Indian Patents. 269101:KETOMETHIONINE KETALS AND THEIR DERIVATIVES

Title of Invention	KETOMETHIONINE KETALS AND THEIR DERIVATIVES
Abstract	The present invention relates to ketomethionine ketals or hemiketals and their derivatives and also their preparation and their use as fodder additives, in particular for the nutrition of ruminants.

Full Text	Ketomethionine ketals and their derivatives Introduction The present invention relates to ketomethionine ketals and hemiketals and derivatives thereof and also production thereof and use thereof as feed additives, in particular for the nutrition of ruminants. Prior art Amino acids such as methionine, lysine or threonine are, as feed additives, important components of animal nutrition. They make possible more rapid growth and also more efficient feed utilization. This usually represents an important economic advantage. The markets for feed additives are of great industrial and economic importance. In addition, they are great growth markets which is due, not least, to the increasing importance of countries such as China and India, for example. WO 2004008874 discloses, inter alia, that methionine is the first limiting amino acid for many animal species, including ruminants. For instance in the case of dairy cows, for example, efficient milk production with respect to the amount and quality is greatly dependent on a sufficient supply of methionine. The methionine requirement of high performance dairy cows cannot be covered in this case by the microbial protein formed in the rumen or by protein from the feed not degraded in the rumen (Graulet et al., J. Animal and Feed Sciences (2004), 269). It is therefore advantageous to supplement methionine to the feed to increase the economic efficiency of milk production and the quality of the milk. In the case of monogastric animals such as, for example, poultry and pigs, customarily, as feed additive, use is made of methionine and the Methionine Hydroxy Analogue (MHA), which is also termed hydroxymethylthiobutyric acid (HMB). This increases the available amount of L-methionine in the body which can then be available to the animal for growth. In contrast thereto, supplementation of the feed with methionine is ineffective in ruminants, since the majority is degraded by microbes in the rumen of ruminants. Owing to this degradation, therefore, only a fragment of the methionine supplemented passes into the small intestine of the animal, where generally the absorption of methionine into the blood proceeds. WO 99/04647 describes the use of MHA for ruminants. Therein it is asserted that MHA is only in part broken down in the rumen and therefore at least 20-40% of the supplemented MHA, after absorption in the small intestine, can pass in to metabolism. In numerous other publications, in contrast, the mode of action of MHA in ruminants is discussed differently. For instance, WO 200028835, for example, describes that MHA can only successfully pass through the rumen and finally into the small intestine for absorption when MHA is administered in very large amounts of 60-120 g/day/animal. However this precludes economic efficiency. In order that methionine products such as D,L-methionine or rac-MHA are available to ruminants with high efficiency, a form protected against rumen degradation must be used. The challenge in this case is to find a suitable methionine product which gives the methionine a rumen stability as high as possible and nevertheless ensures high and efficiency absorption of the methionine in the gut. There is a plurality of possibilities in this case of giving D,L-methionine or rac-MHA these properties: a) Physical protection: By application of a suitable protective layer or distribution of the methionine in a protective matrix, a high rumen stability can be achieved. As a result, the methionine can pass through the rumen virtually without loss. In its further course, the protective layer is then, for example, opened or removed by acid hydrolysis in the abomasum and the methionine released can then be absorbed by the animal in the small intestine. The protective layer or protective matrix can consist of a combination of a plurality of substances such as, for example, lipids, inorganic materials and carbohydrates. The following product forms are commercially available: i) Met-Plus™ from Nisso America is a lipid-protected methionine having a D,L-methionine content of 65%. The protective matrix consists of the calcium salts of long chain fatty acids such as, for example, lauric acid. As preservative, butylated hydroxytoluene is used. ii) Mepron* M85 from Degussa AG is a carbohydrate- protected methionine which has a core of D,L-methionine, starch and stearic acid. As protective layer, ethylcellulose is used. The product has a content of 85% D,L-methionine. iii) Smartamine™ M from Adisseo is a polymer-protected methionine. The pellets, in addition to stearic acid, contain at least 70% D,L-methionine. The protective layer contains vinylpyridine-styrene copolymer. Although the physical protection prevents microbial breakdown of methionine in the rumen and as a result the supply and utilization of methionine in the animal can be increased, there are some serious disadvantages. The production or coating of methionine is usually a technically complicated and laborious process and is therefore expensive. In addition the surface coating of the finished pellets can easily be damaged by mechanical load and abrasion during feed processing which can lead to reduction or up to complete loss of the protection. Therefore, it is also not possible to process and repellet the protected methionine pellets to form a larger compound feed pellet, since, as a result, again the protecting layer would break owing to the mechanical stress. This greatly restricts the use of such products, since compound feed pelleting is a widely used method of feed processing. b) Chemical protection: Increased rumen stability of methionine can, in addition to purely physical protective possibilities, also be achieved by modifying the chemical structure, for example by esterifying the carboxylic acid group. Currently, the following products are commercially available or are described in the literature: i) Methionine esters such as, for example, D,L-tert- butylmethionine: The esters have been tested and demonstrated only moderate rumen stability (Loerch and Oke; "Rumen Protected Amino Acids in Ruminant Nutrition" in "Absorption and Utilization of Amino Acids" Vol. 3, 1989, 187-200, CRC Press, Boca Raton, Florida). For D,L-tert-butylmethionine, in contrast, in WO 0028835, a biological value of 80% was published. ii) Metasmart™ from Adisseo is the racemic isopropyl ester of MHA (HMBi) . This compound is also marketed under the trademark "Sequent" by the American company Novus. In WO 00/28835, a biological value of at least 50% for HMBi in ruminants was published. In this case, especially, the surprisingly rapid absorption of the hydrophobic HMBi through the rumen wall plays a decisive role. The ester can then be hydrolysed to MHA in the blood and, after oxidation and subsequent transamination, can be converted to L-methionine. In the patent EP 1358805, a comparable biological value for HMBi was published. In these studies, HMBi was applied to a porous support. In a further publication, the European Commission reported that, again, approximately 50% HMBi is absorbed via the rumen wall (European Commission: Report of the Scientific Committee on Animal Nutrition on the Use of HMBI; 25 April 2003) . Graulet et al. published in 2004 in the Journal of Animal and Feed Science (269), that better diffusion through the rumen wall is enabled by the lipophilic properties of the isopropyl group of HMBi. For the production of HMBi, two different processes have been published. Thus, HMBi can either be synthesized directly in one stage from the corresponding cyanohydrin (WO 00-59877). Esterification to give the isopropyl ester proceeds in this case in situ, without needing to isolate MHA in advance. Another process, in contrast, esterifies pure MHA with isopropanol (WO 01-58864 and WO 01-56980). In both cases, for the synthesis, use is made of prussic acid which is expensive and in addition is a great potential hazard. iii) Ketomethionine and its carboxylic acid derivatives: The use of this class of compounds, in particular of ketomethionine itself, as feed additives was first described recently in application WO 2006-072711. There, a technical process for producing ketomethionine and carboxylic acid derivatives thereof was also described. Ketomethionine is the direct precursor of methionine and can readily be converted in the body to L-methionine in one step by means of transamination. In comparison therewith, both MHA and HMBi have the disadvantage that they require two or three steps for conversion to L-methionine in the body. For instance, HMBi must first be hydrolysed to free MHA and subsequently oxidized to ketomethionine with the aid of an oxidase. Not until then can in turn the ketomethionine be directly reductively aminated to give L-methionine [Baker; "Utilization of Precursors for L-Amino Acids" in "Amino Acids in Farm Animal Nutrition" (D'Mello, J.P.F., ed.), 1994, 37-64. CAB Intl., Wallingford, Oxon, UK]. Free ketomethionine as ct-ketocarboxylic acid and its salts such as, for example, the sodium or calcium salt, are compounds already known from the literature for a long time and have been produced both biochemically and chemically. Meister, for example, obtained the sodium salt of a-ketomethionine in a yield of 77% by the L-amino oxidase-catalysed oxidation of methionine (Meister, J. Biol. Chem. 1952, 197, 309). Previously, Waelsch et al., showed that the amino oxidases present in liver can convert methionine to a-ketomethionine (Waelsch et al., J. Am. Chem. Soc. 1938, 61, 2252). Mosbach et al., likewise described the production of ketomethionine by the L-amino oxidase-catalysed oxidation of methionine. In this case immobilized Providencia sp. PCM 1298 cells were used (Mosbach et al.. Enzyme Microb. Technol. 