CN108218739A - Butyryl glutamate derivatives and combinations thereof and application - Google Patents
Butyryl glutamate derivatives and combinations thereof and application Download PDFInfo
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- CN108218739A CN108218739A CN201711397106.XA CN201711397106A CN108218739A CN 108218739 A CN108218739 A CN 108218739A CN 201711397106 A CN201711397106 A CN 201711397106A CN 108218739 A CN108218739 A CN 108218739A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- 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
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Abstract
The invention discloses butyryl glutamate derivatives and combinations thereof and application.The butyryl glutamate derivatives or its raceme, stereoisomer, geometric isomer, tautomer, solvate or the acceptable salt of feed of the present invention can be in the application in preparing novel fodder additive and preparing feed.The invention also discloses the feeding compositions of the butyryl glutamate derivatives or its raceme, stereoisomer, geometric isomer, tautomer, solvate or the acceptable salt of feed.Butyryl glutamate derivatives provided by the invention, which are applied, to be had effects that improve animal rate of body weight gain, reduce feedstuff-meat ratio and control the improvement of the breeding performonce fo animals such as diarrhea rate in animal farming industry, can be as the novel fodder additive application of effective and safe.
Description
Technical field：
The invention belongs to animal feed additive fields, and in particular to a kind of butyryl glutamate derivatives and include the fourth
The composition of acyl glutamate derivatives and the butyryl glutamate derivatives and the group for including the butyryl glutamate derivatives
Close application of the object in animal feed additive or feed is prepared.
Background technology：
Feed refers to through industrialization processing, the product used for animal made, is the master for modernizing intensive culture industry
Want animal foodstuff.During animal-breeding, the feed product that raiser thirsts for animal edible can be inhaled by animal to greatest extent
It receives and utilizes, improve the production performance of animal so as to achieve the purpose that improve fanning economics.Being added in feed product has
The feed addictive of corresponding effect can effectively improve the utilization rate of feed product.
Feed addictive refers to a small amount of or micro substance added during feed processing, making, use, including
Nutritional feed additive and general feeds additive.Nutritional feed additive refers to mix for supplement feed nutritional ingredient
Enter a small amount of or micro substance in feed, including feed grade amino acid, vitamin, mineral trace element, enzyme preparation, non-egg
White nitrogen etc..General feeds additive refers to mix in feed to ensure or improving feed quality, improve efficiency of feed utilization
A small amount of or micro substance.This field is currently used to have efficiently and stably raising efficiency of feed utilization improvement breeding performonce fo animals
General feeds additive mainly include high doses of copper agent, Pharmacological Level of Zinc agent, feeding antibiotic, chemical synthesis antiseptic etc., but
It is that these substances are larger using side effect for a long time in aquaculture, liver renal toxicity, inhibition growth such as animal, renal function damage
Wound, teratogenesis, mutagenesis, generates the drawbacks such as drug resistance, medicine residual and pollution environment at urinary-tract disorders.In order to ensure the health of animal
And the productivity effect of aquaculture is improved, it is this field urgent problem to seek effective and safe new feed additive.
Invention content：
Based on this, the present invention provides a kind of butyryl glutamate derivatives or its raceme, stereoisomer, geometrical isomerisms
Body, tautomer, solvate or the acceptable salt of feed, the butyryl glutamate derivatives and its related substances can be used for
Improve the production performance of animal, can be applied in animal feed additive or animal feed is prepared；The present invention also provides one kind
Include the butyryl glutamate derivatives or raceme, its stereoisomer, geometric isomer, tautomer, solvate
Or the feeding composition of the acceptable salt of feed, the composition can be used for preparing animal feed additive or prepare animal
Feed is applied as animal feed in animal farming industry.
On the one hand, the present invention provides a kind of butyryl glutamate derivatives of structure as shown in formula (I) or its raceme,
Stereoisomer, geometric isomer, tautomer, solvate or the acceptable salt of feed：
Wherein, the substituent group A and B in formula are each independently H or alkyl, the alkyl is n-propyl, isopropyl,
C5-C20Linear or branched alkyl group, C1-C8Linear chain or branch chain halogenated alkyl or C3-C7Cycloalkyl.
In some embodiments, the substituent group A and B of the butyryl glutamate derivatives is simultaneously alkyl.
In some embodiments, it is H during the substituent group A and B differences of the butyryl glutamic acid glutamate derivatives.
On the other hand, the present invention provides butyryl glutamate derivatives provided by the invention or its raceme, alloisomerisms
Body, geometric isomer, tautomer, solvate or the acceptable salt of feed answering in animal feed additive is prepared
With.
In some embodiments, the cultivated animals that the animal feed additive is applicable in are selected from domestic animal, poultry, aquatic products
Cultivated animals or pet.
On the other hand, the present invention also provides butyryl glutamate derivatives provided by the invention or its raceme, solid are different
The application of structure body, geometric isomer, tautomer, solvate or the acceptable salt of feed in animal feed is prepared.
In some embodiments, the cultivated animals that the animal feed additive is applicable in are selected from domestic animal, poultry, aquatic products
Cultivated animals or pet.
On the other hand, the present invention also provides a kind of feeding composition, the feeding composition includes the present invention and provides
Butyryl glutamate derivatives or its raceme, stereoisomer, geometric isomer, tautomer, solvate or feed
Acceptable salt at least one and can feeding auxiliary material.
Optionally, it is described can feeding auxiliary material be selected from can be feeding carrier, diluent, excipient, solvent or their group
It closes.
In some embodiments, the feeding composition is also added comprising feedstuff and/or additional animal feed
Agent.
Optionally, the additional animal feed additive is selected from nutritional feed additive, general feeds additive
Or medicated feed additive.
On the other hand, the present invention also provides a kind of methods for improving cultivated animals production performance.
In some embodiments, the method includes giving cultivated animals butyryl glutamic acid derivative provided by the invention
Object or its raceme, stereoisomer, geometric isomer, tautomer, solvate or the acceptable salt of feed.
