Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2002-01-16
2003-10-07
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S589000
Reexamination Certificate
active
06630603
ABSTRACT:
This application is a 371 of PCT/NL00/00189 Mar. 21, 2000.
The present invention relates to a method of industrial-scale purification of lactic acid and to chirally extremely pure products which can be obtained via this method and to uses thereof.
Lactic acid is generally sold as a dilute or concentrated solution, since lactic acid has a strong tendency to form intermolecular esters (dimeric and polymeric lactic acid). Furthermore, lactic acid (even highly pure lactic acid) is strongly hygroscopic. Industrial-scale purification of lactic acid (the racemic mixture and in particular the enantiomers of lactic acid) is a complicated and laborious process according to the prior art.
It is known to prepare lactic acid, or 2-hydroxypropionic acid, by way of fermentation. In general, the fermentative preparation of lactic acid first of all comprises a fermentation step in which a carbohydrate-containing substrate such as glucose or sucrose is converted to lactic acid by a suitable microorganism. Known microorganisms producing (S)-lactic acid are various bacteria of the genus Lactobacillus. for example Lactobacillus casei. Also known, apart from these, are microorganisms which selectively produce (R)-lactic acid. The aqueous fermentation product is then worked up so that lactic acid is obtained. The customary industrial work-up route generally consists of the removal of the biomass, followed by acidification, purification and concentration.
In the case of (S)-lactic acid, the lactic acid thus obtained is sufficiently pure for incorporation into comestibles for human consumption. (S)- or (R)-lactic acid which is ultimately obtained by means of this customary method can have an enantiomeric purity of 98% or even higher (i.e. at 98% or more of the lactic acid present consists of the (S)- or (R)-enantiomer). However, the product still contains residual sugars and other impurities. Moreover, the product has a yellow colour and, when heated, turns brown or even black, due to decomposition of impurities. Furthermore, the product has an unpleasant odour. In addition. in the case of (S)-lactic acid the organoleptic properties are often unsatisfactory. The lactic acid enantiomer is therefore moderately suitable for use in foods, but entirely unsuitable for pharmaceutical applications and in syntheses of chiral compounds.
By means of esterification followed by hydrolysis, the purity of the product can be increased, so that it is suitable for pharmaceutical applications. As a result of this esterification/hydrolysis the enantiomeric purity decreases, however, and the lactic acid still contains a small amount of the alcohol used in the esterification. Examples of other methods of purifying lactic acid comprise subjecting aqueous solutions of lactic acid to one or more extraction, (steam) distillation and/or evaporation steps, electrodialysis steps and crystallizations (see e.g. Ullmans Encyklopädie der Technischen Chemie, Verlag Chemie GmbH, Weinheim, Fourth Edition, Volume 17. pp. 1-7 (1979); H. Benninnga “History of Lactic Acid Making”, Kluwer Academic Publishers, Dordrecht-Boston-London (1990); C. H. Holten, “Lactic Acid; Properties and Chemistry of Lactic Acid and Derivatives”, Verlag Chemie GmbH, Weinheim (1971); The Merck Index, Merck & Co., Inc., eleventh edition, p. 842 (1989); Römmp Chemie Lexicon, G. Thieme Verlag, Stuttgart and New York, Ninth Edition, Volume 4, pp. 2792-2893 (1991) and the Dutch Patent Applications 1013265 and 1013682.
The German Patent 593,657 (granted on Feb. 15, 1934) describes a laboratory experiment in which an aqueous solution of lactic acid which contained an excess of the (S)-component and virtually no lactic anhydride was concentrated by means of a thin-film evaporation technique, at reduced pressure if required, the lactic acid being separated in the process from impurities having a boiling point lower than that of lactic acid. Then the concentrated lactic acid solution was rapidly cooled to form crystals. The crystals were then separated from the mother liquor, washed with ether and recrystallized a sufficient number of times from ethyl acetate or chloroform or a comparable solvent for the crystals to exhibit a sharp melting point of 53° C. The total lactic acid content, the content of monomeric lactic acid, the chiral purity or the enantiomeric excess and the colour are not reported. Moreover, it is obvious to those averagely skilled in the art that such a method is not suitable for efficient industrial-scale purification, especially given the use of solvents such as ether, ethyl acetate or chloroform, which are flammable and/or toxic solvents whose use on an industrial scale is currently not permitted or is subject to very strict standards.
