WO2020093188A1 - 天门冬氨酸脂肪酰基衍生物在制备动物饲料添加剂中的应用 - Google Patents

天门冬氨酸脂肪酰基衍生物在制备动物饲料添加剂中的应用 Download PDF

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WO2020093188A1
WO2020093188A1 PCT/CN2018/113907 CN2018113907W WO2020093188A1 WO 2020093188 A1 WO2020093188 A1 WO 2020093188A1 CN 2018113907 W CN2018113907 W CN 2018113907W WO 2020093188 A1 WO2020093188 A1 WO 2020093188A1
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feed
aspartic acid
fatty acyl
acyl derivative
additives
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PCT/CN2018/113907
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English (en)
French (fr)
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黄华成
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黄华成
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Priority to CN201880012282.3A priority Critical patent/CN110325052B/zh
Priority to PCT/CN2018/113907 priority patent/WO2020093188A1/zh
Publication of WO2020093188A1 publication Critical patent/WO2020093188A1/zh

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K10/00—Animal feeding-stuffs
    • A23K10/30—Animal feeding-stuffs from material of plant origin, e.g. roots, seeds or hay; from material of fungal origin, e.g. mushrooms
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K10/00—Animal feeding-stuffs
    • A23K10/30—Animal feeding-stuffs from material of plant origin, e.g. roots, seeds or hay; from material of fungal origin, e.g. mushrooms
    • A23K10/37—Animal feeding-stuffs from material of plant origin, e.g. roots, seeds or hay; from material of fungal origin, e.g. mushrooms from waste material
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/105—Aliphatic or alicyclic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/142—Amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/142—Amino acids; Derivatives thereof
    • A23K20/147—Polymeric derivatives, e.g. peptides or proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/158—Fatty acids; Fats; Products containing oils or fats
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/163—Sugars; Polysaccharides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/195—Antibiotics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/20—Inorganic substances, e.g. oligoelements
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/20—Inorganic substances, e.g. oligoelements
    • A23K20/24—Compounds of alkaline earth metals, e.g. magnesium
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/20—Inorganic substances, e.g. oligoelements
    • A23K20/28—Silicates, e.g. perlites, zeolites or bentonites
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/20—Inorganic substances, e.g. oligoelements
    • A23K20/30—Oligoelements
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/30—Feeding-stuffs specially adapted for particular animals for swines
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/40—Feeding-stuffs specially adapted for particular animals for carnivorous animals, e.g. cats or dogs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/60—Feeding-stuffs specially adapted for particular animals for weanlings
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/70—Feeding-stuffs specially adapted for particular animals for birds
    • A23K50/75—Feeding-stuffs specially adapted for particular animals for birds for poultry
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/80—Feeding-stuffs specially adapted for particular animals for aquatic animals, e.g. fish, crustaceans or molluscs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
    • C07C275/16—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by carboxyl groups
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P60/00—Technologies relating to agriculture, livestock or agroalimentary industries
    • Y02P60/80—Food processing, e.g. use of renewable energies or variable speed drives in handling, conveying or stacking
    • Y02P60/87—Re-use of by-products of food processing for fodder production

