Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
  • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D317/34—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D263/18—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings

Definitions

• the present invention relates to novel 2-methylthioethyl-substituted heterocycles and their derivatives and their preparation and their use as feed additives, in particular for the nutrition of livestock such.
• Essential amino acids such as methionine, lysine or threonine are very important components of animal nutrition as feed additives. Their supplementation allows for faster growth of the animals on the one hand, but also more efficient utilization of the feed on the other hand. This represents a major economic advantage.
• the markets for feed additives are of great industrial and economic importance. In addition, they are strong growth markets, not least due to the growing importance of countries such as China and India.
• methionine (2-amino-4-methylthiobutyric acid) represents the first limiting amino acid for many animal species.
• methionine (2-amino-4-methylthiobutyric acid) represents the first limiting amino acid for many animal species.
• efficient milk production in terms of quantity and quality is highly dependent on a sufficient intake of methionine.
• the methionine requirement of high-performance dairy cows can not be covered by the rumen-formed microbial protein or by rumen-degraded protein from the feed (Graulet et al., J. Animal and Feed Sciences (2004), 269). It is therefore advantageous to supplement methionine with the feed. to increase the profitability of milk production and the quality of milk.
• dietary supplementation with methionine is not effective in ruminants as the majority of ruminants in the ruminal rumen are degraded by microbes. Because of this degradation, therefore, only a fraction of the supplied methionine enters the small intestine of the
• WO 99/04647 describes the use of MHA for ruminants. It claims that MHA is only partially degraded in the rumen and therefore at least 20-40% of the supplemented MHA can enter the metabolism after absorption in the small intestine. In numerous other publications, however, the mode of action of MHA in ruminants is discussed differently. For example, it is described in WO 200028835 that MHA can only successfully pass through the rumen and finally reach absorption into the small intestine when MHA is administered in very large amounts of 60-120 g / day / animal. However, this is no longer an economic viability.
• the protective layer or matrix may consist of a combination of several substances, e.g. Lipids, inorganic materials and carbohydrates exist.
• Lipids Lipids, inorganic materials and carbohydrates exist.
• the following product forms are commercially available:
• Met-Plus TM from Nisso America is a lipid-protected methionine with a D, L-methionine content of 65%.
• the protective matrix consists of the calcium salts of long-chain fatty acids, e.g. Lauric acid.
• the preservative used is butylated hydroxytoluene.
• Mepron® M85 from Degussa AG is a carbohydrate-protected methionine that has a core of D, L-methionine, starch and stearic acid.
• a protective layer ethyl cellulose is used.
• the product has a content of 85% D, L-methionine.
• Adisseo's Smartamine TM M is a polymer-protected one
• the pellets In addition to stearic acid, the pellets contain at least 70% D, L-methionine.
• the protective layer contains vinylpyridine-styrene copolymer.
• methionine is usually a technically complicated and expensive process and is therefore expensive.
• the superficial coating of the finished pellets can be easily damaged by mechanical stress and abrasion during feed processing, which can lead to the reduction or even to complete loss of protection. Therefore, it is also not possible to process the protected methionine pellets into a larger compound feed pellet and pelletize again, as this in turn would break the protective layer by the mechanical stress. This severely restricts the use of such products because compound pelleting is a widely used method of feed processing.
• methionine esters e.g. D, L-tert-butylmethionine: The esters were tested and showed only moderate rumen stability (Loerch and Oke, "Ruwn Protected Amino Acids in Ruminant Nutrition” in “Absorption and Utilization of Amino Acids” Vol. 3, 1989, 187) -200, CRC Press Boca Raton, Florida).
• D L-tert-butylmethionine
• WO 0028835 published a bioassay of 80%.
• Metasmart TM from Adisseo is the racemic iso-propyl ester of MHA (HMBi).
• HMBi racemic iso-propyl ester of MHA
• WO 00/28835 a biowareness of at least 50% has been published for HMBi in ruminants. Above all, the surprisingly rapid absorption of the hydrophobic HMBi 's over the rumen wall plays a decisive role. The ester can then be hydrolyzed in the blood to MHA and converted to L-methionine after oxidation and subsequent transamination.