In some embodiments, including giving, cultivated animals are provided by the invention to be provided the method comprising the present invention
Butyryl glutamate derivatives or its raceme, stereoisomer, geometric isomer, tautomer, solvate or feed
The feeding composition of acceptable salt.
On the other hand, the present invention also provides the butyryl glutamate derivatives or its raceme, stereoisomer, geometry
Isomers, tautomer, solvate or the acceptable salt of feed preparation, Isolation and purification method.
Beneficial effects of the present invention：
Present invention discover that butyryl glutamic acid and its derivative, which have domestic animal, poultry or aquiculture animal, improves average day
Weightening reduces the effect of feedstuff-meat ratio etc. improves production performance, can also effectively prevent the diarrhea state of domestic animal, poultry or pet.
Screening, which can be done, finds butyryl glutamic acid prodrug esterification provided by the invention in the butyryl glutamate derivatives of novel fodder additive
Conjunction object is more notable to the production performance improvement of animal, this may be because of the oil of the prodrug ester compounds of butyryl glutamic acid
While increasing the absorbent properties for improving cultivated animals to butyryl glutamate derivatives of water partition coefficient, butyryl glutamic acid derivative
Object can be used as a miniature memory library, pass through the slow hydrolysis sustained release butyryl glutamic acid of butyryl glutamate derivatives in animal body
Improve bioavilability.
Any embodiment of the either side of the present invention can be combined with other embodiments, as long as between them
There is not contradiction.In addition, in any embodiment of either side of the present invention, any technical characteristic can be adapted for other realities
The technical characteristic in scheme is applied, as long as between them being not in contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.It is above-mentioned to be related to content
And otherwise content will do more specific complete description below.
The present invention's is described in further detail.
Certain embodiments of the present invention will now be described in more detail, the example is said by the structural formula and chemical formula being appended
It is bright.The intent of the present invention covers all replacements, modification and equivalent technical solution, they are included in claim such as and define
The scope of the present invention in.In addition, certain technical characteristics of the present invention are clearly visible, divide in multiple independent embodiments
It is not described, but can also in combination provide or be provided in the form of any suitable sub-portfolio in single embodiment.
Compound.
Shown in butyryl glutamate derivatives structure provided by the invention such as formula (I)：
Substituent group A and B are each independently H or alkyl in formula, and the alkyl is n-propyl, isopropyl, C5-C20Directly
Chain or branched alkyl, C1-C8Linear chain or branch chain halogenated alkyl or C3-C7Cycloalkyl.
In general, term " substitution " represents that institute is taken to one or more of structure hydrogen atom by specific substituent group
Generation.Unless otherwise indicated, one substitution group can there are one or multiple substituent groups in each commutable position of group
It puts and is replaced.When in given structural formula not only there are one position can be by one or more substituent groups selected from specific group
Replaced, then substituent group can replace in each position identical or differently.
Some chemical groups expression according to the present invention：“C5-C20Linear or branched alkyl group ", which represents, contains 5-20 carbon
The straight chain of atom or branched alkyl；“C1-C8Linear chain or branch chain halogenated alkyl " represents one containing 1-8 carbon atom
Or the straight chain that is optionally substituted by halogen of multiple hydrogen atoms or branched alkyl, the halogen are selected from fluorine, chlorine, bromine or iodine；“C3-C7
Cycloalkyl " represents cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl.
The preparation process that the present invention provides butyryl glutamate derivatives includes：Step 1, in organic reaction solvent Glutamic Acid
With alcohol glutamate is prepared under thionyl chloride or sulphuric acid catalysis；Step 2, glutamate is in dry organic reaction solvent body
Amidation process occurs with butyl chloride under the alkaline condition of system or amidation process generation occurs with butyric anhydride in acid condition
Corresponding butyryl glutamate.
In some embodiments, the step 1 of the preparation method of the butyryl glutamate derivatives is molten in organic reaction
Matchmaker's Glutamic Acid generates glutamate with alcohol under thionyl chloride catalysis, and step 2 is in dry organic reaction solvent system
Amidation process generation butyryl glutamic acid dibasic acid esters occurs under alkaline condition with butyl chloride.
Optionally, involved alcohol is normal propyl alcohol, isopropanol, C5-C20Linear chain or branch chain alkanol, C1-C8Linear chain or branch chain halogen
For alkanol or C3-C7Cyclic alkanol, involved organic reaction solvent are polarity organic solvent.
Further, involved polarity organic solvent includes alcohol organic solvent or aprotic organic solvent.
Specifically, the step 1, which is related to organic action solvent, includes but not limited to the short chain fatty alcohol being related to, methyl- tert fourth
Ether, tetrahydrofuran, N-Methyl pyrrolidone, toluene, dichloromethane, N,N-dimethylformamide or DMAC N,N' dimethyl acetamide.
In some embodiments, glutamate is reacted with butyl chloride occurs the organic reaction that acylation reaction process is related to
Solvent includes but not limited to tetrahydrofuran, N-Methyl pyrrolidone, toluene, dichloromethane, dimethyl sulfoxide (DMSO), N, N- dimethyl methyls
Amide or DMAC N,N' dimethyl acetamide.
In some embodiments, the step 1 of the preparation method of the butyryl glutamate derivatives is molten in organic reaction
Matchmaker's Glutamic Acid prepares glutamic acid monoesters with alcohol under sulphuric acid catalysis；Step 2 for glutamate in acid condition with butyric acid
Acid anhydride occurs amidation process and generates corresponding butyryl glutamic acid monoesters.
Optionally, involved alcohol is normal propyl alcohol, isopropanol, C5-C20Linear chain or branch chain alkanol, C1-C8Linear chain or branch chain halogen
For alkanol or C3-C7Cyclic alkanol, involved organic reaction solvent are polarity organic solvent.