Definitions

  • the invention belongs to the field of animal feed additives, and in particular relates to the application of aspartic acid fatty acyl derivatives in the preparation of animal feed additives and a feed composition containing aspartic acid fatty acyl derivatives and its preparation in animal feed additives and Application in animal feed.
  • Aspartic acid is a non-essential amino acid in animals. N-acylated aspartic acid has a fatty taste and is used as a low-calorie fat substitute in healthy foods. N-acylated aspartic acid is also an amino acid surfactant with good air bubble capacity and stable storage. It is a personal care and public health field such as toothpaste, kitchen cleaner, toilet cleaner, shampoo, shower gel and so on.
  • Acetylated aspartic acid is an ingredient in various plants or foods, and it is also a substance of the central nervous system. It is an acetic acid donor of myelin liquid fatty acid. Studies have shown that acetylated aspartic acid shows It is an irritating and nasty mixed sour taste.
  • Feed refers to products processed and manufactured for animals for industrial use. It is the main animal food for modern and intensive aquaculture. In the process of animal breeding, the farmers desire that the feed products eaten by the animals can be absorbed and utilized by the animals to the greatest extent, improve the production performance of the animals and thus achieve the purpose of improving the economic benefits of the breeding. Adding feed additives with corresponding effects to feed products can effectively improve the utilization rate of feed products.
  • Feed additives refer to small or trace substances added during feed processing, production and use, including nutritive feed additives and general feed additives.
  • General feed additives refer to the small or trace substances incorporated into the feed in order to ensure or improve feed quality and increase feed utilization.
  • Common feed additives commonly used in this field with high efficiency and stable increase in feed utilization and animal performance include high-dose copper, high-dose zinc, feed antibiotics, chemically synthesized antibacterial agents, etc.
  • these substances are used in the breeding industry
  • the medium- and long-term use has large side effects, such as animal liver and kidney toxicity, growth inhibition, kidney function damage, urinary tract disorders, teratogenicity, mutagenicity, drug resistance, drug residues and environmental pollution.
  • the present invention provides a stable and effective aspartic acid fatty acyl derivative or its racemate, stereoisomer, geometric isomer, tautomer, solvate and feed acceptable
  • the application of salt in the preparation of animal feed additives the invention also provides a fatty acyl derivative containing aspartic acid or its racemate, stereoisomer, geometric isomer, tautomer, solvation Composition of feedstuffs and acceptable salts of feedstuffs and the use of the composition in the preparation of animal feed additives and animal feed.
  • the present invention provides a fatty acyl derivative of aspartic acid or its racemate, stereoisomer, geometric isomer, tautomer, solvated structure represented by formula (I)
  • Y and X are independently selected from C 1 -C 20 alkoxy or OH;
  • R 1 is R 1a C ( ⁇ O), R 1a S ( ⁇ O) 2 or H;
  • R 1a and R 2a are independently selected from C 1 -C 20 alkyl or C 3 -C 7 cycloalkyl.
  • R 1 of the fatty acyl derivative of aspartic acid is H.
  • R 2a of the fatty acyl derivative of aspartic acid is selected from C 1 -C 10 alkyl.
  • Y and X of the asparagine fatty acyl derivative are OH.
  • Y and X of the asparagine fatty acyl derivative are independently selected from C 1 -C 20 alkoxy or OH, and are not OH at the same time.
  • Y and X of the asparagine fatty acyl derivative are independently selected from C 1 -C 10 alkoxy or OH, and are not OH at the same time.
  • the acceptable salt of the fatty acyl derivative of aspartic acid is a metal ion salt.
  • the feed acceptable salt of the fatty acyl derivative of aspartic acid is preferably sodium ion salt, calcium ion salt, zinc ion salt, copper ion salt or iron ion salt.
  • the present invention provides a feed composition
  • a feed composition comprising the asparagine fatty acyl derivative of the present invention or its racemate, stereoisomer, geometric isomer, tautomer , At least one of solvates or feed acceptable salts and at least one feedable adjuvant.
  • the feedable auxiliary material is selected from a feedable carrier, diluent, adjuvant, solvent or a combination thereof.
  • the feed composition further includes animal feed materials.
  • the feed composition further includes additional animal feed additives.
  • the feed composition further includes animal feed materials and additional animal feed additives.
  • the additional animal feed additives may be selected from nutritional feed additives and / or general feed additives and / or pharmaceutical feed additives.
  • the present invention provides the use of the feed composition in the preparation of animal feed additives.
  • the present invention provides the use of the feed composition in the preparation of animal feed.
  • the invention also provides a method for improving the production performance of farmed animals.
  • any embodiment of any aspect of the present invention may be combined with other embodiments as long as there is no contradiction between them.
  • any technical feature can be applied to the technical feature in other embodiments as long as there is no contradiction between them.
  • the compound of the present invention is a fatty acyl derivative of aspartic acid having the structure shown in formula (I),
  • Y and X are substituents on the carboxyl group of aspartic acid, and R 1 and R 2 are substituents on the nitrogen atom (abbreviated as N).
  • Y and X are independently selected from C 1 -C 20 alkoxy or OH;
  • R 1 is R 1a C ( ⁇ O), R 1a S ( ⁇ O) 2 or H;
  • R 1a and R 2a are independently selected from C 1 -C 20 alkyl or C 3 -C 7 cycloalkyl.
  • substituted means that one or more substitutable hydrogen atoms in a given structure are replaced by specific substituents.
  • a substituted group may have a substituent at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents of a specific group, then the substituents may be substituted at the same positions or differently.
  • C 1 -C 20 alkyl means a saturated alkyl group containing 1 to 20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, ..., linear or branched An alkyl group containing 20 carbon atoms;
  • C 3 -C 7 cycloalkyl means a cyclic alkyl group containing 3 to 7 carbon atoms containing only two hydrocarbon elements, such as cyclopropyl, 2 -Methylcyclopropyl, cyclopentyl, etc.
  • the R 1a and R 2a They are independently selected from C 1 -C 20 alkyl or C 3 -C 7 cycloalkyl
  • Y and X are independently selected from C 1 -C 20 alkoxy or OH.
  • R 1 is H
  • the R 2a is selected from C 1 -C 20 alkyl or C 3 -C 7 cycloalkyl
  • the Y and X are independently selected from C 1 -C 20 alkoxy or OH.
  • the R 1a and R 2a are independently It is selected from C 1 -C 20 alkyl or C 3 -C 7 cycloalkyl
  • Y and X are independently selected from C 1 -C 20 alkoxy or OH.
  • R 1 is H
  • R 2a is selected from C 1 -C 20 alkyl or C 3 -C 7 cycloalkyl
  • Y And X are independently selected from C 1 -C 20 alkoxy or OH.
  • the R 1a or R 2a is selected from C 1 -C 20 alkyl.
  • the R 1a or R 2a is selected from linear C 1 -C 10 alkyl groups, specifically methyl (CH 3 ), ethyl (CH 2 CH 3 ), n-propyl ((CH 2 ) 2 CH 3 ), n-butyl ((CH 2 ) 3 CH 3 ), n-pentyl ((CH 2 ) 4 CH 3 ), n-pentyl ((CH 2 ) 5 CH 3 ), n-heptyl ((CH 2 ) 6 CH 3 ), n-octyl ((CH 2 ) 7 CH 3 ), n-nonyl ((CH 2 ) 8 CH 3 ), n-decyl ((CH 2 ) 9 CH 3 ) one.
  • linear C 1 -C 10 alkyl groups specifically methyl (CH 3 ), ethyl (CH 2 CH 3 ), n-propyl ((CH 2 ) 2 CH 3 ), n-butyl ((CH 2 ) 3 CH 3
  • the R 1a or R 2a is selected from branched C 1 -C 10 alkyl groups, including but not limited to isopropyl ((CH 3 ) 2 CH), isobutyl ((CH 3 ) 3 C) etc.
  • Y and X of the fatty acyl derivative of aspartic acid are both OH.
  • Y and X of the fatty acyl derivative of aspartic acid are selected from C 1 -C 20 alkoxy or OH, but not OH at the same time, specifically C 1 -C 20 alkoxy Or one of C 1 -C 20 alkoxy and OH, respectively.
  • the alkoxy group is preferably a linear or branched C 1 -C 10 alkoxy group, including but not limited to methoxy (OCH 3 ), ethoxy (OCH 2 CH 3 ), n-propane Oxygen (O (CH 2 ) 2 CH 3 ), isopropylalkoxy (OCH 2 (CH 3 ) 2 ), n-butaneoxy (O (CH 2 ) 3 CH 3 ), tert-butaneoxy (OC (CH 3 ) 3 ), n-pentaneoxy (O (CH 2 ) 4 CH 3 ), n-alkyl alkoxy (O (CH 2 ) 5 CH 3 ), n-heptaneoxy (O (CH 2 ) 6 CH 3 ), n-octaneoxy (O (CH 2 ) 7 CH 3 ), n-nonaneoxy (O (CH 2 ) 8 CH 3 ) or n-decaneoxy (O (CH 2 ) 9 CH 3 ).
  • the acceptable salt of the fatty acyl derivative of aspartic acid is a metal ion salt, specifically a monovalent metal ion salt, a divalent metal ion salt or a trivalent metal ion salt.
  • the monovalent metal ion includes but is not limited to sodium ion, potassium ion, lithium ion, and ammonium ion;
  • the bivalent metal ion includes but is not limited to calcium ion, magnesium ion, zinc ion, copper ion, sub-ion Iron ions, manganese ions;
  • the trivalent metal ions include but are not limited to iron ions, nickel ions, chromium ions, aluminum ions.
  • the metal ion is zinc ion.
  • the metal ions are copper ions.
  • the metal ion is sodium ion.
  • the metal ion is calcium ion.
  • the metal ions are iron ions.
  • the preparation method of aspartic acid fatty acyl derivatives as shown in formula (I) according to the present invention uses aspartic acid (Asp) as a starting material, and the chemical reactions involved mainly include acylation of amino groups and carboxyl groups. Esterified.
  • Y and X in formula (I) are C 1 -C 20 alkoxy or OH but not OH at the same time
  • the preparation method of aspartic acid fatty acyl derivatives represented by formula (I) includes The two-step reaction of esterification of carboxyl groups and acylation of amino groups is shown in formula (II).
  • Y and X in formula (I) are both -OH, and the preparation method of the asparagine fatty acyl derivative represented by formula (I) is represented by formula (III).
  • R 1 in formula (III) only represents a substituent group, and when the material represented by the raw material R 1 OR 1 is not a single substance, R 1 on the target product (TM) should be understood as a collection of substituents.
  • the asparagine fatty acyl derivative reacts with metal chloride or metal bromide under basic conditions to produce aspart Metal ion salts of amino acid fatty acyl derivatives, such as zinc salts, copper salts, calcium salts, iron salts or sodium salts, etc., according to the present invention.
  • the aspartic acid is a chiral compound
  • the aspartic acid according to the present invention is selected from L-(-)-aspartic acid (the structure is as shown in formula (IV) ), D-(+)-aspartic acid (structure as formula (V)) or racemic DL- ( ⁇ ) aspartic acid, reacted with the alcohol and carboxylic acid derivatives The stereoisomer or racemate of the fatty acyl derivative of aspartic acid in the chiral center.
  • the chiral stereoisomer of aspartic acid and the stereoisomer of the fatty acyl derivative of aspartic acid can undergo transformation of the stereoconfiguration under suitable conditions, such as aspartic
  • suitable conditions such as aspartic
  • the steric conformation of the fatty acyl derivatives of amino acid or aspartic acid is interconverted.
  • the steric conformation of aspartic acid is shown in formula (VI):
  • reaction substrate When the reaction substance involved reacts with aspartic acid and the like to form the corresponding aspartic acid fatty acyl derivative having a rigid structure, the reaction substrate can generate different geometric isomer products during the reaction.
  • stereoisomer refers to compounds having the same chemical structure but different arrangement of atoms or groups in space, including enantiomers, diastereomers, and conformational isomers , Geometric isomers, atropisomers, etc.
  • Enantiomer refers to two isomers of a compound that cannot overlap but are mirror images of each other.
  • Diastereomers refers to stereoisomers that have two or more chiral neutrals and whose molecules are not mirror images of each other, and have different physical properties such as different melting points, boiling points, spectral properties, and reactivity.
  • Non-isomer mixtures can be separated by high-resolution analytical operations such as electrophoresis or chromatography;
  • tautomers refer to structural isomers with different energies that can be interconverted by a low energy barrier.
  • the present invention provides that the preparation process of the asparagine fatty acyl derivative also involves the separation, purification, or recrystallization process of the reaction product.
  • the reaction product can be obtained from the reaction system by a solvent removal method.
  • the crude product is dissolved and analyzed in an alcohol solvent, an alcohol-water mixed solvent, or other organic solvents that can be used for product recrystallization under suitable conditions of temperature, light, and mechanical vibration. Crystal or precipitation or recrystallization and separation to obtain fatty acyl derivatives of aspartic acid with a certain crystalline state.
  • the asparagine fatty acyl derivative having a certain crystalline state is a crystal of aspartic acid fatty acyl derivative or a solvate of aspartic acid fatty acyl derivative.
  • the solvate of the fatty acyl derivative of aspartic acid may be selected from the hydrate of the fatty acyl derivative of aspartic acid or the ethanolate of the aspartic acid derivative.
  • solvate refers to the process in which the compound of the present invention is in contact with the solvent molecule, the external condition and the internal condition cause the non-covalent intermolecular force to form a chemical equivalent or non-chemical equivalent of the solvent molecule Eutectic association.
  • Solvent-forming solvents include, but are not limited to, water, acetone, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, isopropyl alcohol, and other solvents.
  • “Hydrate” means that the solvent molecule is an association or crystal formed by water, that is, a compound that combines chemically equivalent or non-chemically equivalent water with non-covalent intermolecular forces.
  • the preparation of the asparagine fatty acyl derivative provided by the present invention can also be processed after salting out.
  • the salting-out method uses the principles of acid-base neutralization method, acid-base coordination method or acid-base chelating method to make aspartic acid derivatives salt-precipitate with corresponding organic bases, inorganic bases, organic acids or inorganic acids The process of obtaining acceptable salt for feed.
  • the acceptable salt for feed is the salt formed by the asparagine fatty acyl derivative of the present invention and an organic base, inorganic base, organic acid or inorganic acid which is non-toxic to animals.
  • feed-acceptable means that the substance or composition must be chemically or toxicologically related to the constituent feed or edible farm animal.
  • the fatty acyl derivative of aspartic acid is a diester or mixed ester (that is, Y and X are the same or different C 1 -C 20 alkyl groups at the same time).
  • Acids or organic acids form acid-base coordination salts and or acid-base chelate salts.