1982, 4, 409). As a further possible synthesis method, Sakurai et al. in 1957 published the first chemical synthesis route for synthesising a-ketomethionine. In this case, as key step, methyl -cc-methoxalyl -y-methylmercaptopropionate was hydrolyzed with dilute hydrochloric acid to give ketomethionine (Sakurai et al., J. of Biochemistry 1957, 44, 9, 557). Yamada et al. published virtually simultaneously the same synthesis route, after first attempts at synthesizing a-ketomethionine via an a-oximo ester formed as an intermediate gave only low yields. (Chibata et al., Bull. Agr. Chem. Soc. Japan 1957, 21, 6, 336) . The biological value of the sodium salt of a-keto- methionine was determined for the first time in 1977 in feeding experiments with rodents and poultry and is significantly above that of MHA (Baker and Harter, Proceedings for the Society for Experimental Biology and Medicine 1977, 156, 2001). In ruminants, a-keto- methionine and salts thereof, however, are broken down in the rumen and therefore offer no advantages over HMB or methionine. As free a-ketocarboxylic acid, a-ketomethionine in addition has the further disadvantage that it dimerizes in a very short time and subsequently irreversibly cyclizes and therefore is not stable as a monomer of biological value and therefore is avoided in direct use as feed additive. Object of the invention Against the background of the disadvantages of the prior art, it was the object to provide a rumen-stable, chemically protected methionine product for ruminants, in particular for dairy cows, which can serve as efficient methionine source for the animals and which does not have the disadvantages of the known products, or has them to a decreased extent. This would have the advantage that milk production and quality could be thereby increased, which would lead to a significant increase in economic efficiency. A further object was to find a feed and a feed additive of very high biological value which should have good handleability and storability and also stability under the customary conditions of compound feed processing, in particular pelleting. The product, in addition, should be useable in animal nutrition in the most general possible way as feed additive. Description of the invention This object and also other objects not explicitly- mentioned, but which can readily be derived or deduced from the contexts discussed herein are achieved by the ketomethionine ketals of the invention and derivatives thereof according to formula I, in particular use thereof as feed, preferably for ruminants. Thereby, not only the disadvantages of the "physically protected" methionine variants, such as, for example, Smartamine, but also the disadvantages of the "chemically protected" variants, such as, for example, HMBi, are overcome. The present invention relates to a chemical compound of the general formula I C allyl, benzyl, phenyl or C3-C6-dihydroxyalkyl, preferably (HO)2C3H5-, or a C3-C12 sugar radical in which one OH group of the sugar is replaced in each case by the ketal-0 atom, by the carboxylic acid-0 atom or by the carboxamide-N atom and M is an alkali metal ion or alkaline earth metal ion, preferably Na+, K+, Mg2+ or Ca2+ or a monovalent or divalent transition metal ion, preferably Zn2+, Mn2+, Cu2+ or Cr2+, or A = and R = OH, OM, OR', NH2, NHR' or NR'R", wherein R' and R" are identical or different and are in each case a branched or straight-chain C1-C18-alkyl or C3-C18-cycloalkyl, allyl, benzyl, phenyl or C1-C18-alkyloxymethyl, preferably C2H5OCH2 C2-C6-hydroxyalkyl/ preferably HOC2H4-, C3-C6-dihydroxyalkyl, preferably (HO)2C3H5-, or a C3-C12 sugar radical in which one OH group of the sugar is replaced by the carboxylic acid-0 atom or by the carboxamide-N atom and M is an alkali metal ion or alkaline earth metal ion, preferably Na+, K+, Mg2+ or Ca2+ or a monovalent or divalent transition metal ion, preferably Zn2+, Mn2+, Cu2+ or Cr2+, and R3 is a C2-C4-alkylene bridge, preferably C2H4, or a C3-C12 sugar radical in which two OH groups of the sugar are replaced by the two ketal-0 atoms, and R4 is a C3-C6-alkylene radical which, if appropriate, is hydroxy substituted, preferably -CH2-C(CH3)3-CH2- and -CH2-C(CH2OH)2-CH2-, or a C3-Ci2 sugar radical in which one OH group of the sugar is replaced by the ketal-0 atom and one is replaced by the carboxylic acid-0 atom, and Rs is a C3-C6-alkylene radical which, if appropriate, is hydroxy substituted, preferably -CH2-CH(-) -CH2-, or a C3-C12 sugar radical in which three OH groups of the sugar are replaced by both ketal-0 atoms and by the carboxylic acid-0 atom, and R5 is a C3-C6-alkylene radical which, if appropriate, is hydroxy substituted, preferably -CH2-CH(-) -CH2-, or a C3-C12 sugar radical in which two OH groups of the sugar are replaced by the two ketal-0 atoms, and wherein X = H or M and M has the meaning given above. Preference in this case is given to a compound of the formula 1,2, in which R = hydroxyl and R3 = C2H4 This can readily be produced by ketalization of ketomethionine with stoichiometric amounts of ethylene glycol in the presence of acid catalysts or with super- stoichiometric amounts of ethylene glycol and subsequent saponification of the ketomethionine ethylene ketal ethylene glycol ester formed as an intermediate with alkali and subsequent neutralization (cf. Example 2). Further preference is given to a compound according to formula 1,2, in which R = OR' and R' = C1-C18-alkyloxy and R3 = C2H4. This compound can be produced by esterification of ketomethionine with a corresponding C1-C18-alcohol in the presence of acid catalysts, and preferably subsequent ketalization with ethylene glycol. Particular preference is given in this case to a compound according to formula 1,2, in which R' = C1-C4 - alkyloxy. Further preference is given to a compound according to formula 1,2, in which R = OR' and R' = hydroxyethoxy and R3 = C2H4: Still more preference is given to a compound according to formula 1,3, in which R* is a C5H10 radical or a C5H10O2 radical. Particular preference is given in this case to a compound characterized by the formula which can be produced from ketomethionine and neopentylidene glycol in the presence of acid catalysts. Likewise preference is given to an analogous compound of the formula which can be produced from ketomethionine and pent a- erythritol in the presence of acid catalysts. Further preference is given to a compound according to formula 1,4, in which R5 is a C3H5 radical. Particular preference is given in this case to a compound characterized by the formula (1,2-ketal) i Both compounds, the 1,2-ketal and the 1,3-ketal, can be produced from ketomethionine and glycerol in the presence of acid catalysts, preferably under dehydrating conditions. All compounds of the general formula I are outstandingly suitable according to the invention for use in animal nutrition, preferably for nutrition of farm animals. Preference is given in this case to use for nutrition of ruminants, in particular dairy cows. For this purpose, the compounds of the invention can be used for producing feeds. In this case, again preference is given to use for producing feeds for ruminants. Likewise, the present invention relates to feed preparations containing at least one of the abovementioned compounds of the invention, preferably for nutrition of ruminants. Accordingly, mixtures of the compounds of the invention with conventional feeds can be produced. For this, the compounds of the invention are mixed in suitable amounts into commercially conventional feed types, such as mineral feed, organic feed (for example soybean meal) or dairy compound feed. Suitable amounts are generally proportions of 0.1% to 5% of methionine equivalents in the form of the compounds of the invention, wherein the proportions are different depending on the type of feed. Dairy compound feed is preferably mixed with equivalents, mineral feed with up to 5% and organic feed in the range from 0.5 to 3%, preferably up to 1%. One methionine equivalent in this context is the part by weight of compound of the invention which is equivalent to the same amount of methionine oh a molar basis. The present invention further relates to a process for producing carboxylic acid or ester compounds of the general formula I, 1-5, wherein, in the case of formula 1,1 and 2 the radical is not OM, NH2, NHR' or NR'R", characterized in that ketomethionine is reacted with a corresponding monovalent, divalent, trivalent alcohol or a C3-C12 sugar in the presence of acid catalysts to give the ester product of the formulae 1-2, where R = 0R#, or to give the ester product 3-4 or to give the acid product 1-2, where R = OH, or to give the acid product 5 where X = H. Corresponding to said preferred compounds, in this case one process is preferred in which, as alcohol, use is made of a branched or straight-chain C1-C18-alkyl alcohol or C3-C18-cycloalkyl alcohol, allyl alcohol, benzyl alcohol, phenyl alcohol, Ca-Cg-hydroxyalkyl alcohol, preferably HOC2H4OH, C3-C6-dihydroxyalkyl alcohol, preferably glycerol or a C3-C12 sugar, preferably glyceraldehyde, dihydroxyacetone, glucose, fructose or sucrose. In this case, in particular by suitable selection of the amount of mole equivalents of the alcohol or sugar required for the ketalization, the formation of the desired product can be influenced. When one mol equivalent of C1-C18-alkyl alcohol is used, the corresponding ester not according to the invention is preferentially formed, when two mol equivalents are used, the carboxylic acid ketal of the formula 1,1 where R = OH is preferentially. formed and when three mol equivalents are used, the corresponding ester ketals of the formula 1,1 where R = OR' are preferentially formed. Correspondingly, when one half mol equivalent of C2-C6-hydroxyalkyl alcohol is used, (such as, for example, H0C2H40H) correspondingly two hydroxy equivalents of the corresponding carboxylic acid ketal of the formula 1,2 where R = OH and R3 = C2H4 are formed. The production of carboxylic acid or ester compounds can advantageously be carried out in the presence of a solvent. Suitable solvents are, for example, aromatic hydrocarbons such as benzene or toluene, and also chlorinated hydrocarbons, such as methylene chloride or chloroform, and alcohols. In the interest of a yield as high as possible of desired condensation products, in this case preference is given to a process in which water formed during the reaction is removed from the equilibrium. This can be achieved both by distillation, preferably by using a solvent and/or entrainer such as, for example, toluene. It is advantageous in this case when the solvent simultaneously acts as entrainer and, if appropriate, further as reactant. Also, in this case, the alcohols used for esterification or ketalization can additionally be used as solvent and/or entrainer. When used as entrainer, the solvent should have a suitable boiling point. This should generally not exceed 120°C. Alcohols suitable for this purpose are, for example, Ci-C4-alkyl alcohols, that is to say methanol, ethanol, 1- or 2-propanol and 1- or 2-butanol, isobutanol, tert-butanol. A further possibility for removing water is the use of dehydrating agents, for example orthoesters, such as, for example trimethyl or triethyl orthoacetate. The methyl or ethyl acetate formed as coupling products can subsequently readily be removed from the reaction mixture by distillation and reused. In this case the carboxylic acids or carboxylic acid