H. Borsook, H. M. Huffman, Y-P. Liu, J. Biol. Chem. 102, 449-460 (1933) describes a laboratory experiment in which an aqueous mixture which contained 50% lactic acid with an excess of (S)-lactic acid, 30% lactic anhydride and lactic acid dimer and 15% water, were subjected to fractional distillation at about 0.13 mbar and 105° C. The middle fraction was subsequently redistilled and then cooled in an ice/salt bath to form a solid mass of crystals. It is stated that the distillation must be carried out using small amounts, as larger amounts will result in a substantial loss of product, owing to the long heating time. The solid mass of crystals was then recrystallized three times from an equal volume of equal quantities of diethyl ether and diisopropyl ether. the crystals were isolated and dried at room temperature in a vacuum desiccator. Thus it was possible to obtain (S)-lactic acid having a melting point of 52.7-52.8° C., which contained less than 0.1% of impurities such as water, lactic anhydride or lactic acid dimer. Again, the chiral purity and the colour are not stated here. Moreover, it is obvious to those averagely skilled in the art that this method too is not suitable for efficient industrial-scale purification.
L. B. Lockwood, D. E. Yoder, M. Zienty, Ann. N.Y. Acad. Sci. 119, 854 (1965) likewise describe distillation and crystallization of lactic acid on a laboratory scale, where the melting point of the optically pure lactic acid obtained was 54° C. The colour and other important properties are not reported.
In 1934, Boehringer Ingelheim studied the crystallization of lactic acid, but this method was found not to produce good results, owing to problems with purification and further treatment. After the Second World War, however, Boehringer Ingelheim proved able to produce lactic acid for pharmaceutical applications on a scale of about 12 to 15 tonnes per month with a yield of about 77 to 86%. This involved purification of an aqueous solution of lactic acid by means of steam distillation at reduced pressure (about 13 mbar) followed by crystallization at −25° C., the crystals then being dissolved in water and the solution being treated with potassium ferrocyanide (to remove heavy metals) and activated carbon. The chiral purity or other properties such as colour and odour of the (S)-lactic acid thus produced are not known. U.S. Pat. No. 5,64,406 discloses a process for the production and purification of lactic acid by ion exchange. In column, line 67—column 2, line , it is further disclosed that cation-free lactic acid solutions can be evaporated or crystallized.
Crystalline (S)-lactic acid has been launched onto the market at purities of more than 99% by Fluka and Sigma, for example, (see, for example, M. L. Buszko, E. R. Andrew, Mol. Phys. 76, 83-87 (1992) and T. S. Ing, A. W. Yu, V. Nagaraja, N. A. Amin, S. Ayache, V. C. Gandhi, J. T. Daugirdas, Int. J. Artif. Organs 17, 70-73 (1994)). Crystalline (S)-lactic acid having a water content of less than 1% by weight is known from Example 1 of EP-A-563,455. The crystal structure of lactic acid is described in A. Schouten, J. A. Kanters, J. van Krieken, J. Mol. Struct. 323, 165-168 (1994).
Lactic acid can also be obtained synthetically. This is known. The product of the synthetic preparation approach, however, is a racemic mixture which therefore contains (S)-l
Breugel Jan Van
Camprubi Vila Margarita
Cerda Baró Agusti
Van Krieken Jan
Vidal Lancis Jose Maria
Killos Paul J.
Purac Biochem B.V.
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