  • the organic acids include but are not limited to acetate, maleate, succinate, mandelate, fumarate, malonic acid Salt, malate, 2-hydroxypropionate, pyruvate, oxalate, glycolate, salicylate, glucuronate, galactitol, citrate, tartrate, aspart Glutamate, glutamate, benzoate, p-toluate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethane Sulfonates or combinations thereof; said inorganic acids include but are not limited to hydrochloride, hydrobromide, phosphate, sulfate, nitrate or combinations thereof.
  • the fatty acyl derivative of aspartic acid is a monoester (that is, Y and X are one of C 1 -C 20 alkyl and H, respectively), and the post-treatment salting out precipitation process is associated with organic acids or inorganic Acids form acid-base coordination salts and or acid-base chelate salts, or form acid salts with organic or inorganic bases.
  • the organic acids include but are not limited to acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, pyruvate, oxalate Salt, glycolate, salicylate, glucuronate, galactitol, citrate, tartrate, aspartate, glutamate, benzoate, p-toluene Formate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate or combinations thereof; the inorganic acids include but are not limited to salts Acid salt, hydrobromide salt, phosphate, sulfate, nitrate or a combination thereof.
  • the organic base includes but is not limited to ammonia or triethylamine.
  • the inorganic base includes but is not limited to sodium hydroxide, potassium hydroxide, magnesium hydro
  • the fatty acyl derivatives of aspartic acid or racemates, stereoisomers, geometric isomers, tautomers, solvates, or feed acceptable salts thereof provided by the present invention are measured at 60 ° C.
  • the stability of the test period is 10 days. During the test period, the content of the compound did not change significantly with time.
  • the invention relates to the use of fatty acyl derivatives of aspartic acid.
  • the "animal” referred to in the present invention refers to a person or farming that cannot synthesize inorganic matter into organic matter and can only use the organic matter as food for life activities such as ingestion, digestion, absorption, respiration, circulation, excretion, sensation, exercise and reproduction. animal.
  • Cosmetic animals include poultry, domestic animals, aquaculture animals, and other animals that are legally captured in captivity including pets, such as cats and dogs.
  • livestock is, for example, any of pigs, cattle, horses, goats, sheep, deer, and many useful rodents.
  • the term “poultry” includes, for example, chickens, ducks, geese, quails, pigeons, and the like.
  • aquaculture animals includes, for example, fish, shrimp, turtles, turtles and the like.
  • the fatty acyl derivatives of aspartic acid and their racemates, stereoisomers, geometric isomers, tautomers, solvates or feed acceptable salts provided by the present invention are prepared as various Non-nutritive additives to improve animal production performance of animals in the growth stage, the animals may be selected from livestock, poultry, aquaculture animals or pets at various growth stages.
  • the domestic animals include but are not limited to pigs, cows, sheep, horses, rabbits, mink or donkeys
  • the domestic poultry include but are not limited to chickens, turkeys, ducks, geese, quails or pigeons
  • Aquaculture animals include but are not limited to fish, shrimp, turtle, crab, turtle, bullfrog, eel or loach, and the pets include but are not limited to dogs or cats of various subspecies.
  • the fatty acyl derivative of aspartic acid provided by the present invention and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed are acceptable
  • the salt is prepared as a feed additive for weaned pigs, which can increase the feed intake of weaned pigs and effectively increase the average daily weight gain of the weaned pigs and improve the feed conversion rate.
  • the fatty acyl derivative of aspartic acid provided by the present invention and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed are acceptable
  • the salt is prepared as a feed additive for laying hens, which can effectively improve the egg production rate of the laying hens, increase the egg weight and reduce the egg-to-egg ratio of the laying hens.
  • the fatty acyl derivative of aspartic acid provided by the present invention and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed are acceptable
  • the feed additives prepared by the salt can significantly improve the performance of broilers.
  • the fatty acyl derivative of aspartic acid provided by the present invention and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed are acceptable
  • the feed additive prepared by the salt can significantly improve the production performance of meat ducks and laying ducks.
  • the fatty acyl derivative of aspartic acid provided by the present invention and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed are acceptable
  • the salt prepared is a feed additive that improves the performance of fish.
  • the fatty acyl derivative of aspartic acid provided by the present invention and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed are acceptable
  • the feed additives prepared by the salt have a more significant effect on the improvement of pet production performance.
  • the feed acceptable salt of the fatty acyl derivative of aspartic acid provided by the present invention used in the preparation of animal feed additives is a metal ion salt.
  • the feed acceptable salt of the fatty acyl derivative of aspartic acid is a metal ion salt of the fatty acyl derivative of aspartic acid having the structure shown in formula (I).
  • Y and X in the asparagine fatty acyl derivative of the structure shown in formula (I) are selected from C 1 -C 20 alkoxy or OH, but not C 1 -C 20 at the same time Alkoxy group, and the metal ion salt is a salt obtained by exchanging the OH of the aspartic acid fatty acyl derivative with the metal ion, which meets the requirements for the preparation of feed additives or feed preparation.
  • the metal ion is selected from a monovalent metal ion, a divalent metal ion or a trivalent metal ion.
  • the monovalent metal ion is sodium ion (Na (I)), potassium ion (K (I)) or lithium ion (Li (I)).
  • the divalent metal ion is calcium ion Ca (II), magnesium ion Mg (II), copper ion Cu (II), zinc ion Zn (II), ferrous ion Fe (II), Manganese ion Mn (II), cobalt ion Co (II) or nickel ion Ni (II).
  • the metal ion salt of the fatty acyl derivative of aspartic acid used in the preparation of animal feed additives is zinc ion salts
  • the animal feed additive is an organic zinc agent for animals as a high-dose inorganic zinc replacement .
  • the metal ion salt of the fatty acyl derivative of aspartic acid used in the preparation of animal feed additives is copper ion salts
  • the animal feed additive is organic copper for animals as high-dose inorganic copper for animals. Thing.
  • the metal ion salt of the fatty acyl derivative of aspartic acid used in the preparation of animal feed additives is an iron ion salt
  • the animal feed additive is an iron element supplement for animals.
  • the trivalent metal ion is aluminum ion Al (III), chromium ion Cr (III) or iron ion Fe (III).
  • a fatty acyl derivative containing aspartic acid and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt and feedable A feed composition using supplementary materials.
  • the feedable supplementary materials are feedable carriers, diluents, adjuvants, solvents or combinations thereof.
  • the feed related to the present invention refers to a product processed and manufactured by an industry for animal consumption.
  • composition refers to a group of compounds comprising one or more compounds as active ingredients.
  • the “carrier” referred to in the present invention refers to a feedable substance capable of carrying active ingredients, improving their dispersibility, and having good chemical stability and adsorption, and is an organic carrier and an inorganic carrier.
  • the organic carrier is a material containing much crude fiber, including but not limited to corn flour, corn cob flour, wheat bran, rice husk powder, defatted rice bran, whole bran, corn stalk powder, peanut shell powder, etc.
  • the inorganic carrier is a mineral substance, which is mainly divided into calcium salts and silicon oxides, which are used for the preparation of trace element premixes, including but not limited to calcium carbonate, silicate, vermiculite, zeolite, sea bubble Stone etc.
  • the "diluent” referred to in the present invention refers to materials that uniformly distribute additive raw materials in materials, dilute high-concentration additive raw materials into low-concentration premixes or premix materials, which can separate trace ingredients from each other and reduce active ingredients.
  • the mutual reaction between the organic diluent and the inorganic diluent in order to increase the stability of the active ingredient but not affect the physical and chemical properties of the related substances.
  • Organic diluents include, but are not limited to, corn flour, degermated corn flour, dextrose (glucose), sucrose, semolina flour with bran, fried soy flour, secondary flour, corn gluten meal, etc .; inorganic diluents include but not Limited to limestone, dibasic calcium phosphate, shell powder, kaolin (white clay), table salt and sodium sulfate.
  • the adjuvant is a wetting agent that induces the inherent viscosity of the substance itself, a binder that binds the substance, a disintegrant that breaks up the whole sheet of the substance into many fine particles, and reduces the gap between the particles Friction retention agent or anti-adhesive agent to prevent material adhesion, including but not limited to magnesium stearate, talc, vegetable oil, magnesium lauryl sulfate, starch, starch slurry, water, inorganic salts, dextrin, powdered sugar, etc. .
  • solvent refers to a solvent required to dissolve or disperse solids, including but not limited to water, ethanol, glycerin and the like.
  • the feed composition further includes additional animal feed additives and / or animal feed ingredients.
  • the animal feed additives are nutritional feed additives, general feed additives or pharmaceutical feed additives.
  • the nutritive feed additives refer to small or trace substances added to compound feeds to balance feed nutrients, improve feed utilization and directly exert nutritional effects on animals, such as amino acids, amino acid salts and their analogs, vitamins and quasi-vitamins , Mineral elements and their complexes (chelates), microbial enzyme preparations or non-protein nitrogen.
  • the general feed additives are also called non-nutritive additives, which refers to some non-nutritive substances added to the feed for improving feed utilization, ensuring feed quality and quality, and beneficial to animal health or metabolism, including growth promoters, Insect repellent health care agent, flavoring and attractant, feed conditioner, feed modulator, feed storage agent, probiotics, prebiotics and Chinese herbal medicine additives.
  • non-nutritive additives are growth promoters, including but not limited to butyric acid, calcium butyrate, sodium butyrate, tannic acid, p-thymol, p-thymol phenolate, p-thyme phenolate, 2 -Hydroxybenzoic acid, ⁇ -acid, ⁇ -ester, ⁇ -acid, hexahydro ⁇ -acid, hexahydro ⁇ -ester, hexahydro ⁇ -acid, benzoic acid or calcium benzoate, zinc oxide, sulfuric acid Zinc, zinc chloride.
  • growth promoters including but not limited to butyric acid, calcium butyrate, sodium butyrate, tannic acid, p-thymol, p-thymol phenolate, p-thyme phenolate, 2 -Hydroxybenzoic acid, ⁇ -acid, ⁇ -ester, ⁇ -acid, hexahydro ⁇ -
  • the non-nutritive additive is calcium butyrate.
  • the non-nutritive additive is tannic acid.
  • the pharmaceutical feed additives include, but are not limited to, veterinary drug pre-mixtures that have the functions of preventing animal diseases, promoting animal growth, and can be used for a long time in the feed and incorporated with carriers or diluents.
  • the pharmaceutical feed additive is a feeding antibiotic
  • the feeding antibiotic includes but is not limited to polymyxin, salinomycin, aviramycin, bacitracin, virginiamycin , Nosiheptide, flavomycin, enramycin, berimycin, olaquindox, oxytetracycline or chlortetracycline.
  • a composition comprising fatty acyl derivatives of aspartic acid and racemates, stereoisomers, geometric isomers, tautomers, solvates, or feed acceptable salts thereof , Also contains one or more of nutritional feed additives, general feed additives and pharmaceutical feed additives.
  • the animal feed materials are cereals and their processed products, oilseeds and their processed products, leguminous crops and their processed products, tubers, roots and their processed products, other seed and fruit products and Its processed products, forage grass, roughage and its processed products, other plants, algae and its processed products, dairy products and their by-products, terrestrial animal products and their by-products, fish, other aquatic organisms and their by-products, minerals, microbial fermentation Products and by-products, other feed materials and other feed materials.
  • the present invention relates to the above feed composition containing aspartic acid fatty acyl derivatives and their racemates, stereoisomers, geometric isomers, tautomers, solvates or feed acceptable salts application.
  • the feed comprising fatty acyl derivatives of aspartic acid and racemates, stereoisomers, geometric isomers, tautomers, solvates, or feed acceptable salts thereof
  • the composition is used in the preparation of animal feed additives.
  • the animal feed additives are livestock feed additives, poultry feed additives, aquaculture animal feed additives or pet feed additives.
  • the feed containing the fatty acyl derivative of aspartic acid and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt described above is applied
  • the composition is used to prepare feed additives for livestock.
  • the livestock include, but are not limited to, pigs, cattle, sheep, horses, rabbits, mink, etc. at various growth stages.
  • the feed containing the fatty acyl derivative of aspartic acid and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt described above is applied
  • the composition is used to prepare poultry feed additives.
  • the poultry includes but is not limited to chickens, ducks, geese, pigeons, etc. at various growth stages.
  • the feed containing the fatty acyl derivative of aspartic acid and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt described above is applied
  • the composition is used to prepare feed additives for aquaculture animals.
  • the aquaculture animals include, but are not limited to, fish, shrimp, crab, turtle, eel, etc. at various growth stages.
  • the feed containing the fatty acyl derivative of aspartic acid and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt described above is applied
  • the composition prepares pet feed additives.
  • the pets include but are not limited to artificially raised dogs or cats.
  • the fatty acyl derivative containing aspartic acid and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt is a premix, a compound premix, a liquid or a granule.
  • the asparagine fatty acyl derivative and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt The feed composition is used in the preparation of animal feed.
  • the animal feed is livestock feed, poultry feed, aquaculture animal feed or pet feed.
  • the feed containing the fatty acyl derivative of aspartic acid and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt described above is applied