salts of the general formula 1,1-2 or 5, in which the radical R = OH or OM and the radical X = H or M, can preferably be produced by converting a carboxylic ester product of the formula 1,1 or 2 where R = OR', or of the formula 1,4, into the corresponding carboxylic acid salt of the formula 1,1 or 2 where R = OM or of the formula 5 where X = M by saponification with an alkali metal hydroxide or alkaline earth metal hydroxide or a monovalent or divalent transition metal hydroxide and, if appropriate, liberating therefrom the free carboxylic acid where R = OH or X = H with the aid of a mineral acid. Suitable mineral acids in this case are, in particular, sulphuric acid, hydrochloric acid and phosphoric acid. The invention also relates to a process for producing carboxylic acid salts of the general formula 1,1-2 or 5, wherein the radical R = OM or' the radical X = M, which is characterized in that an acid product of the formula 1,1-2 where R = OH or an acid product of the formula 1,5 where X = H is neutralized with an alkali metal or alkaline earth metal or a monovalent or divalent transition metal hydroxide or carbonate to give the corresponding carboxylic acid. For production of the abovementioned carboxylic acid salts by saponification or neutralization, in this case, as hydroxides, use is preferably made of NaOH, KOH, Mg(OH)2, Ca(OH)2, Zn(OH)a or Mh(OH)a and, as carbonates, Na2CO3, K2CO3, MgCO3, CaCO3, ZnCO3 or MnCO3. The invention also relates to a process for producing carboxamides of the general formula 1,1-2 where R = NH2, NHR', NR'R", characterized in that an ester product of the formula 1,1-2, where R = OR', is converted into the corresponding amide by reaction with a nitrogenous base of the formula NH3, NH2R' or NHR'R". The invention also relates to a process for producing ester compounds of the general formula 1,1-2, where R = OR', which is characterized in that an ester product I, 1-2, is converted into a corresponding ester product of the formula I, 1-2 by transesterification with an alkali metal alkoxide M'OR' (M' = alkali), with the proviso that R' in the ester product I, 1-2 used must not be equal to the radical R' in the alkoxide M'OR' used. Ketomethionine ketal esters once produced can in this manner be very readily converted into other desired ketomethionine ketal esters. The ketomethionine ketals of the general formula 1,1,2 or 5 where R = OH or OM respectively, X = H or M are polar and non-lipophilic compounds. Owing to the ketal protecting group, these compounds are rumen-stable and cannot be microbially degraded. As a result of the lipophobic carboxylic acid group, however, they are not absorbed via the rumen wall as with HMBi, but pass without, breakdown into the abomasums of the ruminant, where they are hydrolysed owing to the strongly acidic conditions. The ketomethionine released is then subsequently absorbed in the small intestine. The ketomethionine ketal esters of the general formula 1,1,2 where R = OR', or of the general formula 1,4 are lipophilic and non-polar compounds. Owing to the two chemical protecting groups "ketal" and "ester", these compounds are rumen-stable. The absorption, in contrast to ketomethionine ketals, proceeds rapidly and effectively via the rumen wall similarly to the mechanism of HMBi. The subsequent enzymatic cleavage to give the free ketomethionine then proceeds in the blood of the ruminant. The use of ketomethionine ketals or ketomethionine ketal esters thus makes possible for the first time an active control of the absorption site of the "methionine equivalent". The ketomethionine ketals or ketomethionine ketal esters and derivatives thereof have a plurality of advantages over the compounds known in the prior art: In contrast to free ketomethionine, ketomethionine ketals, ketomethionine ketal esters, ketomethionine hemiketal esters and ketomethionine ketal amides of the general formula I are chemically stable with respect to dimerization and cyclization, a precondition for storage and transport as feed additives. Use of the compounds of the general formula I permits the active control of the absorption site in the body of the ruminant. In this case the hydrophilic ketomethionine ketals of the formula 1,1,2 where R - OH, OM, or of the formula 1,5 where X = H, M are absorbed in the small intestine after hydrolysis in the abomasum, and the absorption of the lipophilic ketomethionine ketal esters of the general formula 1,1,2 where R = OR', or of the general formula 1,4 proceeds directly via the rumen wall. In the case of use of certain diols such as, for example ethylene glycol, or selected triols such as, for example, glycerol, or sugars such as, for example, glucose, as building blocks for ketal or ester formation with ketomethionine to give the corresponding compounds of the general formula I, these additionally have a nutritive action, owing to the sugar or alcohol building blocks which can be released again in the body. Ketomethionine ketals and ketomethionine ketal esters have a very high biological value, since they can be hydrolysed in vivo to give a-ketomethionine. The biological value of ketomethionine in this case is significantly higher than that of MHA, since, in contrast thereto, it can be converted to L-methionine in the body in only one stage. In contrast, MHA requires two stages and HMBi even three stages. The high biological value of ketomethionine ketals and ketomethionine ketal esters is a significant economic advantage, since less feed additive is required. On account of the chemical protection, the product and with it the rumen protection can not be damaged by physical forces such as, for example, friction. Therefore, in comparison with a physically protected methionine form, such as, for example Smartamine, it is possible to pellet ketomethionine ketals, ketomethionine ketal esters, ketomethionine hemiketal esters and ketomethionine ketal amides of the general formula I. This is an extraordinary advantage, because a broad usability in compound feed production and final processing is thereby ensured. In addition, the said compounds of the general formula I can generally be used as feed additives in farm animal husbandry, that is to say also in the nutrition of poultry or pigs. In particular, ketomethionine ketals and ketomethionine ketal esters can be produced in a simpler manner, and thus generally at lower production costs, than physically protected methionine forms. The symmetrical ketomethionine ketals of the general formula I are achiral in contrast to MHA, HMBi or D,L-methionine. Natural L-methionine is formed directly from these achiral precursors in the animal body. Conversion of the unnatural enantiomer is omitted thereby. The examples hereinafter show possibilities for producing the compounds according to the invention without acting in a limiting manner in this case. Examples: Example It Release of ketomethionine from Its salts (not according to the invention): To a suspension of 43.3 g of calcium ketomethioninate (M = 334.42 g/mol, 98% purity, 21% water content in the dry mass) in 120 ml of H2O and 320 ml of diethyl ether, a 10% strength aqueous hydrochloric acid solution was added slowly dropwise at 0°C with vigorous stirring until the pH was aqueous phase was washed three times, each with 120 ml of diethyl ether. Subsequently, the combined organic phases were dried over Na2SO4. After filtration of the desiccant, the diethyl ether was distilled off on a rotary evaporator at 30°C and slight vacuum. The last solvent residues were removed in high vacuum. There remained 29.1 g of a slightly yellowish oil of free ketomethionine (yield = 98%, M = 148.18 g/mol). ^-NMR of calcium ketomethioninate 500 MHz, DMSO-d6): "C-NMR of ketomethionine (125.8 MHz, DMSO-d6): 8 = 14.7 (CH3) , 26.7 (CH2) , 38.5 (CH2) , 162.2 (COOH) , 194.9 (CO). Example 2: Production of ketomethionine ketala of the formula 1,2 exemplified by the reaction of ketomethionine and ethylene glycol: A solution of ketomethionine (174 mmol, M = 148.18 g/mol) in toluene (100 ml) was added dropwise over the course of 2 h to a solution of 1 g (-3 mol%) of p-toluenesulphonic acid as catalyst and ethylene glycol (335 mmol, M 62.07 g/mol) in toluene (250 ml) and the reaction was kept under reflux until no more water separated off at the attached water separator (approximately 2 h). Subsequently the toluene was taken off under vacuum and the crude product was admixed with methanol (200 ml) and, after addition of an aqueous solution of 2M sodium hydroxide (200 ml) saponified under alkaline conditions for approximately 2 h. The reaction solution was subsequently extracted by shaking with diethyl ether and the aqueous phase was acidified with dilute hydrochloric acid. The product was extracted at pH 1-2 with diethyl ether, the organic phase washed with water, dried over Na2SO4 and the solvent removed on a rotary evaporator. The oily product (1,2) was subsequently recrystallized from methylene chloride/n-hexane and was obtained as white crystalline solid. (24.6 g, yield = 74%, M = 192.23 g/mol, melting point: 74°C methylene chloride/n- hexane). 1H-NMR of 2-(2-(methylthio)ethyl)-1,3-dioxolane-2- carboxylic acid (1,2) (500 MHz, CDC13) : 5 = 2.11 (s, 3H, SCH3) , 2.24-2.28 (m, 2H# CH2) , 2 .58-2 . 61 (m, 2H, CH2) , 4.07-4.14 (m, 4H, OCH2CH2O) . 