Further, involved polarity organic solvent includes alcohol organic solvent or aprotic organic solvent.
Specifically, the organic reaction solvent that the reaction that the step 1 is related to is related into ester process includes but not limited to be related to
Short chain fatty alcohol, methyl tertiary butyl ether, tetrahydrofuran, N-Methyl pyrrolidone, toluene, dichloromethane, N, N- dimethyl formyls
Amine or DMAC N,N' dimethyl acetamide.
Optionally, the acid condition is organic acid or inorganic acid.
Further, the organic acid includes but not limited to formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid, methanesulfonic acid
Or ethanesulfonic acid.
Further, the organic acid includes but not limited to hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid.
In other embodiments, the glutamic acid that the preparation method of the butyryl glutamate derivatives is related to is to butyryl
Shown in the variation course such as formula (II) of glutamic acid monoesters：
The A is n-propyl, isopropyl, C5-C20Linear or branched alkyl group, C1-C8Linear chain or branch chain halogenated alkyl or
C3-C7Cycloalkyl.
In other embodiments, the glutamic acid that the preparation method of the butyryl glutamate derivatives is related to is to butyryl
The variation course of glutamic acid monoesters is as follows：
The A is n-propyl, isopropyl, C5-C20Linear or branched alkyl group, C1-C8Linear chain or branch chain halogenated alkyl or
C3-C7Cycloalkyl.
In some embodiments, the present invention also provides the systems that butyryl glutamate derivatives are butyryl glutamic acid mixed ester
Preparation Method, the preparation method are that step 1 is that paddy ammonia is prepared under sulphuric acid catalysis in organic reaction solvent Glutamic Acid and alcohol
Acid monoester；Step 2 is to generate glutamic acid mixed ester under thionyl chloride catalysis in organic reaction solvent Glutamic Acid monoesters and alcohol；
Step 3 glutamate occurs amidation process with butyl chloride under the alkaline condition of dry organic reaction solvent system or in acid
Property under the conditions of with butyric anhydride the corresponding butyryl glutamate of amidation process generation occurs.
" mixed ester " of the present invention refers to that with different alcohol esterification occurs for the carboxyl of polyhydric aliphatic acid respectively
The ester compounds generated.
Optionally, involved alcohol is normal propyl alcohol, isopropanol, C5-C20Linear chain or branch chain alkanol, C1-C8Linear chain or branch chain halogen
For alkanol or C3-C7Cyclic alkanol, involved organic reaction solvent are polarity organic solvent.
Further, involved polarity organic solvent includes alcohol organic solvent or aprotic organic solvent.
Specifically, the organic reaction solvent that the reaction that the step 1 is related to is related into ester process includes but not limited to be related to
Short chain fatty alcohol, methyl tertiary butyl ether, tetrahydrofuran, N-Methyl pyrrolidone, toluene, dichloromethane, N, N- dimethyl formyls
Amine or n,N-dimethylacetamide, glutamate is reacted with butyl chloride occurs the organic reaction solvent that acylation reaction process is related to
Including but not limited to tetrahydrofuran, N-Methyl pyrrolidone, toluene, dichloromethane, dimethyl sulfoxide (DMSO), N,N-dimethylformamide
Or DMAC N,N' dimethyl acetamide.
Optionally, the acid condition is organic acid or inorganic acid.
Further, the organic acid includes but not limited to formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid, methanesulfonic acid
Or ethanesulfonic acid.
Further, the organic acid includes but not limited to hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid.
In some embodiments, the glutamic acid is a kind of chipal compounds, and glutamic acid of the present invention is selected from
Levo form L- (-)-glutamic acid (structure such as formula (IV)), d-isomer D- (+)-glutamic acid (structure such as formula (V)) or racemic modification DL-
(±) glutamic acid, the solid that the butyryl glutamate derivatives with chiral centre are obtained after being reacted with the alcohol and butyl chloride being related to are different
Structure body or racemic modification.
In some embodiments, the solid of the chiral stereoisomer of the glutamic acid and butyryl glutamate derivatives
The conversion of spatial configuration can occur under suitable conditions for isomers, such as glutamic acid or the three-dimensional conformation of butyryl glutamate derivatives
Change, process are as follows：
When the alcohol being related to and glutamic acid are when reactions generate corresponding butyryl glutamate derivatives with rigid structure, instead
Answer substrate that can generate different geometric isomer products during the reaction.
Above-mentioned stereoisomer, geometric isomer, tautomer are also included in the practical range of the present invention.
In some embodiments, the preparation process of present invention offer butyryl glutamate derivatives further relates to reaction product
Separation, purifying or recrystallization process.Reaction product can obtain crude product by desolventizing method from reaction system.In order to obtain chemistry
The lower solid matter of purity higher, impurity content, crude product through alcoholic solvent, alcohol water mixed solvent or other tied again available for product
In brilliant organic solvent under the conditions of suitable temperature, illumination and mechanical oscillation etc. dissolving, crystallization or precipitation or recrystallization and
The isolated butyryl glutamate derivatives with certain crystal form state.The butyryl glutamic acid with certain crystal form state spreads out
Biology is the solvate of the crystallization of butyryl glutamate derivatives or butyryl glutamate derivatives.The butyryl glutamate derivatives
Solvate may be selected from the hydrate of butyryl glutamate derivatives or the ethanolates of butyryl glutamate derivatives.
During " solvate " of the present invention refers to that the compound of the present invention is contacted with solvent molecule, outer strip
Part and interior condition factor cause by non-covalent intermolecular forces and with reference to the solvent molecule of chemical equivalent or non-chemical equivalent and
The eutectic associated matter of formation.Formed solvate solvent include but is not limited to water, acetone, ethyl alcohol, methanol, dimethyl sulfoxide,
Ethyl acetate, acetic acid, isopropanol equal solvent." hydrate " refers to that solvent molecule is the associated matter or crystalline solid that water is formed,
It is exactly the compound that the water of chemical equivalent or non-chemical equivalent is combined by non-covalent intermolecular forces.