  • the composition is used to prepare livestock feed.
  • the livestock include, but are not limited to, pigs, cattle, sheep, horses, rabbits, mink, etc. at various growth stages.
  • the feed containing the fatty acyl derivative of aspartic acid and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt described above is applied
  • the composition is used to prepare poultry feed, and the poultry includes but is not limited to chickens, ducks, geese, pigeons, etc. at various growth stages.
  • the feed containing the fatty acyl derivative of aspartic acid and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt described above is applied
  • the composition is used to prepare aquaculture animal feed.
  • the aquaculture animals include, but are not limited to, fish, shrimp, crab, turtle, eel, etc. at various growth stages.
  • the feed containing the fatty acyl derivative of aspartic acid and its racemate, stereoisomer, geometric isomer, tautomer, solvate or feed acceptable salt described above is applied
  • the composition prepares pet feed.
  • the pets include but are not limited to artificially raised dogs or cats.
  • a feed combination comprising asparagine fatty acyl derivatives and their racemates, stereoisomers, geometric isomers, tautomers, solvates, or feed-acceptable salts
  • the feed prepared by the product is a single feed, a concentrated feed, a compound feed, a composite premix or a concentrate supplement.
  • the compound feed is a full-price compound feed.
  • the farmer will include asparagine fatty acyl derivatives and their racemates, stereoisomers, geometric isomers, tautomers, solvates or feed acceptable salts
  • the feed additives and feed companion given to animals can significantly improve animal production performance.
  • the feed additive is a premix, a compound premix, a granule, or a liquid
  • the animal feed is mixed with the animal feed.
  • the animals are domestic animals, poultry, aquaculture animals or pets.
  • the domestic animals include but are not limited to pigs, cattle, sheep, horses, rabbits, mink, etc. at various growth stages;
  • the domestic poultry include but are not limited to chickens, ducks, geese, pigeons, etc. at various growth stages;
  • the aquaculture animals include but are not limited to fish, shrimp, crab, turtle, eel, etc. at various growth stages; pets include but are not limited to dogs or cats raised artificially.
  • the farmer will contain asparagine fatty acyl derivatives and their racemates, stereoisomers, geometric isomers, tautomers, solvates or feed acceptable salts
  • Feed additives and feed companion feeding to weaned pigs significantly increase the average daily weight gain rate of weaned pigs and increase the feed conversion rate.
  • the farmer will administer the asparagine fatty acyl derivative contained in the feed additive consumed by the weaned pig with the feed is the zinc salt of N-butyryl-L-aspartic acid to improve
  • the feed intake and average daily weight gain and effectively improve the feed conversion rate, the feed additives reach the level of high-dose inorganic zinc to improve the performance of weaned pigs.
  • the asparagine fatty acyl derivative contained in the feed additive that the farmer will accompany the feed to the weaned pig is N-butyryl-L-aspartic acid copper salt, which is significantly improved
  • the farmer will contain asparagine fatty acyl derivatives and their racemates, stereoisomers, geometric isomers, tautomers, solvates or feed acceptable salts
  • Feed additives and feed supplements are given to broilers for consumption, which significantly increases the weight gain of broilers and effectively improves the conversion rate of feed.
  • the farmer will contain asparagine fatty acyl derivatives and their racemates, stereoisomers, geometric isomers, tautomers, solvates or feed acceptable salts Feed additives and feed supplements are given to fish for consumption.
  • the farmer will contain asparagine fatty acyl derivatives and their racemates, stereoisomers, geometric isomers, tautomers, solvates or feed acceptable salts Feed additives and feed companion should be given to young dogs.
  • the farmer will contain asparagine fatty acyl derivatives and their racemates, stereoisomers, geometric isomers, tautomers, solvates or feeds acceptable
  • the feed composition of salt is given to animals, which can significantly improve the production performance of animals.
  • the feed composition is a feed additive premix, a feed additive compound premix, granules, or a liquid, which is given to animals for consumption.
  • the feed composition is a feed additive premix.
  • the feed composition is a feed additive compound premix.
  • the feed composition is a concentrated feed, compound feed, compound premix or concentrate supplement, which is directly given to animals as animal feed.
  • the feed composition is a full-price compound feed.
  • Experimental instruments include drug stability incubator, Waters high-performance liquid chromatography (HPLC) and so on.
  • the experimental reagents include raw materials of aspartic acid fatty acyl derivatives as shown in Table 1 (standard products), methanol (chromatographic grade), and phosphoric acid (analytical purity).
  • Preparation of standard solution Weigh accurately 100mg of aspartic acid fatty acyl derivative standard, add 25mL of water to dissolve ultrasonically to make working stock solution. Take an appropriate amount of working stock solution, and dilute with water to 500ppm, 1000ppm, 2000ppm, 4000ppm working solution, HPLC to be tested. Check whether the sample concentration is linear with the peak area response value of HPLC and make a standard curve. If the aspartic acid fatty acyl derivative is a metal ion salt standard solution, the method is to accurately weigh 50 mg of the standard product, add 25 mL of 5% hydrochloric acid solution and dissolve it ultrasonically for 30 min until it is completely dissolved, and make a working stock solution.
  • test solution accurately weigh the appropriate amount of raw material of aspartic acid fatty acyl derivative, 5% premix and 5% feed into the appropriate amount of water and ultrasonically dissolve, make 4000ppm solution, and filter through 0.22 ⁇ m filter membrane HPLC analysis was performed. If the asparagine fatty acyl derivative is a metal ion salt, accurately weigh an appropriate amount of aspartic acid fatty acyl derivative by adding 5% hydrochloric acid solution 25mL and dissolve it ultrasonically for 30min until it is completely dissolved, and prepare a 2000ppm solution, and filter through a 0.22 ⁇ m filter Then HPLC analysis.
  • HPLC detection conditions chromatographic column: waters C18 column (250mm * 4.6mm, 5 ⁇ m) column.
  • Mobile phase 0.02% phosphoric acid: methanol; (gradient elution: methanol: 5% ⁇ 40% (0-25min) curve 6, 40% ⁇ 80% (25-30min) curve 6, 80% methanol (31min) curve 6 , 80% ⁇ 5% (31-32min) curve 1, 5% methanol (32-37min) curve 1, total time 37min; detection wavelength: 210nm; column temperature: 25 ° C; injection volume: 20 ⁇ L; flow rate: 1ml / min.
  • Test method 60 °C stability test: Aspartic acid fatty acyl derivative raw material and its 5% premix sample are placed in a Petri dish, spread into a thin layer of ⁇ 5mm, and placed at 60 °C on the 5th day , 10 days sampling for HPLC detection, each sample was sampled three times in parallel.
  • Test results The test results are expressed as "average”, as shown in Table 1. From the test results, no significant change in the content of aspartic acid fatty acyl derivatives in the raw materials or in the premix during the test has a good stability to 60 ° C high heat.
  • Example B1 Effect of aspartic acid fatty acyl derivatives and their salts on the performance of weaned piglets
  • a total of 390 pigs of 28 ⁇ 2 days old “Du Changda” ternary cross-weaned piglets were selected from 390 pigs with similar body weights for clinical examination. They were randomly divided into 13 groups, with 3 replicates in each group. A total of 10 heads. The piglets start to lure from 7 days old, and the 28-day-old weaned pig house has a concrete floor, reinforced fence, good ventilation and suitable temperature. Sterilize pigpens and utensils before the test.
  • test pigs were housed in pens under the same feeding and management conditions in the same pen, free to eat and drink; the pig house was cleaned once a day and the ground was washed every three days to maintain clean hygienic conditions; feeding 3 times a day.
  • Each test component is a control group and a test group.
  • Group I is the control group, and the piglets are fed the basic diet; the experimental group II to VIII groups are fed the diet based on the basic diet with 45ppm aspartic acid fatty acyl derivatives, as shown in Table 2.
  • the diets fed by piglets in groups IV to VIII are based on the diet, and 1000 ppm of N-butyryl-L-aspartic acid metal ion salts are added respectively, as shown in Table 2.
  • the test period was 40 days.
  • ADFI average daily feed intake Amount
  • ADG average daily weight gain
  • FCR feed ratio
  • Average daily feed intake (total ingredients-remaining feed) / (days of experiment ⁇ number of pigs per repeat);
  • Average daily weight gain (average body weight at the end of the test-average body weight at the beginning of the test) / days of the test;
  • Feed ratio average daily feed intake / average daily gain.
  • test data was statistically analyzed using SPSS18 software. One-way analysis of variance (ANOVA) was performed on the data. If the differences between the treatments were significant, Duncan's method was used for multiple comparisons. The significance level was 0.05. The test results are expressed as "average ⁇ standard error", and the test results are shown in Table 2.
  • Example B2 Effect of asparagine fatty acyl derivatives on production performance of laying hens
  • Experiments II to VIII add 500 ppm of different aspartic acid fatty acyl derivatives to the basic diet respectively. See Table 3 for grouping.
  • the pre-feeding period was 10 days, and the test period was 158 days.
  • the test chickens were free to drink water and feed, feeding twice a day.
  • record the number of eggs, egg production, and feed intake in repeat units every day calculate the egg production rate (EPR), average daily feed intake (ADFI, g / d), egg weight (EW, g) and feed-to-egg ratio (FER). Calculated as follows:
  • Egg weight (g) average daily total egg weight / average daily total egg number
  • Feed ratio average daily feed intake / egg weight.
  • test results were statistically analyzed using SPSS18 software. One-way analysis of variance (ANOVA) was performed on the data. If the differences between the treatments were significant, Duncan's method was used for multiple comparisons. The significance level was 0.05. The test results are expressed as "average value ⁇ standard error”. The test results are shown in Table 3.
  • Example B3 Effect of fatty acyl derivatives of aspartic acid on broiler performance
  • a single-factor random design was used in the experiment.
  • 480 three-yellow feather broilers with a 1-day-old average weight of 50g were selected and randomly divided into 8 treatment groups, with 3 replicates in each group, half male and female, and 20 replicates each.
  • Three yellow feather broilers. Sterilize the house and utensils before the test.
  • cages were housed under the same feeding and management conditions in the same house.
  • the basic diet is mainly corn-soybean meal, and no additional antioxidants and growth promoters are added during the entire feeding process.
  • Each test group is the test I ⁇ VIII group. Among them, experiment I is the control group and only the basic diet is given.
  • Experiments II to VIII add 300 ppm of different aspartic acid fatty acyl derivatives to the basic diet respectively. See Table 4 for grouping.
  • the test period was 20 days.
  • the test chickens were free to drink water and feed, feeding twice a day. Take each repeat as a unit, weigh at 21 days of age (without feeding for 12h, without water), calculate the test chicken consumption, and calculate the average daily feed intake of each group of test chickens (ADFI, g / d * only) 3.
  • the average daily weight gain (ADG, g / d * only) and feed-to-meat ratio (FCR) the calculation formula is as follows:
  • Feed ratio (FCR) average daily feed intake / average daily gain.
  • test data was statistically analyzed using SPSS18 software. One-way analysis of variance (ANOVA) was performed on the data. If the differences between the treatments were significant, Duncan's method was used for multiple comparisons. The significance level was 0.05. The test results are expressed as "mean ⁇ standard error", and the test results are shown in Table 4.
  • Example B4 Use of fatty acyl derivatives of aspartic acid in fish feed
  • Test fish The test fish used were healthy and lively grass carp species with the same specifications in the large cages (4 ⁇ 2 ⁇ 1.5m 3 ) for 4 weeks before they were used in the official breeding experiment.
  • the experimental system was a floating small cage ( Specification 1.1 ⁇ 1.1 ⁇ 1.1m 3 ), each small cage is equipped with an inflatable head, inflated 24h a day. Both small cages and temporary cages are placed in a 3500m 2 pond in the test site. The pond water depth is about 1.5m, and the pond water is fully aerated bottom water.
  • 640 hungry grass carp 640 fish were randomly divided into 8 groups, each group was set up with 4 replicates, 20 fish were placed in each replicate, weighed in units of each replicate, placed in 32 cages and fed Feed the test feed with the same content of different test products.
  • Test feed The test feed is prepared according to the formula in Table 5, and different test groups are fed according to Table 6 with different test products of the same content.
  • the feed material used is ultrafinely crushed and made into a floating puffing feed with a particle size of 3mm by a Jiangsu Muyang puffing unit.
  • the mold temperature is 130 ° C, and 3% soybean oil is sprayed through the oil spraying equipment. The shade is kept in a cool place.
  • Raw material composition content(%) Raw material composition content(%) Fishmeal 9.0 Soybean oil 3.0 Casing powder 3.0 Phospholipid meal 9.0 Soybean meal 12.0 Gluten 4.0 Rapeseed meal 12.0 Blood cell powder 2.0 Monosodium glutamate 3.0 Vc-phosphate 0.1
  • Group testing sample Dose (ppm) Group I - - Group II N-acetyl-L-aspartic acid 3000 Group III N-butyryl-L-aspartic acid 3000 Group IV N-decanoyl-L-aspartic acid 3000 Group V N-lauroyl-L-aspartic acid 3000 Group VI N-myristoyl-L-aspartic acid 3000 VII group N-stearoyl-L-aspartic acid 3000 VIII group Diethyl N-butyryl-L-aspartate 3000
  • Test management The test uses artificial limited feeding, the feeding amount is adjusted once a week, the feeding level of each group (according to the initial body weight) is exactly the same, feeding twice a day (7:30 and 15:00), the total feeding amount It is 580g / repetition test group. The trial will last for 8 weeks. Timing of water quality monitoring during the test, the whole culture temperature 26.88 ⁇ 3.08 °C, DO> 5.0mg O L -1, pH 7.8, ammonia ⁇ 0.50mg N L -1, nitrite nitrogen ⁇ 0.05mg N L -1.
  • Weight gain rate (WG,%) 100 ⁇ (average final weight-average initial weight) / average initial weight;
  • Feed coefficient (FCR) food intake / weight gain of fish.
  • the fatty acyl derivative of aspartic acid can significantly increase the weight gain rate of grass carp and reduce the feed coefficient in the grass carp breeding test but except for N-myristoyl-aspartic acid The effect of decreasing the acid external feed coefficient is not significant.