13C-NMR of 2-(2-(methylthio)ethyl)-l,3-dioxolane-2- carboxylic acid (1,2) (125.8 MHz, CDC13) : 6 = 15.5 (SCH3) , 27.1 (CH2) , 34.9 (CH2) , 66.1 (2 OCH2) , 105.9 (C), 174.1 (COO). Elemental analysis for C7H12O4S (M = 192.24 g/mol) : C 43.74; H 6.29; S 16.68 found: C 43.80; H 6.25; S 16.61. Example 3: Production of the calcium salt of ketomethionine ketal by neutralization: To a solution of 1.0 g (5.20 mmol) of 4-(methylthio)-2- ketobutyric acid ethylene ketal in 2.0 ml of water and 3.0 ml of acetone was added slowly dropwise at RT an aqueous solution of 0.44 g of calcium acetate (93% strength) in 2 ml of water. Subsequently 3 ml of acetone were added and the mixture was stirred overnight at RT. The white solid formed was filtered off by suction and washed thoroughly with 100 ml of a 1:10 water/acetone mixture. The product was subsequently dried in a drying cabinet and in high vacuum. (0.96 g, yield = 82%, 6.3% water content by K.F. method). ^-NMR of calcium 2-(2-(methylthio)ethyl)-1,3- dioxolane-2-carboxylate (1,2) (500 MHz, DMSO-D6): 5= 1.98-2.00 (m, 2H, CH2) , 2.03 (s, 3H, SCH3) , 2.44-2.47 (m, 2H, CH2) , 3.81-3.84 (m, 2H, CH2) , 3.95-4.00 (m, 2H, CH2) . "C-NMR of calcium 2- (2-(methylthio)ethyl)-1,3- dioxolane-2-carboxylate (1,2) (125.8 MHz, DMS0-D6/DC1): 8 = 15.1 (SCH3) , 27.0 (CH2) , 35.2 (CHa) , 65.7, 66.0 (2 0CH2) , 105.6 (C), 171.0 (COO). Example 4: Production of ketomethionine hemiketal esters 1,3 exemplified by the reaction of ketomethionine and 2,2-dimethyl-l,3-propanediol: To a solution of 11.1 g of ketomethionine (75 mmol, M = 148.18 g/mol) in 200 ml of absolute ethanol-free chloroform were added 8.9 g of 2,2-dimethyl-1,3- propanediol (85 mmol, M = 104.15 g/mol) and 0.8 g (-5 mol%) of p-toluenesulphonic acid as catalyst and the mixture was kept under reflux until water no longer separated off (approximately 3.5 h) at the attached water separator. After cooling, the solution was washed with half-saturated NaHC03 solution, the aqueous phase was further rewashed with chloroform and the combined organic phases dried over Na2SO4. After filtration, the solvent was removed on a rotary evaporator and the oily crude product was crystallized from methylene chloride/n-hexane. The product (1,3) was obtained as white crystalline solid (10.8 g, yield = 62%, M = 234.32 g/mol, melting point = 109°C (methylene chloride/n-hexane)). XH-NMR of rac-4,4-dimethyl- 7-hydroxy-7- (2- (methyl - thio)ethyl)-6-oxacaprolactone (1,3) (500 MHz, CDC13) : 8= 0.92 (s, 3H, CH3), 0.99 (s, 3H, CH3) , 2.04-2.19 (m, 2H, CH2) , 2.08 (s, 3H, SCH3) , 2.47-2.52 (m, 1H, SCHH) , 2.61-2.66 (m, 1H, SCHH), 2.92 (d, 2J - 8.0 Hz, 1H, OCHH) , 3.25 (d, 3J m 8.0 Hz, 1H, OCHH) , 3.72 (d, 2J = 10.4 Hz, 1H, COOCHH), 4.30 (d, 2J = 10.4 Hz, 1H, COOCHH), 4.50 (S, 1H, OH). "C-NMR of rac-4,4-dimethyl-7-hydroxy-7-(2-(methyl- thio)ethyl)-6-oxacaprolactone (1,3) (125.8 MHz, CDC13) : 5 = 15.7 (SCH3) , 21.9, 21.3 (2 CH3) , 27.7 (CH2) , 37.7 (CHa) , 66.0 (OCHa) , 70.9 (OCH2) , 96.5 (COH) , 172.5 (COO). Elemental analysis for C10H1804S (M = 234.32 g/mol) : C 51.26; H 7.74; S 13.68 found: C 50.82; H 7.73; S 13.52. Example 5: Production of ketomathionine ketal esters 1,4 as exemplified by the reaction of ketomethionine and glycerol: To a solution of 12.0 g of ketomethionine (81 mmol, M = 148.18 g/mol) in 120 ml of absolute toluene were added 7.8 g of glycerol (1,2,3-propanetriol) (85 mmol, M = 92.09 g/mol) and 0.8 g (-5 mol%) of p-toluene-sulphonic acid as catalyst and the mixture was kept under reflux until no more water separated off (approximately 2.5 h) at the attached water separator. After cooling, the solution was washed with half-saturated NaHCO3 solution, the aqueous phase was further rewashed with chloroform and the combined organic phases were dried over Na2SO4. After filtration, the solvent was removed on a rotary evaporator and the oily crude product (ratio (l,3-ketal:l,2-ketal = 70:30) was chromatographed (diethyl ether/n-hexane 1:1). This separated the two compounds from one another. The main product (1,3-ketal) crystallized in the form of colourless needles from a mixture of methylene chloride/n-hexane (8.8 g, yield = 53%, M = 204.25 g/mol, melting point = 39.5°C (methylene chloride/n-hexane)). hl-NMR of 4-(2-(methylthio)ethyl)-2,5,8-trioxa- bicyclo[2.2.2]octan-3-one (1,3-ketal) (500 MHz, CDC13) : 8= 2.13 (s, 3H, SCH3), 2.17-2.20 (m, 2H, CH2) , 2.65-2.68 (m, 2H, CH2) , 4.12-4.13 (m, 4H, 2 CH2) , 4.76 (s, 1H, CH). "C-NMR of 4-(2-(methylthio)ethyl)-2,5,8-trioxa- bicyclo[2.2.2]octan-3-one (1,3-ketal) (125.8 MHz, CDC13) : 8= 15.4 (SCH3) , 26.9, (CH2) , 33.2 (CH2) , 66.5 (2 OCH2), 70.9 (CH), 92.9 (C) , 166.2 (COO). Elemental analysis for C8H1204S (M = 204.25 g/mol): C 47.04; H 5,92; S 15.70 found: C 47.21; H 5.93; S 15.69. Example 6: Production of ketomethionine ketal salts of the formula 1,5 as exemplified by saponification of 1,2-ketal or 1,3-ketal from Example 5: To a suspension of 50 mg (0.24 mmol) of the 1,3-ketal from Example 5 in 1.0 ml of methanol and 1.5 ml of water were added 15 mg of potassium hydroxide at room temperature and the solution was stirred for 30 min at room temperature. After removal of the solvent and drying under vacuum, the product was obtained as a white solid. (0.60 g, yield = 96%). 1H-NMR of potassium 5-hydroxy-2- (2- (methylthio)ethyl) - l,3-dioxane-2-carboxylate (500 MHz, D2O/TSP) : 6 = 1.96-2.02 (m 2H, CH2) , 2.10 (t, 3H, CH3) , 2.51-2.54 (m, 2H, CH2) , 3.48-3.52 (m, 2H, CH2) , 3.81-3.87 (m, 1H, CH) , 3.98-4.01 (m, 2H# CH2) . Claims: 1. Chemical compound of the general formula I and R = OH, OM, OR', NHa, NHR' or NR'R", wherein R1, R2, R' and R" are identical or different and are in each case a branched or straight-chain C1-C18-alkyl or C3-Ci8-cycloalkyl, allyl, benzyl, phenyl or C1-C18-alkyloxymethyl, preferably C2H5OCH2 C2-C6-hydroxyalkyl, preferably HOC2H4-, C3-C6-dihydroxyalkyl, preferably (HO)aC3H5-, or a C3-C12 sugar radical in which one OH group of the sugar is replaced in each case by the ketal-O atom, by the carboxylic acid-0 atom or by the carboxamide-N atom and M is an alkali metal ion or alkaline earth metal ion, preferably Na+, K+, Mg2+ or Ca2+ or a monovalent or divalent transition metal ion, preferably Zn2+, Mn2+, Cu2+ or Cr2+, or A = and R = OH, OM, OR', NH2, NHR# or NR'R", wherein R' and R" are identical or different and are in each case a branched or straight-chain C1-C18-alkyl or C3-Ci8-cycloalkyl, allyl, benzyl, phenyl or C1-C18-alkyloxymethyl, preferably C2H5OCH2 C2-C6-hydroxyalkyl, preferably HOC2H4-, C3-C6-dihydroxyalkyl, preferably (HO)2C3H5-, or a C3-Ci2 sugar radical in which one OH group of the sugar is replaced by the carboxylic acid-0 atom or by the carboxamide-N atom and M is an alkali metal ion or alkaline earth metal ion, preferably Na+, K+, Mg2+ or Ca2+ or a monovalent or divalent transition metal ion, preferably Zn2+, Mn2+, Cu2+ or Cr2, and R3 is a C2-C4-alkylene bridge, preferably C2H4, or a C3-C12 sugar radical in which two OH groups of the sugar are replaced by the two ketal-0 atoms, and R* is a C3-C6-alkylene radical which, if appropriate, is hydroxy substituted, preferably -CH2-C(CH3)2-CH2- and -CH2-C(CH2OH) 2-CH2-, or a C3-d2 sugar radical in which one OH group of the sugar is replaced by the ketal-0 atom and one is replaced by the carboxylic acid-0 atom, and R5 is a C3-C6-alkylene radical which, if appropriate, is hydroxy substituted, preferably -CH2-CH(-)-CH2-, or a C3-C12 sugar radical in which three OH groups of the sugar are replaced by both ketal-0 atoms and by the carboxylic acid-0 atom, and Rs is a C3-C6-alkylene radical which, if appropriate, is hydroxy substituted, preferably -CH2-CH(-) -CH2-, or a C3-C12 sugar radical in which two OH groups of the sugar are replaced by the two ketal-0 atoms, and wherein X = H or M. 2. Compound according to Claim 1, characterized in that R = hydroxyl and R3 = C2H4. 3. Compound according to Claim 1, characterized in that R - OR' and R' = C1-C18-alkyloxy and R3 = C2H4- 4. Compound according to Claim 3, characterized in that R' = Ci-C4-alkyloxy. 5. Compound according to Claim 1, characterized in that R = OR' and R' = hydroxyethoxy and R3 = C2H4. 6. Compound according to Claim 1, characterized in that R4 is a C5H10 radical or a C5H10O2 radical. 7. Compound according to Claim 6, characterized by the formula: 8. 9. Compound according to Claim 1, characterized in that Rs is a C3H5 radical. 10. Compound according to Claim 9, characterized by the formula: 11. Compound according to Claim 9, characterized by the formula: 12. Process for producing of feeds preferably for ruminants by mixing at least one compound according to claim 1-11 with conventional feeds. 13. Process according to claim 12, wherein the conventional feeds are mineral feed, organic feed or dairy compound feed. 14. Feed preparation containing at least one compound according to Claim 1-13, preferably for nutrition of ruminants. 15. Process for feeding animals preferably ruminants by use of feed preparations according to claim 14. 16. Process for producing carboxylic acid or ester compounds of the general formula I, 1-5 according to Claim 1, wherein, in the case of formula 1 and 2 the radical R is not 0M# NH2, NHR' or NR'R", characterized in that ketomethionine is reacted with a corresponding monovalent, divalent, trivalent alcohol or a C3-C12 sugar in the presence of acid catalysts to give the ester product of the formulae 1-2, where R = OR', or to give the ester product 3-4 or to give the acid product 1-2, where R = OH, or to give the acid product 5 where X = H. • 17. Process according to Claim 16, characterized in that, as alcohol, use is made of a branched or straight-chain C1-C18-alkyl alcohol or C3-C18-cyclo- alkyl alcohol, allyl alcohol, benzyl alcohol, phenyl alcohol, C2-C6-hydroxyalkyl alcohol, preferably HOC2H4OH, C3-C6-dihydroxyal]cyl alcohol, preferably glycerol, or a C3-C12 sugar, preferably glyceraldehyde, dihydroxyacetone, glucose, fructose or sucrose. 1&. Process according to one of Claims 1'6-17, characterized in that water formed during the reaction is removed. .\(\. Process for producing carboxylic acids or carboxylic acid salts of the general formula I, 1-2 or 5 according to Claim 1, wherein the radical R = OH or OM and the radical X = H qr M, characterized in that an ester product of the formula 1 or 2 where R = OR', or of the formula 4 is converted by saponification with an alkali metal hydroxide or alkaline earth metal hydroxide or a monovalent or divalent transition metal hydroxide into the corresponding carboxylic acid salt of the formula 1 or 2 where R = OM or of the formula 5 where X = M and if appropriate the free carboxylic acid where R = OH or X = H is liberated therefrom using a mineral acid. 20. Process for producing carboxylic acid salts of the general formula I, 1-2 or 5 according to Claim 1, wherein the radical R = OM or the radical X * M, characterized in that an acid product of the formula I, 1-2 where R = OH or an acid product of the formula I, 5 where X = H is neutralized with an alkali metal or alkaline earth metal or a monovalent or divalent transition metal hydroxide' or carbonate to give the corresponding carboxylic acid. 21. Process according to Claim .19 or 20, characterized in that, as hydroxide, use is made of NaOH, KOH, Mg(OH)2, Ca(OH)2, Zn(OH)2 or Mn(OH)2. 2%. Process according to Claim \| in that, as carbonate, use is made of Na2CO3, K3CO3, MgCO3, CaCO3, ZnCO3 or MnCO3. 2%. Process for producing carboxamides of the general formula I, 1-2 according to Claim 1 where R = NH2/ NHR', NR'R", characterized in that an ester product of the formula I, 1-2, where R = OR', is converted into the corresponding amide by reaction with NH3, NH2R' or NHR'R". 2 if. Process for producing ester compounds of the general formula I, 1-2 according to Claim 1, where R = OR', characterized in that an ester product I, 1-2, is converted into a corresponding ester product of the formula I, 1-2 by transesterification with alkali metal alkoxide M'OR', with the proviso that R' in the ester product 1-2 used must not be equal to the radical R' in the alkoxide M'OR' used. The present invention relates to ketomethionine ketals or hemiketals and their derivatives and also their preparation and their use as fodder additives, in particular for the nutrition of ruminants.