• EP 1358805 a comparable organic value for HMBi was published. In these studies, HMBi was supported on a porous support.
• HMBi can be prepared either directly in one step from the corresponding cyanohydrin (WO 00-59877).
• the esterification to the isopropyl ester takes place in situ, without first having to isolate MHA.
• another method esterifies pure MHA with isopropanol (WO 01-58864 and WO 01-56980).
• hydrocyanic acid is used for the synthesis, which is expensive and also carries a high risk potential.
• a general task was to provide a feed or feed additive in animal nutrition based on new methionine substitutes.
• methionine product for farm animals.
• this product should be rumen-stable for use by ruminants, especially dairy cows.
• the product should be as suitable as possible for use in feeding fish and shellfish in aquaculture.
• the animals should be provided with a further efficient source of methionine which, if possible, does not have the disadvantages of the known products or only to a lesser extent.
• Another object was to find a feed or a feed additive with very high bio-worth, which should have good handling and storage stability and stability under the usual conditions of compound feed processing, in particular pelleting.
• a feed or a feed additive with very high bio-worth, which should have good handling and storage stability and stability under the usual conditions of compound feed processing, in particular pelleting.
• such a product would have the advantage of a much simpler and standardized compound feed processing / supply, so that the Economy but also the quality of milk production would be increased.
• heterocyclic compounds according to the invention and their derivatives according to formula I or formula II especially their use as feed, preferably for chickens, pigs, Ruminants, fish and crustaceans.
• the present invention therefore provides a chemical compound of the general formula (I) or (II)
• X is O or NR and R is H, an optionally branched C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, aryl, in particular phenyl, or aralkyl, in particular benzyl, and wherein R 1 , R 2 is identical or different and in each case H, an optionally branched C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, allyl, aryl, in particular phenyl, or aralkyl, in particular benzyl, or R 1 and R 2 together is an optionally Ci-C6-alkyl-substituted C2 to C & alkylene group.
• the components of the formula I are free of dimeric and oligomeric by-products, in contrast to the commercially available 2-hydroxy-4-methylthioethylbutyric acid (MHA monomer). This is in equilibrium with their dimeric and higher oligomeric esters (condensation products), which have a significantly lower bioavailability than MHA monomer or D, L-methionine itself. MHA will therefore be similar to the analogous lactic acid as 88%. marketed aqueous solution in order to influence the equilibrium in the direction of the desired monomer.
• MHA monomer 2-hydroxy-4-methylthioethylbutyric acid
• the components of the invention need not be diluted with water, so that the pure active ingredient is available.
• these components can also be applied to solid carriers, which may be inorganic or organic in nature and should be suitable for feed, thus easily producing a solid feed additive which is just as easy to handle where only solid dosing systems are available such as D, L-methionine as a classic solid feed additive.
• Such inorganic carriers may be silicic acids, e.g. Sipernat from Evonik-Degussa, or silicates, as well as aluminum oxides or zeolites, e.g. Calcium, sodium or
• Sodium aluminum silicate, or metal carbonates such as magnesium, calcium or sodium carbonate, individually or in admixture of two or more such carriers.
• Such organic carriers may, for example, be alginates, stearates, starches and gums. Preference is given to calcium, sodium or aluminum alginate, calcium stearate or sodium stearate, corn starch or gum arabic, individually or as a mixture of two or more such carriers.
• the carbonyl compound is formaldehyde, which is easily further oxidized to formate, which itself has significance as a feedstock.
• preferred compounds in the context of the present invention are also compounds of the formula I in which X is NH.
• X is NH.
• This ammonia represents exactly the molar NH 3 - equivalent, which is used in the organism for the metabolism of the inventive compound II to the amino acid methionine.
• the carbonyl compound formed is formaldehyde, which is easily further oxidized to formate, which itself has significance as a feedstock.