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Abstract

公开了一种结构如式(Ⅰ)所示的天门冬氨酸的酰基衍生物或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐在制备动物饲料添加剂中的应用，对养殖动物的生产性能具有良好的改善效果， (I) 其中，Y和X分别独立选自C1-C20烷氧基或OH；R1为R1aC(＝O)、R1aS(＝O)2或H；R2为 2aC(＝O)或R2aS(＝O)2；所述的R1a和R2a分别独立选自C1-C20烷基或C3-C7环烷基。

Description

天门冬氨酸脂肪酰基衍生物在制备动物饲料添加剂中的应用 技术领域：
本发明属于动物饲料添加剂领域，具体涉及天门冬氨酸脂肪酰基衍生物在制备动物饲料添加剂的应用和一种包含天门冬氨酸脂肪酰基衍生物的饲用组合物及其在制备动物饲料添加剂和动物饲料中的应用。
背景技术：
天门冬氨酸是动物体内非必须氨基酸。N-酰基化天门冬氨酸具有脂肪口感，在健康食品中作为低热量脂肪替代物。N-酰基化天门冬氨酸又是一种氨基酸表面活性剂，气泡能力佳，储存稳定，是牙膏、厨房清洁剂、洁厕剂、洗发水、沐浴露等个人护理及公共卫生领域。
乙酰化天门冬氨酸是多种植物或食物中的成分，也是一种中枢神经系统物质，是髓磷脂液体脂肪酸的乙酸供体，有研究表明乙酰化天门冬氨酸在人味觉系统中显示的是刺激性的令人讨厌的混合酸味。
饲料，是指经工业化加工、制作的供动物使用的产品，是现代化集约化养殖业的主要动物食品。在动物养殖过程中，养殖户渴望动物食用的饲料产品能最大限度的被动物吸收利用，改善动物的生产性能从而达到提高养殖经济效益的目的。在饲料产品中添加具有相应功效的饲料添加剂可以有效的提高饲料产品的利用率。
饲料添加剂，是指在饲料加工、制作、使用过程中添加的少量或者微量物质，包括营养性饲料添加剂和一般饲料添加剂。一般饲料添加剂，是指为保证或者改善饲料品质、提高饲料利用率而掺入饲料中的少量或者微量物质。本领域目前常用的具有高效稳定地提高饲料利用率改善动物生产性能的一般饲料添加剂主要包括高剂量铜剂、高剂量锌剂、饲用抗生素、化学合成抗菌剂等，但是，这些物质在养殖业中长期使用副作用较大，如动物的肝肾毒性、抑制生长、肾脏功能损伤、尿路障碍、致畸、致突变、产生耐药性、药残留和污染环境等弊端。为了保障动物的健康以及提高养殖业的生产效益，寻求有效、稳定、安全的新饲料添加剂是本领域急需解决的问题。
发明内容：
基于此，本发明提供一种稳定、有效的天门冬氨酸脂肪酰基衍生物或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物及饲料可接受的盐在制备动物饲料添加剂中的应用；本发明还提供了一种包含天门冬氨酸脂肪酰基衍生物或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物及饲料可接受的盐的饲用组合物以及该组合物在制备动物饲料添加剂和动物饲料中的应用。
一方面，本发明提供了一种结构如式(Ⅰ)所示的天门冬氨酸脂肪酰基衍生物或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐在制备动物饲料添加剂中的应用：
Figure PCTCN2018113907-appb-000001
在一些技术方案中，Y和X分别独立选自C 1-C 20烷氧基或OH；R 1为R 1aC(＝O)、R 1aS(＝O) 2或H；R 2为R 2aC(＝O)或R 2aS(＝O) 2；所述的R 1a和R 2a分别独立选自C 1-C 20烷基或C 3-C 7环烷基。
在一些技术方案中，所述的天门冬氨酸脂肪酰基衍生物的R 1为H。
在一些技术方案中，所述的天门冬氨酸脂肪酰基衍生物的R 2为R 2aC(＝O)，R 2a选自C 1-C 20烷基或C 3-C 7环烷基。
在一些技术方案中，所述的天门冬氨酸脂肪酰基衍生物的R 2a选自C 1-C 10烷基。
在一些技术方案中，所述的天门冬氨酸脂肪酰基衍生物的Y和X为OH。
在一些技术方案中，所述的天门冬氨酸脂肪酰基衍生物的Y和X分别独立选自C 1-C 20烷氧基或OH，并且不同时为OH。
在一些技术方案中，所述的天门冬氨酸脂肪酰基衍生物的Y和X分别独立选自C 1-C 10烷氧基或OH，并且不同时为OH。
在一些技术方案中，所述的天门冬氨酸脂肪酰基衍生物的饲料可接受的盐为金属离子盐。
在一些技术方案中，所述的天门冬氨酸脂肪酰基衍生物的饲料可接受的盐优选为钠离子盐、钙离子盐、锌离子盐、铜离子盐或铁离子盐。
另一方面，本发明提供了一种饲用组合物，包含本发明所述的天门冬氨酸脂肪酰基衍生物或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐中的至少一种和至少一种可饲用辅料。
所述的可饲用辅料选自可饲用的载体、稀释剂、辅剂、溶媒或它们的组合。
在一些技术方案中，所述的饲用组合物还包含动物饲料原料。
在一些技术方案中，所述的饲用组合物还包含附加的动物饲料添加剂。
在一些技术方案中，所述的饲用组合物还包含动物饲料原料和附加的动物饲料添加剂。
在一些技术方案中，所述的附加的动物饲料添加剂可选自营养性饲料添加剂和/或一般饲料添加剂和/或药物饲料添加剂。
另一方面，本发明提供了所述饲用组合物在制备动物饲料添加剂中的应用。
另一方面，本发明提供了所述饲用组合物在制备动物饲料中的应用。
另一方面，本发明还提供了一种改善养殖动物生产性能的方法。
本发明的有益效果：
在动物养殖试验中结果表明，本发明提供的天门冬氨酸脂肪酰基衍生物或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐可作为动物饲料添加剂应用，具有良好的改善动物生产性能的效果。
本发明的任一方面的任一实施方案可以与其他实施方案进行组合，只要它们之间不出现矛盾。此外，在本发明任一方面的任一实施方案中，任一技术特征可以适用于其它实施方案中的该技术特征，只要它们之间不会出现矛盾。
前面所述内容只是概述了本发明的某些方面，但不限于这些方面。上述涉及内容及其他方面的内容将在下面做更加具体完整的描述。
本发明的进一步详细描述。
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式加以说明。本发明的意图涵盖所有的替代、修改和等同的技术方案，它们均包括在如权利要求定义的本发明的范围内。另外，本发明的某些技术特征为清楚可见，在多个独立的实施方案中分别进行描述，但也可以在单个实施例中以组合形式提供或以任意适合的子组合形式提供。
化合物。
本发明涉及的化合物是一种结构如式(Ⅰ)所示的天门冬氨酸脂肪酰基衍生物，
Figure PCTCN2018113907-appb-000002
其中，Y和X为天门冬氨酸的羧基上的取代基，R 1和R 2为氮原子(简写为N)上的取代基。Y和X分别独立选自C 1-C 20烷氧基或OH；R 1为R 1aC(＝O)、R 1aS(＝O) 2或H；R 2为R 2aC(＝O)或R 2aS(＝O) 2；所述的R 1a和R 2a分别独立选自C 1-C 20烷基或C 3-C 7环烷基。
一般的，“取代的”表示所给结构中的一个或多个可被取代的氢原子被具体取代基所取代，一个取代的基团可以有一个取代基在基团各个可取代的位置进行取代，当所给出的结构式中不只一个位置能被具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。
在本发明中，“C 1-C 20烷基”表示含有1个至20个碳原子的饱和烷基，如甲基、乙基、丙基、异丙基、……、直链或支链的含有20个碳原子的烷基；“C 3-C 7环烷基”表示为包含3个-7个碳原子的只含碳氢两种元素的环状烷基，如环丙基、2-甲基环丙基、环戊基等。
可选的，所述的天门冬氨酸脂肪酰基衍生物的R 1为R 1aS(＝O) 2或H，R 2为R 2aS(＝O) 2；所述的R 1a 和R 2a分别独立选自C 1-C 20烷基或C 3-C 7环烷基，所述的Y和X分别独立选自C 1-C 20烷氧基或OH。
进一步的，所述的R 1为H，R 2为R 2aS(＝O) 2；所述的R 2a选自C 1-C 20烷基或C 3-C 7环烷基，所述的Y和X分别独立选自C 1-C 20烷氧基或OH。
可选的，所述的天门冬氨酸脂肪酰基衍生物的R 1为R 1aC(＝O)或H，R 2为R 2aC(＝O)；所述的R 1a和R 2a分别独立选自C 1-C 20烷基或C 3-C 7环烷基，所述的Y和X分别独立选自C 1-C 20烷氧基或OH。
进一步的，所述的R 1为H，R 2为R 2aC(＝O)；所述的R 2a选自C 1-C 20烷基或C 3-C 7环烷基，所述的Y和X分别独立选自C 1-C 20烷氧基或OH。
可选的，所述的R 1a或R 2a选自C 1-C 20烷基。
进一步的，所述的R 1a或R 2a选自直链C 1-C 10烷基，具体为甲基(CH 3)、乙基(CH 2CH 3)、正丙基((CH 2) 2CH 3)、正丁基((CH 2) 3CH 3)、正戊基((CH 2) 4CH 3)、正几基((CH 2) 5CH 3)、正庚基((CH 2) 6CH 3)、正辛基((CH 2) 7CH 3)、正壬基((CH 2) 8CH 3)、正癸基((CH 2) 9CH 3)之一。
还可选的，所述的R 1a或R 2a选自支链C 1-C 10烷基，包括但不限于异丙基((CH 3) 2CH)、异丁基((CH 3) 3C)等。
可选的，所述的天门冬氨酸脂肪酰基衍生物的Y和X同时为OH。
可选的，所述的天门冬氨酸脂肪酰基衍生物的Y和X选自C 1-C 20烷氧基或OH，但不同时为OH，具体是同时为C 1-C 20烷氧基或分别为C 1-C 20烷氧基和OH之一。
进一步的，所述的烷氧基优选为直链或支链的C 1-C 10烷氧基，包括但不限于甲氧基(OCH 3)、乙氧基(OCH 2CH 3)、正丙烷氧基(O(CH 2) 2CH 3)、异丙烷氧基(OCH 2(CH 3) 2)、正丁烷氧基(O(CH 2) 3CH 3)、叔丁烷氧基(OC(CH 3) 3)、正戊烷氧基(O(CH 2) 4CH 3)、正几烷氧基(O(CH 2) 5CH 3)、正庚烷氧基(O(CH 2) 6CH 3)、正辛烷氧基(O(CH 2) 7CH 3)、正壬烷氧基(O(CH 2) 8CH 3)或正癸烷氧基(O(CH 2) 9CH 3)。
可选的，所述的天门冬氨酸脂肪酰基衍生物的饲料可接受的盐为金属离子盐，具体为一价金属离子盐、二价金属离子盐或三价金属离子盐。
具体的，所述的一价金属离子包括但不限于钠离子、钾离子、锂离子、铵离子；所述的二价金属离子包括但不限于钙离子、镁离子、锌离子、铜离子、亚铁离子、锰离子；所述的三价金属离子包括但不限于铁离子、镍离子、铬离子、铝离子。
在一些实施例中，所述的金属离子为锌离子。
在另一些实施例中，所述的金属离子为铜离子。
在另一些实施例中，所述的金属离子为钠离子。
在另一些实施例中，所述的金属离子为钙离子。
在另一些实施例中，所述的金属离子为铁离子。
化合物的制备与纯化。
本发明涉及的如式(Ⅰ)所示的天门冬氨酸脂肪酰基衍生物的制备方法，以天门冬氨酸(Asp)为起始原料，涉及的化学反应主要包括氨基的酰基化和羧基的酯化。
在一些实施方案中，式(Ⅰ)中Y和X为C 1-C 20烷氧基或OH但不同时为OH，式(Ⅰ)所示的天门冬氨酸脂肪酰基衍生物的制备方法包括羧基的酯化和氨基的酰基化两步反应，如式(Ⅱ)所示。
Figure PCTCN2018113907-appb-000003
要明确的是式(Ⅱ)中的X和R 1仅表示取代基团，若原料X-H、R 1OR 1和R 1-Cl所代表的物质不是单一物质则X或R 1应当理解为取代基的集合。
在一些实施方案中，式(Ⅰ)中Y和X同时为-OH，式(Ⅰ)所示的天门冬氨酸脂肪酰基衍生物的制备方法如式(Ⅲ)所示。
Figure PCTCN2018113907-appb-000004
要明确的是，式(Ⅲ)中的R 1仅表示取代基团，当原料R 1OR 1表示的物质不是单一物质时则目标产物(TM)上的R1应当理解为取代基的集合。
进一步的，Y和X同时为OH或分别为C 1-C 20烷氧基和OH之一时的天门冬氨酸脂肪酰基衍生物在碱性条件下与金属氯化物或金属溴化物反应生成天门冬氨酸脂肪酰基衍生物的金属离子盐，如锌盐、铜盐、钙盐、铁盐或钠盐等本发明涉及的金属离子盐。
在一些实施方案中，所述的天门冬氨酸是一种手性化合物，本发明所述的天门冬氨酸选自左旋体L-(-)-天门冬氨酸(结构如式(Ⅳ))、右旋体D-(+)-天门冬氨酸(结构如式(Ⅴ))或外消旋体DL-(±)天 门冬氨酸，与涉及的醇和羧酸衍生物反应后得到具有手性中心的天门冬氨酸脂肪酰基衍生物的立体异构体或外消旋体。
Figure PCTCN2018113907-appb-000005
在一些实施方案中，所述的天门冬氨酸的手性立体异构体和天门冬氨酸脂肪酰基衍生物的立体异构体在合适的条件下可发生立体构型的转化，如天门冬氨酸或天门冬氨酸脂肪酰基衍生物的立体构象互变，例如天门冬氨酸的立体构象互变过程如式(Ⅵ)所示：
Figure PCTCN2018113907-appb-000006
当涉及的反应物质与天门冬氨酸等反应生成了相应的天门冬氨酸脂肪酰基衍生物具有刚性结构时，反应底物在反应过程中可生成不同的几何异构体产物。
上述的立体异构体、几何异构体、互变异构体也包括在本发明的实施范围内。
本发明涉及的“立体异构体”是指具有相同化学构造，但原子或基团在空间上的排列方式不同的化合物，包括对映异构体、非对映异构体、构象异构体、几何异构体、阻转异构体等。“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。“非对映异构体”是指有两个或多个手性中性并且其分子不互为镜像的立体异构体，具有不同的熔点、沸点、光谱性质和反应性等物理性质。非对应异构体混合物可通过高分辨分析操作如电泳或色谱来分离；“互变异构体”是指具有不同能量的可通过低能垒互相转化的结构异构体。
在一些实施方案中，本发明提供天门冬氨酸脂肪酰基衍生物的制备过程还涉及反应产物的分离、纯化或重结晶过程。反应产物可通过脱溶剂法从反应体系中获得粗品。为了获得化学纯度更高、杂质含量更低的固体物质，粗品经醇溶剂、醇水混合溶剂或其他可用于产品重结晶的有机溶剂中在合适的温度、光照以及机械振动等条件下溶解、析晶或沉淀或重结晶和分离得到具有一定晶型状态的天门冬氨酸脂肪酰基衍生物。所述具有一定晶型状态的天门冬氨酸脂肪酰基衍生物是天门冬氨酸脂肪酰基衍生物结晶或天门冬氨酸脂肪酰基衍生物的溶剂合物。所述的天门冬氨酸脂肪酰基衍生物的溶剂合物可选自天门冬氨酸脂肪酰基衍生物的水合物或天门冬氨酸衍生物的乙醇合物。
本发明涉及的“溶剂合物”是指本发明的化合物与溶剂分子接触的过程中，外部条件与内部条件 因素造成通过非共价分子间力而结合化学当量或非化学当量的溶剂分子而形成的共晶缔合物。形成溶剂合物的溶剂包括但是不限于水、丙酮、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸、异丙醇等溶剂。“水合物”是指溶剂分子是水所形成的缔合物或结晶体，也就是通过非共价分子间力而结合化学当量或非化学当量的水的化合物。
本发明提供的天门冬氨酸脂肪酰基衍生物的制备为了获得化学纯度更高、杂质含量更低的固体物质还可通过盐析法后进行处理。所述的盐析法是利用酸碱中和法、酸碱配位法或酸碱螯合法的原理使天门冬氨酸衍生物与相应的有机碱、无机碱、有机酸或无机酸成盐沉淀的过程，获得饲料可接受的盐。
饲料可接受的盐为本发明的天门冬氨酸脂肪酰基衍生物与对动物无毒的有机碱、无机碱、有机酸或无机酸形成的盐。所述的“饲料可接受的”是指物质或组合物必须是适合化学或毒理学的，与组成的饲料或食用的养殖动物有关。
在一些实施方案中，天门冬氨酸脂肪酰基衍生物是双酯或混合酯(也就是Y和X同时为相同或不同的C 1-C 20烷基)，后处理的盐析沉淀过程与无机酸或有机酸形成酸碱配位盐和或酸碱螯合盐，所述的有机酸包括但不限于乙酸盐、马来酸盐、琥珀酸盐、扁桃酸盐、延胡索酸盐、丙二酸盐、苹果酸盐、2-羟基丙酸盐、丙酮酸盐、草酸盐、乙醇酸盐、水杨酸盐、葡萄糖醛酸盐、半乳糖醇酸盐、柠檬酸盐、酒石酸盐、天冬氨酸盐、谷氨酸盐、苯甲酸盐、对甲基苯甲酸盐、肉桂酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐、三氟甲磺酸盐或它们的组合；所述的无机酸包括但不限于盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、硝酸盐或它们的组合。