The preparation of butyryl glutamate derivatives provided by the invention is lower in order to obtain chemical purity higher, impurity content
Solid matter can also be by being handled after salting out method.The salting out method is to utilize acid-base neutralization method, soda acid coordination method or acid
The principle of alkali chelating method makes butyryl glutamate derivatives be precipitated with corresponding organic base, inorganic base, organic acid or inorganic acids
Process, obtain the acceptable salt of feed.
Specifically, the acceptable salt of feed for the present invention butyryl glutamate derivatives and the organic base nontoxic to animal,
The salt that inorganic base, organic acid or inorganic acid are formed." feed is acceptable " refers to that substance or composition must be suitable
It is chemical or toxicology, it is related with the feed of composition or edible cultivated animals.
In some embodiments, butyryl glutamate derivatives are the dibasic acid esters or mixed ester of butyryl glutamic acid, post processing
Salt precipitation process and inorganic acid or organic acid form soda acid coordination salt and/or soda acid chelating salt, and the organic acid is included but not
It is limited to acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid
Salt, acetonate, oxalates, glycollate, salicylate, glucuronate salt, galactitol hydrochlorate, citrate, winestone
Hydrochlorate, aspartate, glutamate, benzoate, p-methylbenzoic acid salt, cinnamate, tosilate, benzene sulfonic acid
Salt, mesylate, esilate, fluoroform sulphonate or combination thereof；The inorganic acid include but not limited to hydrochloride,
Hydrobromate, phosphate, sulfate, nitrate or combination thereof.
In some embodiments, butyryl glutamate derivatives are the monoesters of butyryl glutamic acid, the salt precipitation of post processing
Process forms soda acid coordination salt and/or soda acid chelating salt with organic acid or inorganic acid or forms acid with organic base or inorganic base
Salt.The organic acid includes but not limited to acetate, maleate, succinate, mandelate, fumarate, the third two
Hydrochlorate, malate, 2 hydroxy propanoic acid salt, acetonate, oxalates, glycollate, salicylate, glucuronate salt, half
Lactitol hydrochlorate, citrate, tartrate, aspartate, glutamate, benzoate, p-methylbenzoic acid salt, Chinese cassia tree
Hydrochlorate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate or combination thereof；Described
Inorganic acid includes but not limited to hydrochloride, hydrobromate, phosphate, sulfate, nitrate or combination thereof.Described is organic
Alkali includes but not limited to ammonia or triethylamine.The inorganic base includes but not limited to sodium hydroxide, potassium hydroxide or calcium hydroxide.
Butyryl glutamate derivatives or its raceme provided by the invention, stereoisomer, mutually geometric isomer, variation
Structure body, solvate or the acceptable salt of feed have following structure once being not limited to lower structure：
The present invention relates to the applications of butyryl glutamate derivatives.
Butyryl glutamic acid is acylated glutamic acid soluble easily in water, and the present invention has found it for the first time in the culture experiment of animal
Average daily gain can significantly be improved by being individually used for the cultivation of animal, reduced feedstuff-meat ratio, improved the conversion ratio of feed, can also have
The symptom of diarrhea of the prevention animal of effect.Inventor has found the metabolism of butyryl glutamic acid in animal body in dynamic metabolism research
Approach mainly hydrolyzes generation butyric acid and glutamic acid and is excreted without original shape substance.Butyric acid is the ingredient of the excreta of organism
One of, and the important substance that glutamic acid is biological vivo protein metabolism participates in many important chemical reactions, so as to visible butyryl
Glutamic acid can be as a kind of safe, effective novel animal feed additive application.
Butyryl glutamate derivatives are the prodrug compounds of butyryl glutamic acid." prodrug compound " represent one
Butyryl glutamic acid soluble easily in water, gastrointestinal tract of such conversion by the prodrug compound in vivo are converted into organism
In, in blood or the influence through enzyme or internal acid-base value in tissue fluid.The prodrug compound of butyryl glutamic acid of the present invention
The Determination of oil-water partition coefficient of butyryl glutamate derivatives can be significantly improved, increases fat-soluble, improves the absorbent properties of organism
So as to improve bioavilability.
Therefore, butyryl glutamate derivatives can be used in and prepare in animal feed additive or animal feed.
" animal " of the present invention refer to cannot by inorganic matter synthesis of organic substance, can only using organic matter as foodstuff, with
People for vital movement or the cultivated animals such as ingested, digested, absorbed, breathed, recycled, drained, felt, moved and bred.
Other animals of " cultivated animals " including poultry, domestic animal, aquiculture animal and the legal capture of artificial feeding include pet, example
Such as cat and dog.Term " domestic animal " is, for example, pig, ox, horse, goat, sheep, deer and many useful rodents it is any.Term
" poultry " is to include, such as chicken, duck, goose, quail, dove etc..Term " aquiculture animal " includes, such as fish, shrimp, tortoise, soft-shelled turtle.
The present invention also provides a kind of method for improving cultivated animals production performance, including by butyryl glutamate derivatives,
Or its raceme, stereoisomer, geometric isomer, tautomer, solvate or the acceptable salt of feed, it is raised with animal
Material mixing, then raises animal.
In some cultivation schemes, butyryl glutamate derivatives give poultry food, and the utilization rate that can improve feed is notable
Reduction feedstuff-meat ratio coefficient while poultry diarrhea rate can effectively control.
Optionally, butyryl glutamate derivatives give the poultry foods such as chicken, duck, goose or dove, improve the utilization of poultry feed
The diarrhea rate of poultry can be controlled effectively while rate significantly reduces feedstuff-meat ratio coefficient.
In some cultivation schemes, butyryl glutamate derivatives give domestic animal and eat, and are remarkably improved the gain in weight of domestic animal
With reduction feedstuff-meat ratio, the conversion ratio of feed stripped is improved.
