryl-propionic acids are known. Piccolo et al. (J. Org. Chem. 50, 3945-3946, 1985) describe a stereospecific synthesis by the alkylation of benzene or isobutylbenzene with (S)-methyl-2-[(chlorosulfonyl)-oxy] or 2-(mesyloxy) propionate in the presence of aluminium chloride yielding (S)-methyl-2-phenyl-propionate in good chemical yield (50-80%) and excellent optical yield of &gt;97% as determined by rotation through inversion of configuration at the attacking carbon atoms. The reaction conditions are very similar as described in some patents (Jpn. Kokai Tokkyo Koho 5808045; Chem. Abstracts, 1983, 98; 143138 k; Jpn. Kokai Tokkyo Koho 7979246; Chem. Abstracts, 1980, 92, 6253 f) where racemic reagents have been used. Extensions of this type of reactions to other aromatic substrates, e.g. toluene, isobutylbenzene, tetraline, anisole, naphthalene, 2-methoxy-naphthalene are described in Jpn. Kokai Tokkyo Koho 7971932; Chem. Abstracts 1979, 91, 20125 b; Jpn. Kokai Tokkyo Koho 78128327; Chem. Abstracts 1978, 89, 23975 y; Jpn. Kokai Tokkyo Koho 81145241; Chem. Abstracts 1982, 96, 68650 z; Jpn. Kokai Tokkyo Koho 78149945; Chem. Abstracts 1979, 90, 168303 h; Jpn. Kokai Tokkyo Koho 7844537; Chem. Abstracts 1978, 89, 108693 h; Jpn. Kokai Tokkyo 77131551; Chem. Abstracts 1978, 88, 104920 h. In a recent paper Piccolo et al. (J. Org. Chem. 51, 10, 1987) describe a synthesis leading to R-(-) ibuprofen, whereas Tsuchihashi et al. (Eur. Pat. Appl. EP 67,698, (1982); Chem. Abstracts 98, 178945 y, (1983) report a stereospecific synthesis of the R-(-) ibuprofen- methylester with excellent yields of about 75.0% and high optical purity (&gt;95%) in contrast to Piccolo et al. (J. Org. Chem. 32, 10, 1987) having an optical purity of 15% only for the R-(-) ibuprofen. However, the same authors have reported chemical yields of 68% of S-(+) ibuprofen having an optical purity of 75-78%, only. Hayashi, et al. (J. Org. Chem. 48, 2195, 1983; in: Asymmetric Reactions and Processes In Chemistry; eds E. L. Eliel and S. Otsuka, ACS-Symposium Ser. 1985, 1982, 177) describe a stereospecific synthesis of S-(+) ibuprofen through asymmetric Grignard cross-coupling which are catalyzed by chiral phosphine-nickel and phosphine- palladium complexes. The enantiomeric excess of the coupling products with various alkenyl halides under the influence of the above-mentioned metal phosphine complexes, including amino acids, depends strongly on the ligand and ranges up to 94% with enantiomeric excesses in the 60-70% range. A very useful ligand has been found in chiral 2-aminoalkyl phosphines achieving reasonable chemical yields and high optical purity. Furthermore, optically active 2-aryl-alkonates have been synthesized via a Friedel-Crafts synthesis by Sato and Murai (Jpn. Kokai Tokkyo Koho JP 61,210,049 t 86,210,049, 1986) yield 46% S-(+) ibuprofen. Giordano et al. (EP application 0 158 913, 1985) has reported a process for the preparation of optically active 2-aryl-alkanoic acids and intermediates thereof by halogenation on the aliphatic carbon atom to the ketal group and rearrangements of the haloketals yielding pharmacologically active 2-aryl-alkanoic acids. A stereochemical synthesis of 2-aryl-propionic acids is described by Robertson et al. (EP application 0 205 215 A2, 1986) using 2)R.sub.1)-alkane as the carbon source for the fungi Cordyceps in particular for Cordiceps militaris, yield enantiomeric S-(+) products of high optical purity.
Methods for the synthesis of anti-inflammatory 2-aryl-propionic acids are listed in the review by Rieu et al. (J. P. Rieu, A. Boucherle, H. Coussee and G. Mouzin, Tetrahedron Report No. 205, 4095-4131, 1986), also. However, this report is mostly concerned with the racemates rather than an evaluation of stereospecific chemical synthesis of 2-aryl-propionic acids.