在一些实施方案中，天门冬氨酸脂肪酰基衍生物是单酯(也就是Y和X分别为C 1-C 20烷基和H之一)，后处理的盐析沉淀过程与有机酸或无机酸形成酸碱配位盐和或酸碱螯合盐，或与有机碱或无机碱形成酸式盐。所述的有机酸包括但不限于乙酸盐、马来酸盐、琥珀酸盐、扁桃酸盐、延胡索酸盐、丙二酸盐、苹果酸盐、2-羟基丙酸盐、丙酮酸盐、草酸盐、乙醇酸盐、水杨酸盐、葡萄糖醛酸盐、半乳糖醇酸盐、柠檬酸盐、酒石酸盐、天冬氨酸盐、谷氨酸盐、苯甲酸盐、对甲基苯甲酸盐、肉桂酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐、三氟甲磺酸盐或它们的组合；所述的无机酸包括但不限于盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、硝酸盐或它们的组合。所述的有机碱包括但不限于氨或三乙胺。所述的无机碱包括但不限于氢氧化钠、氢氧化钾、氢氧化镁、或氢氧化钙。
天门冬氨酸的脂肪酰基衍生物的稳定性研究。
本发明提供的天门冬氨酸脂肪酰基衍生物或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐在60℃条件下测定化合物的稳定性，试验周期为10天，在试验期内化合物的含量随着时间的变化没有发生显著变化。
本发明涉及天门冬氨酸的脂肪酰基衍生物的应用。
本发明提供的结构如(Ⅰ)所示天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐应用在制备动物饲料添加剂中。
本发明涉及的“动物”是指不能将无机物合成有机物，只能以有机物作为食料，以进行摄食、消化、吸收、呼吸、循环、排泄、感觉、运动和繁殖等为生命活动的人或养殖动物。“养殖动物”包括家禽、家畜、水产养殖动物以及人工饲养合法捕获的其他动物包括宠物，例如猫狗。术语“家畜”是，例如猪、牛、马、山羊、绵羊、鹿和许多有用啮齿动物的任一种。术语“家禽”是包括，例如鸡、鸭、鹅、鹌鹑、鸽等。术语“水产养殖动物”包括，如鱼、虾、龟、鳖等。
应用本发明提供的天门冬氨酸的脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是作为各个生长阶段的动物的改善动物生产性能的非营养性添加剂，所述动物可选自各个生长阶段的家畜、家禽、水产养殖动物或宠物。
可选的，所述的家畜包括但不限于猪、牛、羊、马、兔、貂或驴，所述的家禽包括但不限于鸡、火鸡、鸭、鹅、鹌鹑或鸽，所述的水产养殖动物包括但不限于鱼、虾、龟、蟹、鳖、牛蛙、鳝或泥鳅，所述的宠物包括但不限于各个亚种的狗或猫。
在一实施例中，应用本发明提供的天门冬氨酸的脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是断奶猪用饲料添加剂，可提高断奶猪的采食量的同时有效提升断奶猪的平均日增重并改善饲料转化率。
在另一实施例中，应用本发明提供的天门冬氨酸的脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是作为蛋鸡用饲料添加剂，可有效的改善蛋鸡的产蛋率、提高蛋重并降低蛋鸡的料蛋比。
在另一实施例中，应用本发明提供的天门冬氨酸的脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的饲料添加剂可显著改善肉鸡的生产性能。
在另一实施例中，应用本发明提供的天门冬氨酸的脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的饲料添加剂可显著的改善肉鸭及蛋鸭的生产性能。
在另一实施例中，应用本发明提供的天门冬氨酸的脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的是改善鱼的生产性能的饲料添加剂。
在另一实施例中，应用本发明提供的天门冬氨酸的脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐制备的饲料添加剂对宠物生产性能的改善出现了较为显著的效果。
应用在制备动物饲料添加剂中的本发明提供的天门冬氨酸的脂肪酰基衍生物的饲料可接受的盐是 一种金属离子盐。
可选的，所述的天门冬氨酸的脂肪酰基衍生物的饲料可接受的盐是结构如式(Ⅰ)所示的天门冬氨酸的脂肪酰基衍生物的金属离子盐。
进一步的，所述的结构如式(Ⅰ)所示的天门冬氨酸脂肪酰基衍生物中的Y和X选自C 1-C 20烷氧基或OH，但不同时为C 1-C 20烷氧基，所述的金属离子盐是所述天门冬氨酸脂肪酰基衍生物的OH与金属离子交换所得的符合饲料添加剂制备或饲料制备要求的盐。
具体的，所述的金属离子选自一价金属离子、二价金属离子或三价金属离子。
在一些实施例中，所述的一价金属离子为钠离子(Na(Ⅰ))、钾离子(K(Ⅰ))或锂离子(Li(Ⅰ))。
在一些实施例中，所述的二价金属离子为钙离子Ca(II)、镁离子Mg(II)、铜离子Cu(II)、锌离子Zn(II)、亚铁离子Fe(II)、锰离子Mn(II)、钴离子Co(II)或镍离子Ni(II)。
在一实施例中，应用在制备动物饲料添加剂中的天门冬氨酸脂肪酰基衍生物的金属离子盐是锌离子盐，所述的动物饲料添加剂是动物用有机锌剂作为高剂量无机锌替换物。
在一实施例中，应用在制备动物饲料添加剂中的天门冬氨酸脂肪酰基衍生物的金属离子盐是铜离子盐，所述的动物饲料添加剂是动物用有机铜作为动物用高剂量无机铜替换物。
在一实施例中，应用在制备动物饲料添加剂中的天门冬氨酸脂肪酰基衍生物的金属离子盐是铁离子盐，所述的动物饲料添加剂是动物用铁元素补充剂。
在一些实施例中，所述的三价金属离子为铝离子Al(III)、铬离子Cr(III)或铁离子Fe(III)。
本发明涉及的饲用组合物。
一种包含天门冬氨酸的脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的至少一种和可饲用辅料的饲用组合物，所述的可饲用辅料为可饲用的载体、稀释剂、辅剂、溶媒或它们的组合。
本发明涉及的饲料是指经工业化加工、制作的供动物食用的产品。
本发明涉及的“组合物”是指包含一种或一种以上的化合物组成有效成分的化合物集体。
本发明所述的“包含”为开放式表达，既包括本发明所明指的内容，但并不排除其他方面的内容。
本发明涉及的“载体”是指能够承载活性成分，改善其分散性，并有良好的化学稳定性和吸附性的可饲用物质，为有机载体和无机载体。所述的有机载体是含粗纤维多的物料，包括但不限于玉米粉、玉米芯粉、麦麸、稻壳粉、脱脂米糠、统糠、玉米秸秆粉、花生壳粉等。所述的无机载体是矿物质，主要分为钙盐类和硅的氧化物类，用于微量元素预混料的制作，包括但不限于碳酸钙、硅酸盐、蛭石、沸石、海泡石等。
本发明涉及的“稀释剂”是指将添加剂原料均匀分布于物料中，将高浓度的添加剂原料稀释为低 浓度的预混剂或预混料的物质，可将微量成分彼此分开，减少活性成分之间的相互反应，以增加活性成分的稳定性但不影响有关物质的物化性质，为有机稀释剂和无机稀释剂。有机稀释剂包括但不限于玉米粉、去胚玉米粉、右旋糖(葡萄糖)、蔗糖、带有麸皮的粗小麦粉、炒大豆粉、次粉、玉米蛋白粉等；无机稀释剂包括但不限于石灰石、磷酸二氢钙、贝壳粉、高岭土(白陶土)、食盐和硫酸钠。
所述的辅剂为使物质本身固有的黏性诱发出来的润湿剂、使物质黏合起来的粘合剂、使物质整体的片状物裂碎为许多细小颗粒的崩解剂、降低颗粒间摩擦力的助留剂或防止物料黏着的抗黏剂，包括但不限于硬脂酸镁、滑石粉、植物油、月桂醇硫酸镁、淀粉、淀粉浆、水、无机盐、糊精、糖粉等。
本发明涉及的“溶媒”是指溶解或分散固体所需的溶剂，包括但不限于水、乙醇、甘油等。
在一些实施方案中，所述的饲用组合物进一步包含附加的动物饲料添加剂和/或动物饲料原料。
所述的动物饲料添加剂为营养性饲料添加剂、一般饲料添加剂或药物饲料添加剂。
所述的营养性饲料添加剂是指添加到配合饲料中，平衡饲料养分，提高饲料利用率，直接对动物发挥营养作用的少量或微量物质，为氨基酸、氨基酸盐及其类似物、维生素及类维生素、矿物元素及其络(螯)合物、微生物酶制剂或非蛋白氮。
所述的一般饲料添加剂也叫非营养性添加剂，是指加入到饲料中用于改善饲料利用率、保证饲料质量和品质、有利于动物健康或代谢的一些非营养性物质，包括生长促进剂、驱虫保健剂、调味和诱食剂、饲料调质剂、饲料调制剂、饲料贮藏剂、益生菌、益生元和中草药添加剂。
进一步具体地，所述的非营养性添加剂为生长促进剂，包括但不限于丁酸、丁酸钙、丁酸钠、单宁酸、对百里香酚、对百里香酚酯、对百里香酚盐、2-羟基苯甲酸、β-酸、β-酸酯、β-酸盐、六氢β-酸、六氢β-酸酯、六氢β-酸盐、苯甲酸或苯甲酸钙、氧化锌、硫酸锌、氯化锌。
在一实施例中，所述的非营养性添加剂为丁酸钙。
在另一实施例中，所述的非营养性添加剂为单宁酸。
具体地，所述的药物饲料添加剂包括但不限于具有预防动物疾病、促进动物生长作用并可在饲料中长期添加使用而掺入载体或稀释剂的兽药预混合物质。
更进一步具体地，所述的药物饲料添加剂为饲用抗生素，所述的饲用抗生素包括但不限于多粘菌素、盐霉素、阿维拉霉素、杆菌肽、维吉尼亚霉素、那西肽、黄霉素、恩拉霉素、北里霉素、喹乙醇、土霉素或金霉素。
在一些实施例中，包含天门冬氨酸的脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的组合物，还包含营养性饲料添加剂、一般饲料添加剂和药物饲料添加剂中的一种或多种。
在一些实施例中，所述的动物饲料原料为谷物及其加工产品，油料籽实及其加工产品，豆科作物 籽实及其加工产品，块茎、块根及其加工产品，其它籽实、果实类产品及其加工产品，饲草、粗饲料及其加工产品，其它植物、藻类及其加工产品，乳制品及其副产品，陆生动物产品及其副产品，鱼、其它水生生物及其副产品，矿物质，微生物发酵产品及副产品，其它饲料原料等饲用物质。
饲用组合物的用途。
本发明涉及上述包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物的应用。
在一些实施例中，所述包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物应用于制备动物饲料添加剂中。
应用所述的包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物制备的动物饲料添加剂为家畜饲料添加剂、家禽饲料添加剂、水产养殖动物饲料添加剂或宠物饲料添加剂。
具体地，应用所述的包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物制备家畜饲料添加剂，所述的家畜包括但不限于各个生长阶段的猪、牛、羊、马、兔、貂等。
具体地，应用所述的包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物制备家禽饲料添加剂，所述的家禽包括但不限于各个生长阶段的鸡、鸭、鹅、鸽等。
具体地，应用所述的包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物制备水产养殖动物饲料添加剂，所述的水产养殖动物包括但不限于各个生长阶段鱼、虾、蟹、鳖、鳝等。
具体地，应用所述的包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物制备宠物饲料添加剂，所述的宠物包括但不限于人工饲养的狗或猫。
在一些实施例中，以所述的包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的组合物制备的动物饲料添加剂为预混剂、复合预混剂、水剂或颗粒剂。
在一些实施例中，所述的包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物应用于制备动物饲料中。
应用所述的包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物制备的动物饲料为家畜饲料、家禽饲料、水产养殖动物饲料 或宠物饲料。
具体地，应用所述的包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物制备家畜饲料，所述的家畜包括但不限于各个生长阶段的猪、牛、羊、马、兔、貂等。
具体地，应用所述的包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物制备家禽饲料，所述的家禽包括但不限于各个生长阶段的鸡、鸭、鹅、鸽等。
具体地，应用所述的包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物制备水产养殖动物饲料，所述的水产养殖动物包括但不限于各个生长阶段鱼、虾、蟹、鳖、鳝等。
具体地，应用所述的包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物制备宠物饲料，所述的宠物包括但不限于人工饲养的狗或猫。
在一些实施方案中，包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物制备的饲料为单一饲料、浓缩饲料、配合饲料、复合预混料或精料补充料。
具体地，所述的配合饲料为全价配合饲料。
改善养殖动物生产性能的方法。
在一些养殖实施方案中，养殖户将包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲料添加剂与饲料伴服给与动物食用，可显著地改善动物的生产性能。
在一些实施例中，所述的饲料添加剂为预混剂、复合预混剂、颗粒剂或水剂，与动物饲料混匀后动物食用。
所述的动物为家畜、家禽、水产养殖动物或宠物。
具体地，所述的家畜包括但不限于各个生长阶段的猪、牛、羊、马、兔、貂等；所述的家禽包括但不限于各个生长阶段的鸡、鸭、鹅、鸽等；所述的水产养殖动物包括但不限于各个生长阶段鱼、虾、蟹、鳖、鳝等；所述的宠物包括但不限于人工饲养的狗或猫。
在一实施例中，养殖户将包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲料添加剂与饲料伴服给与断奶猪食用，显著提高断奶猪的平均日增重的增重率并提高饲料转化率。
在一具体实施例中，养殖户将与饲料伴服给与断奶猪食用的饲料添加剂包含的天门冬氨酸脂肪酰基衍生物是N-丁酰-L-天门冬氨酸锌盐，提高断奶猪的采食量及平均日增重并有效提高饲料转化率，所述饲料添加剂达到高剂量无机锌对断奶猪生产性能改善水平。
在另一具体实施例中，养殖户将与饲料伴服给与断奶猪食用的饲料添加剂包含的天门冬氨酸脂肪酰基衍生物是N-丁酰-L-天门冬氨酸铜盐，显著提高断奶猪的平均日增重且有效提高饲料转化率，所述饲料添加剂达到高剂量无机铜对断奶猪生产性能改善水平。
在一实施例中，养殖户将包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲料添加剂与饲料伴服给与肉鸡食用，显著提高肉鸡的增重并有效提高饲料的转化率。
在一实施例中，养殖户将包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲料添加剂与饲料伴服给与鱼食用。
在一实施例中，养殖户将包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲料添加剂与饲料伴服给与幼狗食用。
在另一些饲喂实施例中，养殖户将包含天门冬氨酸脂肪酰基衍生物及其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物或饲料可接受的盐的饲用组合物给与动物食用，可显著地改善动物的生产性能。
可选地，所述的饲用组合物是饲料添加剂预混剂、饲料添加剂复合预混剂、颗粒剂或水剂，与饲料伴服给与动物食用。
在一实施例中，所述的饲用组合物是饲料添加剂预混剂。
在一实施例中，所述的饲用组合物是饲料添加剂复合预混剂。