Optionally, butyryl glutamate derivatives give domestic animal that the is simple stomach such as pig, ox, sheep or ruminating and eat, can be effective
Improve the conversion ratio of feed stripped.
In some cultivation schemes, butyryl glutamate derivatives are used cooperatively with aquatic feeds, the feed system of aquatic livestock
Number has different degrees of improvement.
Optionally, butyryl glutamate derivatives and fish material, shrimp material etc. are used cooperatively, and different degrees of reduces feed system
Number.
In some cultivation schemes, butyryl glutamate derivatives can be used in combination with pets grain rations such as cat food, dog foods, reach
The effect of adjusting cat, the functions of intestines and stomach of pets such as dog effectively alleviates pet and has loose bowels caused by indigestion symptom.
" feed addictive " of the present invention refer to add during feed processing, making, use a small amount of or
Micro substance, is divided into nutritional feed additive and general feeds additive is also non-nutritional feed additive.Trophism is raised
Feed additives refer to be added in mixed feed, balanced feed nutrient, improve efficiency of feed utilization, and directly playing nutrition to animal makees
A small amount of or micro substance, including vitamin, trace element, amino acid and small peptide and nonprotein nitrogen.General feeds additive
Also non-nutritive additive is, is referred to be added in feed for improving efficiency of feed utilization, ensure feeding quality and quality, advantageous
In some of animal health or metabolism non-nutritive substances, including growth promoter, vermifuge, feed adjusting material, feed
Modulator, feed storage agent and Chinese herb feed additive.
Feed of the present invention refers to through industrialization processing, the product for animal edible made.
The present invention provides a kind of feeding composition, comprising butyryl glutamate derivatives provided by the invention or its raceme,
Stereoisomer, geometric isomer, tautomer, solvate or the acceptable salt of feed one or more and can be feeding
Auxiliary material.
" composition " of the present invention refers to include the chemical combination of one or more kinds of compound composition active ingredient
Object collective.
"comprising" of the present invention is open language, both include the present invention bright finger content, but it is not precluded
Content in terms of him.
Optionally, it is described can feeding auxiliary material include feed addictive or the common carrier of feed, binding agent, anti-caking agent,
Stabilizer, emulsifier, diluent, solvent or combination thereof.
" carrier " of the present invention is to refer to carrying active constituent, improves its dispersibility, and have good chemical stability
With adsorptivity can feeding substance, be divided into organic carrier and inorganic carrier.It is containing the object more than crude fibre as the organic carrier
Material, including but not limited to corn flour, maize cob meal, wheat bran, powdered rice hulls, defatted rice bran, system chaff, corn stalk powder, peanut shell powder
Deng.The inorganic carrier is usually minerals, the oxide-based of calcium salt class and silicon is broadly divided into, for microelement pre-mix material
Making, including but not limited to calcium carbonate, silicate, vermiculite, zeolite, sepiolite etc..
" diluent " of the present invention refers to additive raw material being uniformly distributed in material, by the additive of high concentration
Raw material is diluted to the pre-mixing agent of low concentration or the substance of premix, and micro constitutent can be separated from each other, between reduction active constituent
React to each other, to increase the stability of active constituent but not influence the physico-chemical property in relation to substance.The type of diluent is divided into
Organic diluent and inorganic diluents, the machine diluent of common are include but not limited to corn flour, degermed maize powder, dextrose
(glucose), sucrose, with chaffy wheat middling, stir-fry soybean powder, wheat-middlings, corn protein powder etc., common inorganic diluents
Including but not limited to lime stone, calcium dihydrogen phosphate, oyster shell whiting, kaolin (white bole), salt and sodium sulphate.
Adjuvant of the present invention including but not limited to refers to adhesive, wetting agent, disintegrant, lubricant, antioxidant, prevents
Rotten agent.
" medium " of the present invention refer to dissolving or dispersing solid needed for solvent, including but not limited to water, ethyl alcohol,
Glycerine etc..
Further, the feeding composition includes additional animal feed additive, and the additional animal is raised
Material addition is selected from nutritional feed additive, general feed addictive or medicated feed additive.
Specifically, the nutritional feed additive includes but not limited to amino acid, amino-acid salt and the like, dimension
Raw element and biostearin, mineral element and its network (chela) close object, micro-organism enzyme preparation or nonprotein nitrogen；The general feed
Additive includes but not limited to growth promoter, vermifuge, seasoning and phagostimulant, feed adjusting material, feed preparation agent, raises
Material storage agent and Chinese herb feed additive；The medicated feed additive includes but not limited to have prevention Animal diseases, promote
Growth of animal acts on and can add the veterinary drug premixing substance for using and mixing carrier or diluent for a long time in feed.
Further, the feeding composition may include feedstuff, and the feedstuff is added selected from non-feed
The feeding substances such as animal, plant, microorganism or the mineral available for processing and fabricating feed of agent.
In some embodiments, the feeding composition for additive premix, concentrated feed, mixed feed or
Concentrate supplement.
The feed addictive premixed feed, refers to mineral trace element, vitamin, microorganism, amino acid
In based on more than any two class or two classes nutritional feed additive, with butyryl glutamate derivatives provided by the invention or its
The homogeneous mixture that his feed addictive, carrier and (or) diluent are prepared according to a certain percentage, wherein nutritional feed add
The content of agent disclosure satisfy that it is applicable in the basic nutrition demand of the specific physiological stage of animal, mixed feed, concentrate supplement or
Additive amount in animal drinking water is not less than 0.1% and not higher than 10%.
The animal feed can be prepared according to different animals according to method well known in the art, for example, can include with
It is one or more in lower ingredient：Corn, sorghum, wheat, barley, soybean, pea, the flesh of fish, dairy produce, fat and oil, dimension life
Element and minerals etc..
The concentrated feed refers to the feeding for mainly having protein, minerals and feed addictive to prepare according to a certain percentage
Material.