Full Text

Ketomethionine ketals and their derivatives
Introduction
The present invention relates to ketomethionine ketals
and hemiketals and derivatives thereof and also
production thereof and use thereof as feed additives,
in particular for the nutrition of ruminants.
Prior art
Amino acids such as methionine, lysine or threonine
are, as feed additives, important components of animal
nutrition. They make possible more rapid growth and
also more efficient feed utilization. This usually
represents an important economic advantage. The markets
for feed additives are of great industrial and economic
importance. In addition, they are great growth markets
which is due, not least, to the increasing importance
of countries such as China and India, for example.
WO 2004008874 discloses, inter alia, that methionine is
the first limiting amino acid for many animal species,
including ruminants. For instance in the case of dairy
cows, for example, efficient milk production with
respect to the amount and quality is greatly dependent
on a sufficient supply of methionine. The methionine
requirement of high performance dairy cows cannot be
covered in this case by the microbial protein formed in
the rumen or by protein from the feed not degraded in
the rumen (Graulet et al., J. Animal and Feed Sciences
(2004), 269). It is therefore advantageous to
supplement methionine to the feed to increase the
economic efficiency of milk production and the quality
of the milk.
In the case of monogastric animals such as, for
example, poultry and pigs, customarily, as feed

additive, use is made of methionine and the Methionine
Hydroxy Analogue (MHA), which is also termed
hydroxymethylthiobutyric acid (HMB). This increases the
available amount of L-methionine in the body which can
then be available to the animal for growth.
In contrast thereto, supplementation of the feed with
methionine is ineffective in ruminants, since the
majority is degraded by microbes in the rumen of
ruminants. Owing to this degradation, therefore, only a
fragment of the methionine supplemented passes into the
small intestine of the animal, where generally the
absorption of methionine into the blood proceeds.
WO 99/04647 describes the use of MHA for ruminants.
Therein it is asserted that MHA is only in part broken
down in the rumen and therefore at least 20-40% of the
supplemented MHA, after absorption in the small
intestine, can pass in to metabolism. In numerous other
publications, in contrast, the mode of action of MHA in
ruminants is discussed differently. For instance,
WO 200028835, for example, describes that MHA can only
successfully pass through the rumen and finally into
the small intestine for absorption when MHA is
administered in very large amounts of
60-120 g/day/animal. However this precludes economic
efficiency.
In order that methionine products such as
D,L-methionine or rac-MHA are available to ruminants
with high efficiency, a form protected against rumen
degradation must be used. The challenge in this case is
to find a suitable methionine product which gives the
methionine a rumen stability as high as possible and
nevertheless ensures high and efficiency absorption of
the methionine in the gut. There is a plurality of
possibilities in this case of giving D,L-methionine or
rac-MHA these properties:

a) Physical protection:
By application of a suitable protective layer or
distribution of the methionine in a protective matrix,
a high rumen stability can be achieved. As a result,
the methionine can pass through the rumen virtually
without loss. In its further course, the protective
layer is then, for example, opened or removed by acid
hydrolysis in the abomasum and the methionine released
can then be absorbed by the animal in the small
intestine. The protective layer or protective matrix
can consist of a combination of a plurality of
substances such as, for example, lipids, inorganic
materials and carbohydrates. The following product
forms are commercially available:
i) Met-Plus™ from Nisso America is a lipid-protected
methionine having a D,L-methionine content of 65%.
The protective matrix consists of the calcium
salts of long chain fatty acids such as, for
example, lauric acid. As preservative, butylated
hydroxytoluene is used.
ii) Mepron* M85 from Degussa AG is a carbohydrate-
protected methionine which has a core of
D,L-methionine, starch and stearic acid. As
protective layer, ethylcellulose is used. The
product has a content of 85% D,L-methionine.
iii) Smartamine™ M from Adisseo is a polymer-protected
methionine. The pellets, in addition to stearic
acid, contain at least 70% D,L-methionine. The
protective layer contains vinylpyridine-styrene
copolymer.
Although the physical protection prevents microbial
breakdown of methionine in the rumen and as a result

the supply and utilization of methionine in the animal
can be increased, there are some serious disadvantages.
The production or coating of methionine is usually a
technically complicated and laborious process and is
therefore expensive. In addition the surface coating of
the finished pellets can easily be damaged by
mechanical load and abrasion during feed processing
which can lead to reduction or up to complete loss of
the protection. Therefore, it is also not possible to
process and repellet the protected methionine pellets
to form a larger compound feed pellet, since, as a
result, again the protecting layer would break owing to
the mechanical stress. This greatly restricts the use
of such products, since compound feed pelleting is a
widely used method of feed processing.
b) Chemical protection:
Increased rumen stability of methionine can, in
addition to purely physical protective possibilities,
also be achieved by modifying the chemical structure,
for example by esterifying the carboxylic acid group.
Currently, the following products are commercially
available or are described in the literature:
i) Methionine esters such as, for example, D,L-tert-
butylmethionine: The esters have been tested and
demonstrated only moderate rumen stability (Loerch and
Oke; "Rumen Protected Amino Acids in Ruminant
Nutrition" in "Absorption and Utilization of Amino
Acids" Vol. 3, 1989, 187-200, CRC Press, Boca Raton,
Florida). For D,L-tert-butylmethionine, in contrast, in
WO 0028835, a biological value of 80% was published.
ii) Metasmart™ from Adisseo is the racemic isopropyl
ester of MHA (HMBi) . This compound is also marketed
under the trademark "Sequent" by the American company

Novus. In WO 00/28835, a biological value of at least
50% for HMBi in ruminants was published. In this case,
especially, the surprisingly rapid absorption of the
hydrophobic HMBi through the rumen wall plays a
decisive role. The ester can then be hydrolysed to MHA
in the blood and, after oxidation and subsequent
transamination, can be converted to L-methionine. In
the patent EP 1358805, a comparable biological value
for HMBi was published. In these studies, HMBi was
applied to a porous support. In a further publication,
the European Commission reported that, again,
approximately 50% HMBi is absorbed via the rumen wall
(European Commission: Report of the Scientific
Committee on Animal Nutrition on the Use of HMBI; 25
April 2003) . Graulet et al. published in 2004 in the
Journal of Animal and Feed Science (269), that better
diffusion through the rumen wall is enabled by the
lipophilic properties of the isopropyl group of HMBi.
For the production of HMBi, two different processes
have been published. Thus, HMBi can either be
synthesized directly in one stage from the
corresponding cyanohydrin (WO 00-59877). Esterification
to give the isopropyl ester proceeds in this case in
situ, without needing to isolate MHA in advance.
Another process, in contrast, esterifies pure MHA with
isopropanol (WO 01-58864 and WO 01-56980). In both
cases, for the synthesis, use is made of prussic acid
which is expensive and in addition is a great potential
hazard.
iii) Ketomethionine and its carboxylic acid
derivatives: The use of this class of compounds, in
particular of ketomethionine itself, as feed additives
was first described recently in application
WO 2006-072711. There, a technical process for
producing ketomethionine and carboxylic acid
derivatives thereof was also described. Ketomethionine

is the direct precursor of methionine and can readily
be converted in the body to L-methionine in one step by
means of transamination. In comparison therewith, both
MHA and HMBi have the disadvantage that they require
two or three steps for conversion to L-methionine in
the body. For instance, HMBi must first be hydrolysed
to free MHA and subsequently oxidized to ketomethionine
with the aid of an oxidase. Not until then can in turn
the ketomethionine be directly reductively aminated to
give L-methionine [Baker; "Utilization of Precursors
for L-Amino Acids" in "Amino Acids in Farm Animal
Nutrition" (D'Mello, J.P.F., ed.), 1994, 37-64. CAB
Intl., Wallingford, Oxon, UK].
Free ketomethionine as ct-ketocarboxylic acid and its
salts such as, for example, the sodium or calcium salt,
are compounds already known from the literature for a
long time and have been produced both biochemically and
chemically. Meister, for example, obtained the sodium
salt of a-ketomethionine in a yield of 77% by the
L-amino oxidase-catalysed oxidation of methionine
(Meister, J. Biol. Chem. 1952, 197, 309). Previously,
Waelsch et al., showed that the amino oxidases present
in liver can convert methionine to a-ketomethionine
(Waelsch et al., J. Am. Chem. Soc. 1938, 61, 2252).
Mosbach et al., likewise described the production of
ketomethionine by the L-amino oxidase-catalysed
oxidation of methionine. In this case immobilized
Providencia sp. PCM 1298 cells were used (Mosbach et
al.. Enzyme Microb. Technol. 1982, 4, 409).
As a further possible synthesis method, Sakurai et al.
in 1957 published the first chemical synthesis route
for synthesising a-ketomethionine. In this case, as key
step, methyl -cc-methoxalyl -y-methylmercaptopropionate
was hydrolyzed with dilute hydrochloric acid to give
ketomethionine (Sakurai et al., J. of Biochemistry
1957, 44, 9, 557). Yamada et al. published virtually

simultaneously the same synthesis route, after first
attempts at synthesizing a-ketomethionine via an
a-oximo ester formed as an intermediate gave only low
yields. (Chibata et al., Bull. Agr. Chem. Soc. Japan
1957, 21, 6, 336) .
The biological value of the sodium salt of a-keto-
methionine was determined for the first time in 1977 in
feeding experiments with rodents and poultry and is
significantly above that of MHA (Baker and Harter,
Proceedings for the Society for Experimental Biology
and Medicine 1977, 156, 2001). In ruminants, a-keto-
methionine and salts thereof, however, are broken down
in the rumen and therefore offer no advantages over HMB
or methionine. As free a-ketocarboxylic acid,
a-ketomethionine in addition has the further
disadvantage that it dimerizes in a very short time and
subsequently irreversibly cyclizes and therefore is not
stable as a monomer of biological value and therefore
is avoided in direct use as feed additive.
Object of the invention
Against the background of the disadvantages of the
prior art, it was the object to provide a rumen-stable,
chemically protected methionine product for ruminants,
in particular for dairy cows, which can serve as
efficient methionine source for the animals and which
does not have the disadvantages of the known products,
or has them to a decreased extent. This would have the
advantage that milk production and quality could be
thereby increased, which would lead to a significant
increase in economic efficiency.
A further object was to find a feed and a feed additive
of very high biological value which should have good
handleability and storability and also stability under
the customary conditions of compound feed processing,

in particular pelleting. The product, in addition,
should be useable in animal nutrition in the most
general possible way as feed additive.
Description of the invention
This object and also other objects not explicitly-
mentioned, but which can readily be derived or deduced
from the contexts discussed herein are achieved by the
ketomethionine ketals of the invention and derivatives
thereof according to formula I, in particular use
thereof as feed, preferably for ruminants. Thereby, not
only the disadvantages of the "physically protected"
methionine variants, such as, for example, Smartamine,
but also the disadvantages of the "chemically
protected" variants, such as, for example, HMBi, are
overcome.
The present invention relates to a chemical compound of
the general formula I
C

allyl,
benzyl,
phenyl or

C3-C6-dihydroxyalkyl, preferably (HO)2C3H5-, or a C3-C12
sugar radical in which one OH group of the sugar is
replaced in each case by the ketal-0 atom, by the
carboxylic acid-0 atom or by the carboxamide-N atom and
M is an alkali metal ion or alkaline earth metal ion,
preferably Na+, K+, Mg2+ or Ca2+ or a monovalent or
divalent transition metal ion, preferably Zn2+, Mn2+,
Cu2+ or Cr2+,
or A =
and R = OH, OM, OR', NH2, NHR' or NR'R",
wherein R' and R" are identical or different and are in
each case a branched or straight-chain C1-C18-alkyl or
C3-C18-cycloalkyl,
allyl,
benzyl,

phenyl or
C1-C18-alkyloxymethyl, preferably C2H5OCH2
C2-C6-hydroxyalkyl/ preferably HOC2H4-,
C3-C6-dihydroxyalkyl, preferably (HO)2C3H5-, or a C3-C12
sugar radical in which one OH group of the sugar is
replaced by the carboxylic acid-0 atom or by the
carboxamide-N atom and
M is an alkali metal ion or alkaline earth metal ion,
preferably Na+, K+, Mg2+ or Ca2+ or a monovalent or
divalent transition metal ion, preferably Zn2+, Mn2+,
Cu2+ or Cr2+,
and R3 is a C2-C4-alkylene bridge, preferably C2H4, or a
C3-C12 sugar radical in which two OH groups of the sugar
are replaced by the two ketal-0 atoms,

and R4 is a C3-C6-alkylene radical which, if
appropriate, is hydroxy substituted, preferably
-CH2-C(CH3)3-CH2- and -CH2-C(CH2OH)2-CH2-, or a C3-Ci2
sugar radical in which one OH group of the sugar is
replaced by the ketal-0 atom and one is replaced by the
carboxylic acid-0 atom,

and Rs is a C3-C6-alkylene radical which, if
appropriate, is hydroxy substituted, preferably
-CH2-CH(-) -CH2-, or a C3-C12 sugar radical in which three
OH groups of the sugar are replaced by both ketal-0
atoms and by the carboxylic acid-0 atom,

and R5 is a C3-C6-alkylene radical which, if
appropriate, is hydroxy substituted, preferably
-CH2-CH(-) -CH2-, or a C3-C12 sugar radical in which two
OH groups of the sugar are replaced by the two ketal-0
atoms, and wherein X = H or M and M has the meaning
given above.
Preference in this case is given to a compound of the
formula 1,2, in which R = hydroxyl and R3 = C2H4

This can readily be produced by ketalization of
ketomethionine with stoichiometric amounts of ethylene
glycol in the presence of acid catalysts or with super-
stoichiometric amounts of ethylene glycol and
subsequent saponification of the ketomethionine
ethylene ketal ethylene glycol ester formed as an
intermediate with alkali and subsequent neutralization
(cf. Example 2).