可选地，所述的饲用组合物是浓缩饲料、配合饲料、复合预混料或精料补充料，直接作为动物饲粮给与动物食用。
在一实施例中，所述的饲用组合物是全价配合饲料。
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式加以说明。本发明的意图涵盖所有的替代、修改和等同的技术方案，它们均包括在如权利要求定义的本发明的范围内。另外，本发明的某些技术特征为清楚可见，在多个独立的实施方案中分别进行描述，但也可以在单个实施例中以组合形式提供或以任意适合的子组合形式提供。
具体实施方式：
为了使本发明的目的、技术方案及优点更加清楚明白，以下通过实施例对本发明的化合物、组合物及应用进行进一步的详细说明。应当理解，此处所描述的具体实施例仅用于解释本发明，并不用于 限定本发明。
A化合物的制备
以下仅以N-丁酰-L-天门冬氨酸、N-丁酰-L-天门冬氨酸乙酯及其一种盐的制备过程为例对天门冬氨酸的脂肪酰基衍生物的制备方法进行详细的介绍，其他天门冬氨酸的脂肪酰基衍生物可以此为参照制备得到。
实施例A1 N-丁酰-L-天门冬氨酸的制备
Figure PCTCN2018113907-appb-000007
室温下将100.0g(0.75mol,1eq)L-天门冬氨酸溶于400mL含有氢氧化钠60.2g(1.50mol,1.5eq)的水中，搅拌溶解澄清，将106.4g(0.67mol,0.89eq)丁酸酐缓慢滴入，反应期间用6mol/L氢氧化钠水溶液控制反应液pH8左右，室温搅拌24h。反应结束后，用浓盐酸调反应液pH至2，乙酸乙酯萃取(600mL×2)，乙酸乙酯层合并、无水硫酸钠干燥后浓缩得到粗产品为油状物。粗产品经石油醚重结晶析出白色固体，过滤、干燥得到白色固体产物100g(0.49mol)，产率为65.3％。
1HNMR(500MHz,DMSO-d6):δ(ppm)8.05(d,1H),4.95(q,1H),2.51-2.69(m,2H),2.05(t,2H),1.46(q,H),0.83(t,3H).
实施例A2 N-丁酰-L-天门冬氨酸铁的制备
Figure PCTCN2018113907-appb-000008
室温下将22.2g(0.08mol,0.67eq)六水合三氯化铁溶于100mL水中，搅拌下将25g(0.12mol,1eq)N-丁酰-L-天门冬氨酸溶于100mL含有氢氧化钠9.85g(1.50mol,1.5eq)的水溶液后缓慢滴入反应体系中，有铁红色固体产生，继续搅拌反应5.0h后过滤，滤饼经水洗、干燥后得到铁红色固体27g(0.086mol)，收率为71.7％。
实施例A3 N-丁酰-L-天门冬氨酸双乙酯的制备
Figure PCTCN2018113907-appb-000009
步骤1：L-天门冬氨酸双乙酯盐酸盐的合成
向1000mL单口瓶中加入320mL(5.48mol,40eq.)无水乙醇，冷却至-10度，向其中滴加28mL(378.92mmol,2.8eq.)SOCl 2，控制滴加速度控制溶液温度在-10度左右，滴加完毕后于-10度搅拌1小时，再向其中加入18.16g(136.48mmol,1eq.)L-天门冬氨酸，并于室温下搅拌2小时，随后80℃反应，TLC板检测反应，反应完毕后减压旋干溶剂，并加入少量无水乙醇重复几次，于冰箱冷却过夜，析出固体，固体用乙酸乙酯重结晶，抽滤，干燥得到白色固体18.08g，收率58.70％。ESI[M-Cl] +190， 1HNMR(500MHz,D 2O)δ:1.11(t,3H),1.24(t,3H),2.19(m,2H),2.58(td,2H),4.21(m,2H),5.14(m,1H)。
步骤2：丁酰L-天门冬氨酸双乙酯的合成
称取23.92g(106.00mmol,1eq.)L-天门冬氨酸双乙酯盐酸盐于500mL单口瓶中，加入150mL DCM溶解，再加入26.93g(266.13mmol,2.5eq.)三乙胺，冷却至0度，随后滴加17.07g(160.21mmol,1.5eq.)丁酰氯溶于50mL DCM的溶液，控制滴加丁酰氯时温度在0度左右，滴加完毕后，于0度搅拌1小时，随后升至室温反应2小时，停止反应。向反应体系100mL水，分离有机相，水相用DCM萃取2次，合并有机相，有机相用水洗，饱和食盐水洗，无水硫酸钠干燥，减压浓缩得到无色液体12.47g，收率45.36％。ESI[M+H] +260， 1HNMR(500MHz,DMSO-d6):δ0.67(t,3H),1.06(t,3H),1.20(t,3H),1.38(m,2H),2.05(m,2H),2.91(m,2H),4.04(q,2H),4.11(q,2H),5.02(td,1H),7.99(d,1H).
实施例B天门冬氨酸脂肪酰基衍生物的稳定性研究试验
考察天门冬氨酸脂肪酰基衍生物及其质量分数为5％的预混剂(下文简称为5％预混剂)分别在60℃稳定性试验条件下其主要成分含量随时间的变化情况。
实验仪器包括药物稳定性培养箱、Waters高效液相色谱仪(HPLC)等。
实验试剂包括如表1所示的天门冬氨酸脂肪酰基衍生物原料(标准品)、甲醇(色谱级)、磷酸(分析纯)。
标准溶液的制备：准确称取100mg天门冬氨酸脂肪酰基衍生物标准品，加入25mL水超声溶解，制成工作储备液。取适量工作储备液，用水分别稀释至浓度为500ppm、1000ppm、2000ppm、4000ppm的工作液，HPLC待测。检验样品浓度与HPLC峰面积响应值是否成线性,做标准曲线。若天门冬氨酸脂肪酰基衍生物是金属离子盐的标准溶液的制备方法为准确称取50mg标准品，加入25mL5％盐酸溶液超声溶解30min直至完全溶解，制成工作储备液。取适量工作储备液，用5％盐酸溶液分别稀释至浓度为250ppm、500ppm、1000ppm、2000ppm的工作液，HPLC待测，检验样品浓度与HPLC峰面积响应值是否成线性,做标准曲线。
供试品溶液的制备：准确称取适量的天门冬氨酸脂肪酰基衍生物的原料、5％预混剂和5％饲料加入适量水超声溶解，配成4000ppm溶液，经0.22μm滤膜过滤后进行HPLC分析。若天门冬氨酸脂肪 酰基衍生物是金属离子盐准确称取适量的天门冬氨酸脂肪酰基衍生物加入5％盐酸溶液25mL超声溶解30min直至完全溶解,配成2000ppm溶液，经0.22μm滤膜过滤后进行HPLC分析。
HPLC检测条件：色谱柱：waters C18柱(250mm*4.6mm，5μm)柱。流动相：0.02％磷酸：甲醇；(梯度洗脱:甲醇:5％→40％(0-25min)曲线6，40％→80％(25-30min)曲线6，80％甲醇(31min)曲线6，80％→5％(31-32min)曲线1，5％甲醇(32-37min)曲线1，总时间37min；检测波长：210nm；柱温：25℃；进样量：20μL；流速：1ml/min。
试验方法：60℃稳定性试验：天门冬氨酸脂肪酰基衍生物原料及其5％预混剂样品放置于培养皿中，摊成≤5mm的薄层，放置于60℃下，于第5天、10天取样进行HPLC检测，每种样品平行取样三次。
试验结果：试验结果以“平均值”表示，如表1所示。从试验结果看，天门冬氨酸脂肪酰基衍生物无论是原料还是在预混剂中在试验期间对60℃高热具有很好的稳定性含量均没有发生明显的变化。
表1天门冬氨酸脂肪酰基衍生物的稳定性影响因素研究
Figure PCTCN2018113907-appb-000010
Figure PCTCN2018113907-appb-000011
B养殖试验
实施例B1天门冬氨酸脂肪酰基衍生物及其盐对断奶仔猪生产性能的影响
从100窝28±2日龄“杜长大”三元杂交断奶仔猪中选择临床检查健康的体重相近的390头为试验猪，随机分成13组，每组3个重复，每个重复公母各半共10头。仔猪从7日龄开始诱食，28日龄断奶猪舍为水泥地板，钢筋围栏，通风良好，温度适宜。试验前对猪圈及器具进行消毒。试验期，试验猪在同一猪圈同一饲养管理条件下分栏圈养，自由采食和饮水；猪舍每天清扫一次，每三天冲洗地面一次，保持清洁的卫生条件；日喂料3次。各试验组分为对照组和试验组。Ⅰ组为对照组，仔猪饲喂基础日粮；试验组Ⅱ～Ⅷ组仔猪饲喂的日粮为基础日粮基础上分别添加45ppm的天门冬氨酸的脂肪酰基衍生物，如表2所示；Ⅳ～Ⅷ组仔猪饲喂的日粮为基础日粮基础上分别添加1000ppm的N-丁酰-L-天门冬氨酸金属离子盐，如表2所示。整个饲养过程各试验组不额外添加其它抗氧化成分及促生长剂，试验期为40天。试验期，每天观察仔猪采食和健康状况并称量剩余的日粮，记录饲料消耗量，并在0和40天的上午7:00～9:00对试验猪称重，计算平均日采食量(ADFI，g/d*只)、平均日增重(ADG，g/d*只)和料肉比(FCR)。计算公式如下：
平均日采食量＝(配料总量-剩料量)/(试验天数×每重复猪数)；
平均日增重＝(试验末平均体重-试验初平均体重)/试验天数；
料肉比＝平均日采食量/平均日增重。
试验数据采用SPSS18软件进行统计分析，先对数据作单因素方差分析(ANOVA)，若处理间差异显著，再用Duncan's法进行多重比较，显著性水平为0.05。试验结果以“平均值±标准误”表示，试验结果如表2所示。
从断奶仔猪的饲养试验结果可知，在平均日采食量方面与空白对照组相比各组断奶仔猪的采食量均有提高，其中N-癸酰-L-天门冬氨酸和N-丁酰-L-天门冬氨酸锌盐的效果非常显著；关于平均日增重，与空白对照组相比各组断奶猪的平均日增重均有提高的效果，其中给与N-癸酰-L-天门冬氨酸、N-丁酰-L-天门冬氨酸二乙酯以及N-丁酰-L-天门冬氨酸的钠盐、锌盐、铁盐及钙盐的试验组效果更为显著；在料肉比方面，与对照组相比各试验的效果未出现显著的变化，但是下降幅度为5％～7％。
表2天门冬氨酸的脂肪酰基衍生物及其盐对断奶仔猪的生产性能影响研究
Figure PCTCN2018113907-appb-000012
Figure PCTCN2018113907-appb-000013
实施例B2天门冬氨酸脂肪酰基衍生物对蛋鸡生产性能的影响
试验采用单因子随机设计，选择147日龄、体重相近的京白蛋鸡480只，随机分为8个处理组，每组3个重复，公母各半，每个重复20只京白蛋鸡。试验前对鸡舍及器具进行消毒。试验期在同一鸡舍同一饲养管理条件下进行笼养。基础日粮以玉米-豆粕为主，整个饲养过程不额外添加其它抗氧化成分及促生长剂。各试验组分别为试验Ⅰ～Ⅷ组。其中试验Ⅰ为对照组仅给与基础日粮，试验Ⅱ～Ⅷ在基础日粮中分别添加500ppm的不同的天门冬氨酸脂肪酰基衍生物，分组见表3。预饲期10天，试验期158天，试验鸡自由饮水和采食，日喂料2次。试验期间，每天以重复为单位记录产蛋数、产蛋量、采食量，计算试验全期蛋鸡的产蛋率(EPR)、平均日采食量(ADFI，g/d)、蛋重(EW，g)和料蛋比(FER)。计算公式如下：
产蛋率(％)＝平均日总蛋数/鸡数×100；
蛋重(g)＝平均日总蛋重/平均日总蛋数；
料蛋比＝平均日采食量/蛋重。
试验数据采用SPSS18软件进行统计分析，先对数据作单因素方差分析(ANOVA)，若处理间差异显著，再用Duncan's法进行多重比较，显著性水平为0.05。试验结果以“平均值±标准误”表示， 试验结果如表3所示。
从结果可知，供试品对试验鸡的产蛋率和料蛋比的影响与对照组相比改善效果不显著但均体现出了不同程度的改善效果，产蛋率提高1.9％-5.5％，料蛋比下降2.3％-6.4％；供试品对试验鸡的采食量和蛋重的影响无影响。
表3天门冬氨酸脂肪酰基衍生物在蛋鸡料中的应用效果研究
Figure PCTCN2018113907-appb-000014
实施例B3天门冬氨酸的脂肪酰基衍生物对肉鸡生产性能的影响
试验采用单因子随机设计，选择1日龄、体重相近的平均体重为50g的三黄羽肉鸡480只，随机分为8个处理组，每组3个重复，公母各半，每个重复20只三黄羽肉鸡。试验前对鸡舍及器具进行消毒。试验期在同一鸡舍同一饲养管理条件下进行笼养。基础日粮以玉米-豆粕为主，整个饲养过程不额外添加其它抗氧化成分及促生长剂。各试验组分别为试验Ⅰ～Ⅷ组。其中试验Ⅰ为对照组仅给与基础日粮，试验Ⅱ～Ⅷ在基础日粮中分别添加300ppm的不同的天门冬氨酸脂肪酰基衍生物，分组见表4。试验期共20天，试验鸡自由饮水和采食，日喂料2次。以每个重复为单位，于21日龄称重(停料12h、不停水)，统计试验鸡耗料量，计算各组试验鸡的平均日采食量(ADFI，g/d*只)、平均日增重(ADG，g/d*只)和料肉比(FCR)，计算公式如下：
料肉比(FCR)＝平均日采食量/平均日增重。
试验数据采用SPSS18软件进行统计分析，先对数据作单因素方差分析(ANOVA)，若处理间差异显著，再用Duncan's法进行多重比较，显著性水平为0.05。试验结果以“平均值±标准误”表示，试验结果如表4所示。
从结果可知，试验涉及的天门冬氨酸脂肪酰基衍生物在肉鸡养殖中在试验期间对肉鸡的采食量和 料肉比没有显著的影响，但是均对肉鸡的料肉比有不同程度的改善效果；另外供试品对肉鸡的增重提高效果较为显著，由此可见，天门冬氨酸的脂肪酰基衍生物对肉鸡的生产性能从整体上来看具有较为显著的改善效果。
表4天门冬氨酸的脂肪酰基衍生物在肉鸡料中的应用效果研究
Figure PCTCN2018113907-appb-000015
实施例B4天门冬氨酸的脂肪酰基衍生物在鱼料中的应用
1)试验材料
试验用鱼：所用试验鱼为当年的健康活泼、规格一致的草鱼种在大网箱中(4×2×1.5m 3)饲养4周后才用于正式养殖试验，实验体系为浮性小网箱(规格1.1×1.1×1.1m 3)，每个小网箱均置有一个充气头，每天24h充气。小网箱与暂养网箱均置于试验场一个3500m 2的池塘中，池塘水深约1.5m，池塘水为充分曝气底下水。试验时，将饥饿1天的草鱼640尾随机分成8组，每组设4个重复，每个重复放20尾鱼，以每个重复为单位称重后放入32个网箱中，分别饲喂添加相同含量的不同供试品的试验饲料。
试验饲料：试验用饲料按表5配方自行配制，不同试验组按表6分别饲喂添加相同含量的不同供试品。所用饲料原料经超微粉碎后通过江苏牧羊膨化机组制成粒径3mm浮性膨化饲料，出模温度130℃，通过喷油设备外喷3％豆油，阴凉处密封保存备用。
表5试验用草鱼饲料配方及化学成分(％wt.)
原料组成 含量(％) 原料组成 含量(％)
鱼粉 9.0 豆油 3.0
肠衣粉 3.0 磷脂菜粕 9.0
豆粕 12.0 谷朊粉 4.0
菜粕 12.0 血球粉 2.0
味精蛋白 3.0 Vc-磷酸酯 0.1
次粉 12.6 磷酸二氢钙 1.8
面粉 17.0 氯化胆碱 0.2
膨润土 0.70 多维 0.1
米糠 10.0 微矿预混剂 0.5
表6天门冬氨酸脂肪酰基衍生物在鱼料中的应用研究试验分组
组别 供试品 剂量(ppm)
Ⅰ组 - -
Ⅱ组 N-乙酰-L-天门冬氨酸 3000
Ⅲ组 N-丁酰-L-天门冬氨酸 3000
Ⅳ组 N-癸酰-L-天门冬氨酸 3000
Ⅴ组 N-月桂酰-L-天门冬氨酸 3000
Ⅵ组 N-肉豆蔻酰-L-天门冬氨酸 3000
Ⅶ组 N-硬脂酰-L-天门冬氨酸 3000
Ⅷ组 N-丁酰-L-天门冬氨酸二乙酯 3000
(2)试验方法
试验管理：试验采用人工限食投喂，投食量每周调整一次，每组投喂水平(按初始体重)完全一致，每天投喂两次(7:30及15:00)，总投喂食量为580g/重复试验组。试验为期8周。试验期间定时对水质进行监控，养殖全程水温26.88±3.08℃、DO>5.0mg O L -1、pH 7.8、氨氮<0.50mg N L -1、亚硝酸盐氮<0.05mg N L -1。
参数统计：试验时，停喂1d后对各网箱鱼进行整体称重，计算其增重率(WG,％),和饲料系数(FCR)。计算公式如下：
增重率(WG，％)＝100×(平均末重－平均初重)/平均初重；
饲料系数(FCR)＝摄食量/鱼体增重。
(3)试验结果
从表7所示的试验结果可知，在草鱼的养殖试验中天门冬氨酸的脂肪酰基衍生物可显著的提高草鱼的增重率并降低了饲料系数但是除了N-肉豆蔻酰-天门冬氨酸外饲料系数下降效果不显著。
表7天门冬氨酸的脂肪酰基衍生物在水产料中的应用试验结果
Figure PCTCN2018113907-appb-000016
以上所述实施例仅表达了本发明的几种实施方式，还有其他方式用来实施本发明。相应地，本发明的实施例是将作为例证进行说明，但并不能因此而理解为对本发明的专利范围的限制，还可能是在本发明范围内以及同一发明构思内所作的修改或在权利要求中所添加的等同内容。