The mixed feed refers to according to cultivated animals nutritional need, by a variety of feedstuffs and feed addictive according to
The feed that certain proportion is prepared.
The concentrate supplement refers to the nutrition to supplement plant-eating animal, and a variety of feedstuffs and feed addictive are pressed
The feed prepared according to certain proportion.
The invention further relates to the preparation process of the feeding composition, including weigh raw material and auxiliary material, the mixing of mixing unit,
The process of granulation, quality inspection and packaging.
Description of the drawings
Fig. 1 is the preparation technology flow chart of hybrid particle feed addictive, and * represents critical control point.
Specific embodiment：
In order to make the purpose , technical scheme and advantage of the present invention be clearer, by the following examples to the present invention
Compound, composition and application be described in further detail.It should be appreciated that specific embodiment described herein is only used
In explaining the present invention, it is not intended to limit the present invention.
First, the preparation of butyryl glutamate derivatives：
1 butyryl glutamic acid of embodiment
In 2L three-necked flasks, the NaOH aqueous solutions 850mL of Pidolidone 200.34g (1.36mol, 1eq), 4M are sequentially added
Butyric anhydride 215.44g (1.36mol, 1eq.) is added dropwise after stirring 0.5 hour at room temperature, so in (136.00g, 3.40mol, 2.5eq)
The NaOH aqueous solutions that 4M is added dropwise again afterwards are adjusted to pH8~9, and TLC monitoring reaction is to terminal.In reaction solution be added dropwise concentrated hydrochloric acid adjust to
Behind pH2~3, ethyl acetate extraction (1L × 3) merges organic phase.Organic phase anhydrous sulphur after saturated common salt water washing (1L × 3)
The drying of sour sodium, be concentrated under reduced pressure crude product is colourless transparent liquid, and be cooled to 0 DEG C of crystallization, filter, filter residue is washed with normal heptane
(100mL × 3), be dried in vacuum overnight at 40 DEG C product (butyryl glutamic acid) is white solid, yield 237.97g, yield is
79.86%.LC-MS(ESI,neg.ion)m/z:216[M-H]-；1HNMR(400MHz,d6-DMSO):δ(ppm)0.85(t,
3H),1.51(m,2H),1.76(m,1H),1.95(m,1H),2.09(t,2H),2.26(t,2H),4.19(td,1H),8.02
(d,1H),12.34(s,2H)。
Embodiment 2N- bytyries-Pidolidone diethylester
Step 1：The synthesis of the double carbethoxy hydrochlorides of Pidolidone
Absolute ethyl alcohol 320mL (5.48mol, 40eq) is added in into 1000mL single port bottles, subzero 10 DEG C are cooled to, to reaction
Thionyl chloride 28mL (378.92mmol, 2.8eq) is slowly added dropwise in system.It is added dropwise, reaction solution is at subzero 10 DEG C of constant temperature
It is stirred to react 1 hour, then Pidolidone 20.08g (136.48mmol, 1eq) is added in into reaction system.Reaction solution is at room temperature
Stirring 2 hours then raises temperature to 80 DEG C of reactions, and TLC monitoring reaction is to terminal.Reaction solution, which is concentrated under reduced pressure, removes solvent, in refrigerator
Cooling crystallization adds in after ethyl acetate (150mL × 3) washs and filters separation, is dried to obtain product (the double ethyl esters of Pidolidone
Salt) for white solid 25.44g, yield 77.76%.LC-MS(ESI,pos.ion)m/z:204[M-Cl]+；1HNMR(400MHz,
D2O):δ(ppm)1.20(t,3H),1.25(t,3H),2.19(m,2H),2.58(m,2H),4.12(m,3H),4.24(q,2H).
Step 2：The synthesis of N- bytyries-Pidolidone diethylester
The double carbethoxy hydrochlorides of 25.44g (106.13mmol, 1eq) Pidolidone are weighed in 500mL single port bottles, are added in
150mL dichloromethane dissolves, and adds 26.93g (266.13mmol, 2.5eq) triethylamine, is cooled to 0 DEG C, subsequent 17.07g
(160.21mmol, 1.5eq) butyl chloride is dissolved in 50mL dichloromethane, and being slowly added dropwise makes temperature of reaction system at 0 DEG C or so, drop
It after adding, is stirred 1 hour in 0 DEG C, then room temperature reaction 2 hours, stops reaction.The quenching of 100mL water is added in reaction system
Reaction detaches organic phase, and water phase is extracted (100mL × 2) with dichloromethane, merges organic phase, organic phase washed with water (300mL
× 3) it is dried 30 minutes with saturated salt solution (300mL × 3) washing, anhydrous sodium sulfate, N- bytyry-L- paddy ammonia is concentrated under reduced pressure to obtain
Diethyl phthalate is colourless liquid, yield 16.00g, yield 55.36%.LC-MS(ESI,pos.ion)m/z:274.2[M+H]+；1HNMR(400MHz,CDCl3):δ(ppm)0.97(t,3H),1.26(t,3H),1.30(t,3H),1.68(m,2H),2.00(m,
2H),2.21(m,3H),2.40(m,2H),4.14(q,2H),4.21(q,2H),4.62(td,1H),6.19(d,1H)。
The double N-butyls of embodiment 3N- bytyries-Pidolidone
Step 1：The synthesis of the double N-butyl hydrochlorides of Pidolidone
N-butanol 403.03g (5.44mol, 40eq) is added in into 1000mL single port bottles, subzero 10 DEG C are cooled to, to reaction
Thionyl chloride 45.28g (380.62mmol, 2.8eq) is slowly added dropwise in system.It is added dropwise, subzero 10 DEG C in constant temperature of reaction solution
Under be stirred to react 1 hour, then into reaction system add in Pidolidone 20.00g (135.93mmol, 1eq).Reaction solution is in room temperature
Lower stirring 2 hours then raises temperature to 85 DEG C of reactions, and TLC monitoring reaction is to terminal.Reaction solution, which is concentrated under reduced pressure, removes solvent, Yu Bing
Case cooling crystallization adds in after ethyl acetate (150mL × 3) washs and filters separation, is dried to obtain product (the double N-butyls of Pidolidone
Hydrochloride) for white solid 22.06g, yield 62.33%.LC-MS(ESI,pos.ion)m/z:260.1[M-Cl]+。
Step 2：The synthesis of the double N-butyls of N- bytyries-Pidolidone
The double N-butyl hydrochlorides of 22.00g (74.37mmol, 1eq) Pidolidone are weighed in 500mL single port bottles, are added in
150mL dichloromethane dissolves, and adds 18.81g (185.93mmol, 2.5eq) triethylamine, is cooled to 0 DEG C, subsequent 11.89g
(111.56mmol, 1.5eq) butyl chloride is dissolved in 50mL dichloromethane, and being slowly added dropwise makes temperature of reaction system at 0 DEG C or so, drop
It after adding, is stirred 1 hour in 0 DEG C, then room temperature reaction 2 hours, stops reaction.The quenching of 100mL water is added in reaction system
Reaction detaches organic phase, and water phase is extracted (100mL × 2) with dichloromethane, merges organic phase, organic phase washed with water (300mL
× 3) it is dried 30 minutes with saturated salt solution (300mL × 3) washing, anhydrous sodium sulfate, N- bytyry-L- paddy ammonia is concentrated under reduced pressure to obtain
Sour double N-butyls are colourless liquid, yield 14.11g, yield 57.58%.LC-MS(ESI,pos.ion)m/z:330.3[M+H
]+。
The double N-butyls of embodiment 4N- bytyries-D-Glu
Preparation process is the same as embodiment 2.