Further preference is given to a compound according to
formula 1,2, in which R = OR' and R' = C1-C18-alkyloxy
and R3 = C2H4. This compound can be produced by
esterification of ketomethionine with a corresponding
C1-C18-alcohol in the presence of acid catalysts, and
preferably subsequent ketalization with ethylene
glycol.
Particular preference is given in this case to a
compound according to formula 1,2, in which R' =
C1-C4 - alkyloxy.
Further preference is given to a compound according to
formula 1,2, in which R = OR' and R' = hydroxyethoxy
and R3 = C2H4:

Still more preference is given to a compound according
to formula 1,3, in which R* is a C5H10 radical or a
C5H10O2 radical.
Particular preference is given in this case to a
compound characterized by the formula

which can be produced from ketomethionine and
neopentylidene glycol in the presence of acid
catalysts.
Likewise preference is given to an analogous compound
of the formula

which can be produced from ketomethionine and pent a-
erythritol in the presence of acid catalysts.
Further preference is given to a compound according to
formula 1,4, in which R5 is a C3H5 radical.
Particular preference is given in this case to a
compound characterized by the formula (1,2-ketal)
i
Both compounds, the 1,2-ketal and the 1,3-ketal, can be
produced from ketomethionine and glycerol in the
presence of acid catalysts, preferably under
dehydrating conditions.
All compounds of the general formula I are
outstandingly suitable according to the invention for
use in animal nutrition, preferably for nutrition of
farm animals.

Preference is given in this case to use for nutrition
of ruminants, in particular dairy cows.
For this purpose, the compounds of the invention can be
used for producing feeds.
In this case, again preference is given to use for
producing feeds for ruminants.
Likewise, the present invention relates to feed
preparations containing at least one of the
abovementioned compounds of the invention, preferably
for nutrition of ruminants.
Accordingly, mixtures of the compounds of the invention
with conventional feeds can be produced.
For this, the compounds of the invention are mixed in
suitable amounts into commercially conventional feed
types, such as mineral feed, organic feed (for example
soybean meal) or dairy compound feed.
Suitable amounts are generally proportions of 0.1% to
5% of methionine equivalents in the form of the
compounds of the invention, wherein the proportions are
different depending on the type of feed. Dairy compound
feed is preferably mixed with equivalents, mineral feed with up to 5% and organic
feed in the range from 0.5 to 3%, preferably up to 1%.
One methionine equivalent in this context is the part
by weight of compound of the invention which is
equivalent to the same amount of methionine oh a molar
basis.
The present invention further relates to a process for
producing carboxylic acid or ester compounds of the
general formula I, 1-5, wherein, in the case of formula
1,1 and 2 the radical is not OM, NH2, NHR' or NR'R",

characterized in that ketomethionine is reacted with a
corresponding monovalent, divalent, trivalent alcohol
or a C3-C12 sugar in the presence of acid catalysts to
give the ester product of the formulae 1-2, where R =
0R#, or to give the ester product 3-4 or to give the
acid product 1-2, where R = OH, or to give the acid
product 5 where X = H.
Corresponding to said preferred compounds, in this case
one process is preferred in which, as alcohol, use is
made of a branched or straight-chain C1-C18-alkyl
alcohol or C3-C18-cycloalkyl alcohol, allyl alcohol,
benzyl alcohol, phenyl alcohol, Ca-Cg-hydroxyalkyl
alcohol, preferably HOC2H4OH, C3-C6-dihydroxyalkyl
alcohol, preferably glycerol or a C3-C12 sugar,
preferably glyceraldehyde, dihydroxyacetone, glucose,
fructose or sucrose.
In this case, in particular by suitable selection of
the amount of mole equivalents of the alcohol or sugar
required for the ketalization, the formation of the
desired product can be influenced. When one mol
equivalent of C1-C18-alkyl alcohol is used, the
corresponding ester not according to the invention is
preferentially formed, when two mol equivalents are
used, the carboxylic acid ketal of the formula 1,1
where R = OH is preferentially. formed and when three
mol equivalents are used, the corresponding ester
ketals of the formula 1,1 where R = OR' are
preferentially formed. Correspondingly, when one half
mol equivalent of C2-C6-hydroxyalkyl alcohol is used,
(such as, for example, H0C2H40H) correspondingly two
hydroxy equivalents of the corresponding carboxylic
acid ketal of the formula 1,2 where R = OH and R3 = C2H4
are formed.
The production of carboxylic acid or ester compounds
can advantageously be carried out in the presence of a

solvent. Suitable solvents are, for example, aromatic
hydrocarbons such as benzene or toluene, and also
chlorinated hydrocarbons, such as methylene chloride or
chloroform, and alcohols.
In the interest of a yield as high as possible of
desired condensation products, in this case preference
is given to a process in which water formed during the
reaction is removed from the equilibrium. This can be
achieved both by distillation, preferably by using a
solvent and/or entrainer such as, for example, toluene.
It is advantageous in this case when the solvent
simultaneously acts as entrainer and, if appropriate,
further as reactant. Also, in this case, the alcohols
used for esterification or ketalization can
additionally be used as solvent and/or entrainer.
When used as entrainer, the solvent should have a
suitable boiling point. This should generally not
exceed 120°C. Alcohols suitable for this purpose are,
for example, Ci-C4-alkyl alcohols, that is to say
methanol, ethanol, 1- or 2-propanol and 1- or
2-butanol, isobutanol, tert-butanol.
A further possibility for removing water is the use of
dehydrating agents, for example orthoesters, such as,
for example trimethyl or triethyl orthoacetate. The
methyl or ethyl acetate formed as coupling products can
subsequently readily be removed from the reaction
mixture by distillation and reused.
In this case the carboxylic acids or carboxylic acid
salts of the general formula 1,1-2 or 5, in which the
radical R = OH or OM and the radical X = H or M, can
preferably be produced by converting a carboxylic ester
product of the formula 1,1 or 2 where R = OR', or of
the formula 1,4, into the corresponding carboxylic acid
salt of the formula 1,1 or 2 where R = OM or of the

formula 5 where X = M by saponification with an alkali
metal hydroxide or alkaline earth metal hydroxide or a
monovalent or divalent transition metal hydroxide and,
if appropriate, liberating therefrom the free
carboxylic acid where R = OH or X = H with the aid of a
mineral acid. Suitable mineral acids in this case are,
in particular, sulphuric acid, hydrochloric acid and
phosphoric acid.
The invention also relates to a process for producing
carboxylic acid salts of the general formula 1,1-2 or
5, wherein the radical R = OM or' the radical X = M,
which is characterized in that an acid product of the
formula 1,1-2 where R = OH or an acid product of the
formula 1,5 where X = H is neutralized with an alkali
metal or alkaline earth metal or a monovalent or
divalent transition metal hydroxide or carbonate to
give the corresponding carboxylic acid.
For production of the abovementioned carboxylic acid
salts by saponification or neutralization, in this
case, as hydroxides, use is preferably made of NaOH,
KOH, Mg(OH)2, Ca(OH)2, Zn(OH)a or Mh(OH)a and, as
carbonates, Na2CO3, K2CO3, MgCO3, CaCO3, ZnCO3 or MnCO3.
The invention also relates to a process for producing
carboxamides of the general formula 1,1-2 where R =
NH2, NHR', NR'R", characterized in that an ester
product of the formula 1,1-2, where R = OR', is
converted into the corresponding amide by reaction with
a nitrogenous base of the formula NH3, NH2R' or NHR'R".
The invention also relates to a process for producing
ester compounds of the general formula 1,1-2, where R =
OR', which is characterized in that an ester product I,
1-2, is converted into a corresponding ester product of
the formula I, 1-2 by transesterification with an
alkali metal alkoxide M'OR' (M' = alkali), with the

proviso that R' in the ester product I, 1-2 used must
not be equal to the radical R' in the alkoxide M'OR'
used. Ketomethionine ketal esters once produced can in
this manner be very readily converted into other
desired ketomethionine ketal esters.
The ketomethionine ketals of the general formula 1,1,2
or 5 where R = OH or OM respectively, X = H or M are
polar and non-lipophilic compounds. Owing to the ketal
protecting group, these compounds are rumen-stable and
cannot be microbially degraded. As a result of the
lipophobic carboxylic acid group, however, they are not
absorbed via the rumen wall as with HMBi, but pass
without, breakdown into the abomasums of the ruminant,
where they are hydrolysed owing to the strongly acidic
conditions. The ketomethionine released is then
subsequently absorbed in the small intestine.
The ketomethionine ketal esters of the general formula
1,1,2 where R = OR', or of the general formula 1,4 are
lipophilic and non-polar compounds. Owing to the two
chemical protecting groups "ketal" and "ester", these
compounds are rumen-stable. The absorption, in contrast
to ketomethionine ketals, proceeds rapidly and
effectively via the rumen wall similarly to the
mechanism of HMBi. The subsequent enzymatic cleavage to
give the free ketomethionine then proceeds in the blood
of the ruminant.
The use of ketomethionine ketals or ketomethionine
ketal esters thus makes possible for the first time an
active control of the absorption site of the
"methionine equivalent".
The ketomethionine ketals or ketomethionine ketal
esters and derivatives thereof have a plurality of
advantages over the compounds known in the prior art:

In contrast to free ketomethionine, ketomethionine
ketals, ketomethionine ketal esters, ketomethionine
hemiketal esters and ketomethionine ketal amides of the
general formula I are chemically stable with respect to
dimerization and cyclization, a precondition for
storage and transport as feed additives.
Use of the compounds of the general formula I permits
the active control of the absorption site in the body
of the ruminant. In this case the hydrophilic
ketomethionine ketals of the formula 1,1,2 where R -
OH, OM, or of the formula 1,5 where X = H, M are
absorbed in the small intestine after hydrolysis in the
abomasum, and the absorption of the lipophilic
ketomethionine ketal esters of the general formula
1,1,2 where R = OR', or of the general formula 1,4
proceeds directly via the rumen wall.
In the case of use of certain diols such as, for
example ethylene glycol, or selected triols such as,
for example, glycerol, or sugars such as, for example,
glucose, as building blocks for ketal or ester
formation with ketomethionine to give the corresponding
compounds of the general formula I, these additionally
have a nutritive action, owing to the sugar or alcohol
building blocks which can be released again in the
body.
Ketomethionine ketals and ketomethionine ketal esters
have a very high biological value, since they can be
hydrolysed in vivo to give a-ketomethionine. The
biological value of ketomethionine in this case is
significantly higher than that of MHA, since, in
contrast thereto, it can be converted to L-methionine
in the body in only one stage. In contrast, MHA
requires two stages and HMBi even three stages.