Claims (14)

  1. 一种结构如以下通式所示的天门冬氨酸脂肪酰基衍生物或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物、或其饲料可接受的盐在制备动物饲料添加剂中的应用：
    Figure PCTCN2018113907-appb-100001
    其中，Y和X分别独立选自C 1-C 20烷氧基或OH；R 1为R 1aC(＝O)、R 1aS(＝O) 2或H；R 2为R 2aC(＝O)或R 2aS(＝O) 2；所述的R 1a和R 2a分别独立选自C 1-C 20烷基或C 3-C 7环烷基。
  2. 根据权利要求1所述的应用，其特征在于，所述的R 1为H。
  3. 根据权利要求1所述的应用，其特征在于，所述的R 2为R 2aC(＝O)，R 2a选自C 1-C 20烷基或C 3-C 7环烷基。
  4. 根据权利要求3所述的应用，其特征在于，所述的R 2a选自C 1-C 10烷基。
  5. 根据权利要求1所述的应用，其特征在于，所述的Y和X为OH。
  6. 根据权利要求1所述的应用，其特征在于，所述的Y和X分别独立选自C 1-C 20烷氧基或OH，并且不同时为OH。
  7. 根据权利要求6所述的应用，其特征在于，所述的Y和X分别独立选自C 1-C 10烷氧基或OH，并且不同时为OH。
  8. 根据权利要求1所述的应用，其特征在于，所述的饲料可接受的盐为金属离子盐。
  9. 根据权利要求8所述的应用，其特征在于，所述的金属离子盐为钠离子盐、钙离子盐、锌离子盐、铜离子盐或铁离子盐。
  10. 一种饲用组合物，其特征在于，包含权利要求1-9任一项所述的天门冬氨酸脂肪酰基衍生物或其消旋体、立体异构体、几何异构体、互变异构体、溶剂合物、或其饲料可接受的盐中的至少一种和可饲用辅料。
  11. 根据权利要求10所述的饲用组合物，其特征在于，所述的饲用组合物还包含附加的动物饲料添加剂，所述的附加的动物饲料添加剂选自营养性饲料添加剂、非营养性饲料添加剂或药物饲料添加剂。
  12. 根据权利要求10或11所述的饲用组合物，其特征在于，还包含动物饲料原料。
  13. 权利要求10-12任一项所述的饲用组合物在制备动物饲料添加剂中的应用。
  14. 权利要求10-12任一项所述的饲用组合物在制备动物饲料中的应用。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220015393A1 (en) * 2018-11-05 2022-01-20 Peng Xianfeng Application of aspartic acid derivative in preparing animal feed additive

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4791215A (en) * 1984-06-25 1988-12-13 Rotta Research Laboratorium S.P.A. Derivatives of glutamic acid and aspartic acid
JPH10150923A (ja) * 1996-11-20 1998-06-09 Ajinomoto Co Inc 反すう動物用飼料添加組成物
US6359008B1 (en) * 1998-03-05 2002-03-19 Lovesgrove Research Limited Acylated aminoacids for increasing the uptake of selected substances by organisms
CN106998771A (zh) * 2014-12-10 2017-08-01 马斯公司 风味组合物及包含该组合物的宠物食品

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2200209A1 (fr) * 1995-07-26 1997-02-13 Eric Frerot Produits aromatises et procede pour leur preparation
CN101507468A (zh) * 2009-03-16 2009-08-19 浙江大学 一种纳米饲料添加剂的制备方法
CN106916076A (zh) * 2015-12-24 2017-07-04 长沙道勤生物科技有限公司 一种猪生长基因表达促使剂的制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4791215A (en) * 1984-06-25 1988-12-13 Rotta Research Laboratorium S.P.A. Derivatives of glutamic acid and aspartic acid
JPH10150923A (ja) * 1996-11-20 1998-06-09 Ajinomoto Co Inc 反すう動物用飼料添加組成物
US6359008B1 (en) * 1998-03-05 2002-03-19 Lovesgrove Research Limited Acylated aminoacids for increasing the uptake of selected substances by organisms
CN106998771A (zh) * 2014-12-10 2017-08-01 马斯公司 风味组合物及包含该组合物的宠物食品

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220015393A1 (en) * 2018-11-05 2022-01-20 Peng Xianfeng Application of aspartic acid derivative in preparing animal feed additive

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