Glutamic acid used in step 1 is D-Glu, and reaction product is white solid, yield 20.27g, and yield is
57.28%.LC-MS(ESI,pos.ion)m/z:260.0[M-Cl]+。
The double N-butyls of reaction product N- bytyries-D-Glu of step 2 are colourless liquid, yield 14.48g, yield
It is 59.11%.LC-MS(ESI,pos.ion)m/z:330.4[M+H]+。
The double just own esters of embodiment 5N- bytyries-Pidolidone
Step 1：The synthesis of the double just own ester hydrochlorides of Pidolidone
N-hexyl alcohol 41.67g (407.8mmol, 3.0eq) and toluene 400mL is sequentially added into 1000mL single port bottles, is cooled down
To subzero 10 DEG C, thionyl chloride 45.28g (380.62mmol, 2.8eq) is slowly added dropwise into reaction system.It is added dropwise, reacts
Liquid is stirred to react 1.5 hours for subzero 10 DEG C in constant temperature, then add in into reaction system Pidolidone 20.00g (135.93mmol,
1eq).Reaction solution is stirred at room temperature 2 hours, then raises temperature to 85 DEG C of reactions, TLC monitoring reaction is to terminal.Reaction solution depressurizes
Concentration removes solvent, in refrigerator cooling crystallization, adds in after ethyl acetate (150mL × 3) washs and filters separation, be dried to obtain product
For white solid (the double just own ester hydrochlorides of Pidolidone) 32.88g, yield 68.74%.LC-MS(ESI,pos.ion)m/z:
316.4[M-Cl]+。
Step 2：The synthesis of the double just own esters of N- bytyries-Pidolidone
The double just own ester hydrochlorides of 22.00g (62.52mmol, 1.0eq) Pidolidone are weighed in 1000mL single port bottles, are added
Enter the dissolving of 200mL dichloromethane, add triethylamine 15.82g (156.29mmol, 2.5eq), be cooled to 0 DEG C, subsequent 9.99g
(93.77mmol, 1.5eq) butyl chloride is dissolved in 50mL dichloromethane, and being slowly added dropwise makes temperature of reaction system at 0 DEG C or so, drop
It after adding, stirs 1 hour in 0 DEG C, then reacts at room temperature, TLC monitoring reaction to reaction end.It is added in reaction system
The quenching reaction of 100mL water, detaches organic phase, and water phase is extracted (100mL × 2) with dichloromethane, merges organic phase, organic phase is successively
It is washed with water (400mL × 3) and saturated salt solution (400mL × 3), anhydrous sodium sulfate is dried 30 minutes, and N- fourths are concentrated under reduced pressure to obtain
The double just own esters of acyl group-Pidolidone are colourless liquid, yield 14.98g, yield 62.17%.LC-MS(ESI,pos.ion)m/z:
386.6[M+H]+。
The double n-octyls of embodiment 6N- bytyries-Pidolidone
Preparation scheme is the same as embodiment 4.
The raw material put into successively in step 1 is n-octyl alcohol 53.11g (407.8mmol, 3.0eq), toluene 420mL, dichloro Asia
Sulfone 45.28g (380.62mmol, 2.8eq) and Pidolidone 20.00g (135.93mmol, 1eq), product Pidolidone are double just pungent
Ester hydrochloride is gray solid, yield 38.76g, yield 69.89%.LC-MS(ESI,pos.ion)m/z:372.5[M-Cl]+。
The raw material put into successively in step 2 be the double n-octyl hydrochloride 22.00g (53.92mmol, 1.0eq) of Pidolidone,
300mL dichloromethane, triethylamine 13.64g (134.80mmol, 2.5eq) and 8.62g (80.88mmol, 1.5eq) butyl chloride, production
The double n-octyls of object N- bytyries-Pidolidone are pale yellow oil, yield 16.96g, yield 71.20%.LC-MS(ESI,
pos.ion)m/z:442.4[M-H]+。
The double lauryls of embodiment 7N- bytyries-Pidolidone
Preparation scheme is the same as embodiment 4.