The high biological value of ketomethionine ketals and
ketomethionine ketal esters is a significant economic
advantage, since less feed additive is required.
On account of the chemical protection, the product and
with it the rumen protection can not be damaged by
physical forces such as, for example, friction.
Therefore, in comparison with a physically protected
methionine form, such as, for example Smartamine, it is
possible to pellet ketomethionine ketals,
ketomethionine ketal esters, ketomethionine hemiketal
esters and ketomethionine ketal amides of the general
formula I. This is an extraordinary advantage, because
a broad usability in compound feed production and final
processing is thereby ensured.
In addition, the said compounds of the general formula
I can generally be used as feed additives in farm
animal husbandry, that is to say also in the nutrition
of poultry or pigs.
In particular, ketomethionine ketals and ketomethionine
ketal esters can be produced in a simpler manner, and
thus generally at lower production costs, than
physically protected methionine forms.
The symmetrical ketomethionine ketals of the general
formula I are achiral in contrast to MHA, HMBi or
D,L-methionine. Natural L-methionine is formed directly
from these achiral precursors in the animal body.
Conversion of the unnatural enantiomer is omitted
thereby. The examples hereinafter show possibilities
for producing the compounds according to the invention
without acting in a limiting manner in this case.

Examples:
Example It Release of ketomethionine from Its salts
(not according to the invention):

To a suspension of 43.3 g of calcium ketomethioninate
(M = 334.42 g/mol, 98% purity, 21% water content in the
dry mass) in 120 ml of H2O and 320 ml of diethyl ether,
a 10% strength aqueous hydrochloric acid solution was
added slowly dropwise at 0°C with vigorous stirring
until the pH was aqueous phase was washed three times, each with 120 ml
of diethyl ether. Subsequently, the combined organic
phases were dried over Na2SO4. After filtration of the
desiccant, the diethyl ether was distilled off on a
rotary evaporator at 30°C and slight vacuum. The last
solvent residues were removed in high vacuum. There
remained 29.1 g of a slightly yellowish oil of free
ketomethionine (yield = 98%, M = 148.18 g/mol).
^-NMR of calcium ketomethioninate 500 MHz, DMSO-d6):

"C-NMR of ketomethionine (125.8 MHz, DMSO-d6): 8 = 14.7
(CH3) , 26.7 (CH2) , 38.5 (CH2) , 162.2 (COOH) , 194.9 (CO).

Example 2: Production of ketomethionine ketala of the
formula 1,2 exemplified by the reaction of
ketomethionine and ethylene glycol:

A solution of ketomethionine (174 mmol, M =
148.18 g/mol) in toluene (100 ml) was added dropwise
over the course of 2 h to a solution of 1 g (-3 mol%)
of p-toluenesulphonic acid as catalyst and ethylene
glycol (335 mmol, M 62.07 g/mol) in toluene (250 ml)
and the reaction was kept under reflux until no more
water separated off at the attached water separator
(approximately 2 h). Subsequently the toluene was taken
off under vacuum and the crude product was admixed with
methanol (200 ml) and, after addition of an aqueous
solution of 2M sodium hydroxide (200 ml) saponified
under alkaline conditions for approximately 2 h. The
reaction solution was subsequently extracted by shaking
with diethyl ether and the aqueous phase was acidified
with dilute hydrochloric acid. The product was
extracted at pH 1-2 with diethyl ether, the organic
phase washed with water, dried over Na2SO4 and the
solvent removed on a rotary evaporator. The oily
product (1,2) was subsequently recrystallized from
methylene chloride/n-hexane and was obtained as white
crystalline solid. (24.6 g, yield = 74%, M =
192.23 g/mol, melting point: 74°C methylene chloride/n-
hexane).
1H-NMR of 2-(2-(methylthio)ethyl)-1,3-dioxolane-2-
carboxylic acid (1,2) (500 MHz, CDC13) : 5 = 2.11 (s, 3H,

SCH3) , 2.24-2.28 (m, 2H# CH2) , *2 .58-2 . 61 (m, 2H, CH2) ,
4.07-4.14 (m, 4H, OCH2CH2O) .
13C-NMR of 2-(2-(methylthio)ethyl)-l,3-dioxolane-2-
carboxylic acid (1,2) (125.8 MHz, CDC13) : 6 = 15.5
(SCH3) , 27.1 (CH2) , 34.9 (CH2) , 66.1 (2 OCH2) , 105.9
(C), 174.1 (COO).
Elemental analysis for C7H12O4S (M = 192.24 g/mol) : C
43.74; H 6.29; S 16.68 found: C 43.80; H 6.25; S 16.61.
Example 3: Production of the calcium salt of
ketomethionine ketal by neutralization:

To a solution of 1.0 g (5.20 mmol) of 4-(methylthio)-2-
ketobutyric acid ethylene ketal in 2.0 ml of water and
3.0 ml of acetone was added slowly dropwise at RT an
aqueous solution of 0.44 g of calcium acetate (93%
strength) in 2 ml of water.
Subsequently 3 ml of acetone were added and the mixture
was stirred overnight at RT. The white solid formed was
filtered off by suction and washed thoroughly with
100 ml of a 1:10 water/acetone mixture. The product was
subsequently dried in a drying cabinet and in high
vacuum. (0.96 g, yield = 82%, 6.3% water content by
K.F. method).
^-NMR of calcium 2-(2-(methylthio)ethyl)-1,3-
dioxolane-2-carboxylate (1,2) (500 MHz, DMSO-D6):
5= 1.98-2.00 (m, 2H, CH2) , 2.03 (s, 3H, SCH3) ,
2.44-2.47 (m, 2H, CH2) , 3.81-3.84 (m, 2H, CH2) ,
3.95-4.00 (m, 2H, CH2) .

"C-NMR of calcium 2- (2-(methylthio)ethyl)-1,3-
dioxolane-2-carboxylate (1,2) (125.8 MHz, DMS0-D6/DC1):
8 = 15.1 (SCH3) , 27.0 (CH2) , 35.2 (CHa) , 65.7, 66.0
(2 0CH2) , 105.6 (C), 171.0 (COO).
Example 4: Production of ketomethionine hemiketal
esters 1,3 exemplified by the reaction of
ketomethionine and 2,2-dimethyl-l,3-propanediol:

To a solution of 11.1 g of ketomethionine (75 mmol, M =
148.18 g/mol) in 200 ml of absolute ethanol-free
chloroform were added 8.9 g of 2,2-dimethyl-1,3-
propanediol (85 mmol, M = 104.15 g/mol) and 0.8 g
(-5 mol%) of p-toluenesulphonic acid as catalyst and
the mixture was kept under reflux until water no longer
separated off (approximately 3.5 h) at the attached
water separator. After cooling, the solution was washed
with half-saturated NaHC03 solution, the aqueous phase
was further rewashed with chloroform and the combined
organic phases dried over Na2SO4. After filtration, the
solvent was removed on a rotary evaporator and the oily
crude product was crystallized from methylene
chloride/n-hexane. The product (1,3) was obtained as
white crystalline solid (10.8 g, yield = 62%, M =
234.32 g/mol, melting point = 109°C (methylene
chloride/n-hexane)).

XH-NMR of rac-4,4-dimethyl- 7-hydroxy-7- (2- (methyl -
thio)ethyl)-6-oxacaprolactone (1,3) (500 MHz, CDC13) :
8= 0.92 (s, 3H, CH3), 0.99 (s, 3H, CH3) , 2.04-2.19 (m,
2H, CH2) , 2.08 (s, 3H, SCH3) , 2.47-2.52 (m, 1H, SCHH) ,
2.61-2.66 (m, 1H, SCHH), 2.92 (d, 2J - 8.0 Hz, 1H,
OCHH) , 3.25 (d, 3J m 8.0 Hz, 1H, OCHH) , 3.72 (d, 2J =
10.4 Hz, 1H, COOCHH), 4.30 (d, 2J = 10.4 Hz, 1H,
COOCHH), 4.50 (S, 1H, OH).
"C-NMR of rac-4,4-dimethyl-7-hydroxy-7-(2-(methyl-
thio)ethyl)-6-oxacaprolactone (1,3) (125.8 MHz, CDC13) :
5 = 15.7 (SCH3) , 21.9, 21.3 (2 CH3) , 27.7 (CH2) , 37.7
(CHa) , 66.0 (OCHa) , 70.9 (OCH2) , 96.5 (COH) , 172.5
(COO).
Elemental analysis for C10H1804S (M = 234.32 g/mol) : C
51.26; H 7.74; S 13.68 found: C 50.82; H 7.73; S 13.52.
Example 5: Production of ketomathionine ketal esters
1,4 as exemplified by the reaction of ketomethionine
and glycerol:

To a solution of 12.0 g of ketomethionine (81 mmol, M =
148.18 g/mol) in 120 ml of absolute toluene were added
7.8 g of glycerol (1,2,3-propanetriol) (85 mmol, M =
92.09 g/mol) and 0.8 g (-5 mol%) of p-toluene-sulphonic
acid as catalyst and the mixture was kept under reflux
until no more water separated off (approximately 2.5 h)
at the attached water separator. After cooling, the
solution was washed with half-saturated NaHCO3

solution, the aqueous phase was further rewashed with
chloroform and the combined organic phases were dried
over Na2SO4. After filtration, the solvent was removed
on a rotary evaporator and the oily crude product
(ratio (l,3-ketal:l,2-ketal = 70:30) was
chromatographed (diethyl ether/n-hexane 1:1). This
separated the two compounds from one another. The main
product (1,3-ketal) crystallized in the form of
colourless needles from a mixture of methylene
chloride/n-hexane (8.8 g, yield = 53%, M =
204.25 g/mol, melting point = 39.5°C (methylene
chloride/n-hexane)).
hl-NMR of 4-(2-(methylthio)ethyl)-2,5,8-trioxa-
bicyclo[2.2.2]octan-3-one (1,3-ketal) (500 MHz, CDC13) :
8= 2.13 (s, 3H, SCH3), 2.17-2.20 (m, 2H, CH2) ,
2.65-2.68 (m, 2H, CH2) , 4.12-4.13 (m, 4H, 2 CH2) ,
4.76 (s, 1H, CH).
"C-NMR of 4-(2-(methylthio)ethyl)-2,5,8-trioxa-
bicyclo[2.2.2]octan-3-one (1,3-ketal) (125.8 MHz,
CDC13) : 8= 15.4 (SCH3) , 26.9, (CH2) , 33.2 (CH2) , 66.5 (2
OCH2), 70.9 (CH), 92.9 (C) , 166.2 (COO).
Elemental analysis for C8H1204S (M = 204.25 g/mol): C
47.04; H 5,92; S 15.70 found: C 47.21; H 5.93; S 15.69.
Example 6: Production of ketomethionine ketal salts of
the formula 1,5 as exemplified by saponification of
1,2-ketal or 1,3-ketal from Example 5:

To a suspension of 50 mg (0.24 mmol) of the 1,3-ketal
from Example 5 in 1.0 ml of methanol and 1.5 ml of
water were added 15 mg of potassium hydroxide at room
temperature and the solution was stirred for 30 min at
room temperature. After removal of the solvent and
drying under vacuum, the product was obtained as a
white solid. (0.60 g, yield = 96%).
1H-NMR of potassium 5-hydroxy-2- (2- (methylthio)ethyl) -
l,3-dioxane-2-carboxylate (500 MHz, D2O/TSP) :
6 = 1.96-2.02 (m 2H, CH2) , 2.10 (t, 3H, CH3) , 2.51-2.54
(m, 2H, CH2) , 3.48-3.52 (m, 2H, CH2) , 3.81-3.87 (m, 1H,
CH) , 3.98-4.01 (m, 2H# CH2) .

Claims:
1. Chemical compound of the general formula I

and R = OH, OM, OR', NHa, NHR' or NR'R",
wherein R1, R2, R' and R" are identical or
different and are in each case a branched or
straight-chain C1-C18-alkyl or
C3-Ci8-cycloalkyl,
allyl,
benzyl,
phenyl or
C1-C18-alkyloxymethyl, preferably C2H5OCH2
C2-C6-hydroxyalkyl, preferably HOC2H4-,
C3-C6-dihydroxyalkyl, preferably (HO)aC3H5-, or a
C3-C12 sugar radical in which one OH group of the
sugar is replaced in each case by the ketal-O
atom, by the carboxylic acid-0 atom or by the
carboxamide-N atom and

M is an alkali metal ion or alkaline earth metal
ion, preferably Na+, K+, Mg2+ or Ca2+ or a
monovalent or divalent transition metal ion,
preferably Zn2+, Mn2+, Cu2+ or Cr2+,
or A =

and R = OH, OM, OR', NH2, NHR# or NR'R",
wherein R' and R" are identical or different and
are in each case a branched or straight-chain
C1-C18-alkyl or
C3-Ci8-cycloalkyl,
allyl,
benzyl,
phenyl or
C1-C18-alkyloxymethyl, preferably C2H5OCH2
C2-C6-hydroxyalkyl, preferably HOC2H4-,
C3-C6-dihydroxyalkyl, preferably (HO)2C3H5-, or a
C3-Ci2 sugar radical in which one OH group of the
sugar is replaced by the carboxylic acid-0 atom or
by the carboxamide-N atom and M is an alkali metal
ion or alkaline earth metal ion, preferably Na+,
K+, Mg2+ or Ca2+ or a monovalent or divalent
transition metal ion, preferably Zn2+, Mn2+, Cu2+ or
Cr2*,

and R3 is a C2-C4-alkylene bridge, preferably C2H4,
or a C3-C12 sugar radical in which two OH groups of
the sugar are replaced by the two ketal-0 atoms,

and R* is a C3-C6-alkylene radical which, if
appropriate, is hydroxy substituted, preferably
-CH2-C(CH3)2-CH2- and -CH2-C(CH2OH) 2-CH2-, or a C3-d2
sugar radical in which one OH group of the sugar
is replaced by the ketal-0 atom and one is
replaced by the carboxylic acid-0 atom,

and R5 is a C3-C6-alkylene radical which, if
appropriate, is hydroxy substituted, preferably
-CH2-CH(-)-CH2-, or a C3-C12 sugar radical in which
three OH groups of the sugar are replaced by both
ketal-0 atoms and by the carboxylic acid-0 atom,

and Rs is a C3-C6-alkylene radical which, if
appropriate, is hydroxy substituted, preferably
-CH2-CH(-) -CH2-, or a C3-C12 sugar radical in which
two OH groups of the sugar are replaced by the two
ketal-0 atoms, and wherein X = H or M.
2. Compound according to Claim 1, characterized in
that R = hydroxyl and R3 = C2H4.
3. Compound according to Claim 1, characterized in
that R - OR' and R' = C1-C18-alkyloxy and R3 = C2H4-
4. Compound according to Claim 3, characterized in
that R' = Ci-C4-alkyloxy.
5. Compound according to Claim 1, characterized in
that R = OR' and R' = hydroxyethoxy and R3 = C2H4.
6. Compound according to Claim 1, characterized in
that R4 is a C5H10 radical or a C5H10O2 radical.
7. Compound according to Claim 6, characterized by
the formula:
8.

9. Compound according to Claim 1, characterized in
that Rs is a C3H5 radical.
10. Compound according to Claim 9, characterized by
the formula:

11. Compound according to Claim 9, characterized by
the formula:

12. Process for producing of feeds preferably for
ruminants by mixing at least one compound according to
claim 1-11 with conventional feeds.
13. Process according to claim 12, wherein the
conventional feeds are mineral feed, organic feed or
dairy compound feed.
14. Feed preparation containing at least one compound
according to Claim 1-13, preferably for nutrition
of ruminants.
15. Process for feeding animals preferably ruminants by
use of feed preparations according to claim 14.
16. Process for producing carboxylic acid or ester
compounds of the general formula I, 1-5 according
to Claim 1, wherein, in the case of formula 1 and

2 the radical R is not 0M# NH2, NHR' or NR'R",
characterized in that ketomethionine is reacted
with a corresponding monovalent, divalent,
trivalent alcohol or a C3-C12 sugar in the presence
of acid catalysts to give the ester product of the
formulae 1-2, where R = OR', or to give the ester
product 3-4 or to give the acid product 1-2, where
R = OH, or to give the acid product 5 where X = H. •

17. Process according to Claim 16, characterized in
that, as alcohol, use is made of a branched or
straight-chain C1-C18-alkyl alcohol or C3-C18-cyclo-
alkyl alcohol, allyl alcohol, benzyl alcohol,
phenyl alcohol, C2-C6-hydroxyalkyl alcohol,
preferably HOC2H4OH, C3-C6-dihydroxyal]cyl alcohol,
preferably glycerol, or a C3-C12 sugar, preferably
glyceraldehyde, dihydroxyacetone, glucose,
fructose or sucrose.
1&. Process according to one of Claims 1'6-17,
characterized in that water formed during the
reaction is removed.
.\(\. Process for producing carboxylic acids or
carboxylic acid salts of the general formula I,
1-2 or 5 according to Claim 1, wherein the radical
R = OH or OM and the radical X = H qr M,
characterized in that an ester product of the
formula 1 or 2 where R = OR', or of the formula 4
is converted by saponification with an alkali
metal hydroxide or alkaline earth metal hydroxide
or a monovalent or divalent transition metal
hydroxide into the corresponding carboxylic acid
salt of the formula 1 or 2 where R = OM or of the
formula 5 where X = M and if appropriate the free
carboxylic acid where R = OH or X = H is liberated
therefrom using a mineral acid.

20. Process for producing carboxylic acid salts of the
general formula I, 1-2 or 5 according to Claim 1,
wherein the radical R = OM or the radical X * M,
characterized in that an acid product of the
formula I, 1-2 where R = OH or an acid product of
the formula I, 5 where X = H is neutralized with
an alkali metal or alkaline earth metal or a
monovalent or divalent transition metal hydroxide'
or carbonate to give the corresponding carboxylic
acid.
21. Process according to Claim .19 or 20, characterized
in that, as hydroxide, use is made of NaOH, KOH,
Mg(OH)2, Ca(OH)2, Zn(OH)2 or Mn(OH)2.
2%. Process according to Claim | in that, as carbonate, use is made of Na2CO3,
K3CO3, MgCO3, CaCO3, ZnCO3 or MnCO3.
2%. Process for producing carboxamides of the general
formula I, 1-2 according to Claim 1 where R = NH2/
NHR', NR'R", characterized in that an ester
product of the formula I, 1-2, where R = OR', is
converted into the corresponding amide by reaction
with NH3, NH2R' or NHR'R".
2 if. Process for producing ester compounds of the
general formula I, 1-2 according to Claim 1, where
R = OR', characterized in that an ester product I,
1-2, is converted into a corresponding ester
product of the formula I, 1-2 by
transesterification with alkali metal alkoxide
M'OR', with the proviso that R' in the ester
product 1-2 used must not be equal to the radical
R' in the alkoxide M'OR' used.

The present invention relates to ketomethionine ketals or hemiketals and their derivatives and also their preparation and their use as fodder additives, in particular for the nutrition of ruminants.

Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=HG37WmMT1W6YgR1DZoln2g==&loc=wDBSZCsAt7zoiVrqcFJsRw==

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Patent Number

269101

Indian Patent Application Number

1828/KOLNP/2009

PG Journal Number

40/2015

Publication Date

02-Oct-2015

Grant Date

30-Sep-2015

Date of Filing

18-May-2009

Name of Patentee

EVONIK DEGUSSA GMBH

Applicant Address

RELLINGHAUSER STRASSE 1-11, 45128 ESSEN

Inventors:

#	Inventor's Name	Inventor's Address
1	DR. CHRISTOPH KOBLER	HOCHSTR. 20 63755 ALZENAU
2	DR. CHRISTOPH WECKBECKER	AUGUST-IMHOF-STR. 25, 63584 GRÜNDAU-LIEBLOS
3	DR. KLAUS HUTHMACHER	LÄRCHENWEG 18, 63571 GELNHAUSEN
4	PHILIPP ROTH	AM LAUBERSBERG 1 7, 63456 HANAU
5	BARBARA JÄGER	BABENHÄUSER STRASSE 90, 63533 MAINHAUSEN
6	RAINER PETER	FRANKENSTR. 5A, 63829 KROMBACH
7	DR. MARTIN HATELEY	SONNWENDJOCHSTR. 70, 81825 MÜNCHEN

PCT International Classification Number

C07D 317/20

PCT International Application Number

PCT/EP2007/061908

PCT International Filing date

2007-11-06

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	102006055470.1	2006-11-24	Germany