• the carbonyl compound is benzaldehyde, which is a natural constituent of bitter almonds.
• Such compounds can be used in particular for feeding poultry, pigs, ruminants, but also for feeding fish or crustaceans.
• Feed mixtures for the nutrition of livestock containing at least one of the compounds of the general formula I or II are also the subject of the present invention, as well as the corresponding use of these compounds for the production of feed mixtures for the nutrition of livestock.
• X, R 1 and R 2 are each as defined above.
• X O
• III stands for the 2-hydroxy-4-methylthiobutyric acid (compound 3, MHA monomer), which also generates from its salts, preferably the calcium salt (compound 1, see Example 1) with acid in situ can be.
• X NH
• III is 2-hydroxy-4-methylthiobutyric acid amide (compound 9, MHA amide), which is obtained from 2-hydroxy-4-methylthiobutyric acid nitrile by known hydrolysis processes, for example with 55-70 percent sulfuric acid can be.
• Suitable solvents are, for example, toluene or chloroform, which can simultaneously serve as entrainer, and tetrahydrofuran, dioxane, methylene chloride and dimethylformamide. It is particularly advantageous, however, to use the carbonyl compound used simultaneously as a solvent, especially if it is a ketone, such as in the case of acetone or methyl ethyl ketone. The excess carbonyl compound can be easily recovered after completion of the reaction in the usual manner and used directly, possibly even after further purification.
• Such a process is preferably carried out by acid catalysis.
• Suitable catalysts used are suitable Lewis acids or Bronsted acids.
• Preferred catalysts are HCl, H 2 SO 4 , p-
• Toluene sulfonic acid CF3SO3H as Bronsted acids and ZnCl 2 , CuSO 4 , FeCl 3 , AlCl 3 , MgCl 2 and MgBr 2 as Lewis acids.
• the catalysts can be recovered after completion of the reaction in the usual manner and used directly, if necessary after cleaning again.
• the invention also provides a process for the preparation of compounds of the formula II, characterized in that a compound of the general formula
• X 1 X 2 C O
• X 1 and X 2 are identical or different and independently of one another chlorine, OCCl 3 , OCH 3 , OCH 2 CH 3 or imidazolyl or triazolyl bound via the nitrogen.
• OCCl 3 used as a reactive carbonic acid equivalent.
• dimethyl carbonate or diethyl carbonate and the N-containing carbonic acid equivalents shown, such as carbonyldiimidazole, are also very suitable and easy to handle.
• Such a reaction may advantageously be carried out both acidic or basic catalyzed.
• acid catalysts the abovementioned Brönstedt or Lewis acids can be used (??).
• Suitable basic catalysts are, in particular, alkali metal alcoholates of C 1 -C 4 -alcohols, for example sodium methoxide or ethoxide or else potassium tert-butylate.
• a further suitable process variant for the preparation of compounds of the formula I where X NH, which comprises reacting 2-hydroxy-4-methylthiobutyric acid nitrile of the formula IV
• sulfuric acid and / or acetic acid are preferably used as the acid and acetic anhydride is preferably used as the carboxylic acid anhydride.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Fodder In General (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

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• 2007
  • 2007-12-21 DE DE102007062199A patent/DE102007062199A1/de not_active Withdrawn
• 2008
  • 2008-12-01 EP EP08865833A patent/EP2222654B1/de not_active Not-in-force
  • 2008-12-01 JP JP2010538543A patent/JP5511679B2/ja active Active
  • 2008-12-01 BR BRPI0821237A patent/BRPI0821237A8/pt not_active IP Right Cessation
  • 2008-12-01 WO PCT/EP2008/066525 patent/WO2009080446A1/de not_active Ceased
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  • 2008-12-01 RU RU2010129556/04A patent/RU2516833C2/ru not_active IP Right Cessation
  • 2008-12-01 CN CN2008801222986A patent/CN101903363A/zh active Pending
  • 2008-12-01 ES ES08865833T patent/ES2410357T3/es active Active
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