The raw material put into successively in step 1 be laruyl alcohol 53.19g (285.46mmol, 2.1eq), tetrahydrofuran 420mL,
Thionyl chloride 45.28g (380.62mmol, 2.8eq) and Pidolidone 20.00g (135.93mmol, 1eq), product Pidolidone
Bimonthly osmanthus ester hydrochloride be white solid, yield 41.48g, yield 58.65%.LC-MS(ESI,pos.ion)m/z:484.9
[M-Cl]+。
The raw material put into successively in step 2 be the bimonthly osmanthus ester hydrochloride 22.00g (42.29mmol, 1.0eq) of Pidolidone,
300mL dichloromethane, triethylamine 10.70g (105.72mmol, 2.5eq) and 6.76g (63.43mmol, 1.5eq) butyl chloride, production
The double lauryls of object N- bytyries-Pidolidone are yellow oil, yield 12.80g, yield 54.67%.LC-MS(ESI,
pos.ion)m/z:554.9[M-H]+。
The double palm esters of embodiment 8N- bytyries-Pidolidone
Preparation scheme is the same as embodiment 4.
The raw material put into successively in step 1 be palmityl alcohol 79.75g (328.96mmol, 2.1eq), tetrahydrofuran 450mL,
Thionyl chloride 45.28g (380.62mmol, 2.8eq) and Pidolidone 20.00g (135.93mmol, 1.0eq), product L- paddy ammonia
Sour double palm ester hydrochlorides are faint yellow solid, yield 60.06g, yield 63.51%.LC-MS(ESI,pos.ion)m/z:
583.1[M-Cl]+。
The raw material put into successively in step 2 be the double palm ester hydrochloride 22.00g (34.79mmol, 1.0eq) of Pidolidone,
300mL dichloromethane, triethylamine 8.80g (86.96mmol, 2.5eq) and 5.56g (52.18mmol, 1.5eq) butyl chloride, product
For yellow solid, the double palm esters of yield N- bytyries-Pidolidone are 11.27g, yield 48.63%.LC-MS(ESI,
pos.ion)m/z:667.1[M-H]+。
Embodiment 9N- bytyries-Pidolidone mono ethyl ester
Step 1：The preparation of Pidolidone mono ethyl ester
Pidolidone 50.10g (340.52mmol, 1.0eq) is dissolved in ethyl alcohol 473.4g (10.28mol, 30.2eq), cold
But to 0 DEG C, concentrated sulfuric acid 46.00g (469.01mmol, 1.4eq) being added dropwise, is added dropwise, cooled to room temperature reaction is stayed overnight,
TLC monitoring reaction is to terminal.Reaction solution is cooled to 0~5 DEG C, and triethylamine is added dropwise to pH7~8, is added dropwise and continues to stir at room temperature
It mixes 2 hours, filters, filter cake ethanol water (ethanol/water (v:V)=4:1,250mL) it is filtered after recrystallizing, filter residue is at 40 DEG C
Under be dried in vacuum overnight product Pidolidone mono ethyl ester be white solid, yield 43.00g, yield 72.08%.LC-MS
(ESI,pos.ion)m/z:176[M+H]+；1HNMR(400MHz,CDCl3):δ(ppm)1.16(t,3H),2.07(m,2H),
2.47(m,2H)),3.68(t,1H),4.14(q,2H),4.08(q,2H)。
Step 2：The preparation of N- bytyries-Pidolidone mono ethyl ester
Pidolidone mono ethyl ester 2.01g (11.47mmol, 1.0eq) is added in 10mL glacial acetic acids, is stirred to dissolve, after
It is continuous to add in butyric anhydride 2.20g (13.91mmol, 1.2eq), it is stirred to react at room temperature overnight, TLC monitoring reaction is to terminal.Reaction
Liquid is concentrated under reduced pressure removing reaction dissolvent and obtains pale yellow oil, through reversed silica gel column chromatography (methanol/water (v:V)=4:1) production
Object N- bytyries-Pidolidone mono ethyl ester be colorless oil, yield 1.98g, yield 70.36%.LC-MS(ESI,
neg.ion)m/z:244.4[M-H]-。
Embodiment 10N- bytyries-Pidolidone mono-n-butylester
Preparation method is the same as embodiment 8.
The raw material that step 1 is put into successively is Pidolidone 50.10g (340.52mmol, 1.0eq), n-butanol 640.0g
(8.51mol, 25.0eq) and concentrated sulfuric acid 46.00g (469.01mmol, 1.4eq), product Pidolidone mono-n-butylester are solid for white
Body, yield 60.0g, yield 73.10%.LC-MS(ESI,pos.ion)m/z:204.1[M+H]+。
The raw material that step 2 is put into successively is glacial acetic acid 20mL, Pidolidone mono-n-butylester 5.01g (24.60mmol, 1.0eq)
With butyric anhydride 4.67g (29.52mmol, 1.2eq), reversed silica gel column chromatography (methanol/water (v in post processing:V)=9:2) production
Object N- bytyries-Pidolidone mono-n-butylester be colorless oil, yield 4.49g, yield 66.77%.LC-MS(ESI,
neg.ion)m/z:272.2[M-H]-。
Embodiment 11N- bytyries-Pidolidone mono octyl ester
Preparation method is the same as embodiment 8.
The raw material that step 1 is put into successively be N,N-dimethylformamide 300mL, Pidolidone 50.10g (340.52mmol,
1.0eq), n-octyl alcohol 53.21g (408.62mmol, 1.2eq) and concentrated sulfuric acid 46.80g (476.72mmol, 1.4eq), product L-
Glutamic acid mono octyl ester be white solid, yield 61.41g, yield 69.54%.LC-MS(ESI,pos.ion)m/z:260.3
[M+H]+。
The raw material that step 2 is put into successively is glacial acetic acid 20mL, Pidolidone mono octyl ester 5.01g (19.28mmol, 1.0eq)
With butyric anhydride 3.66g (23.14mmol, 1.2eq), reversed silica gel column chromatography (methanol/water (v in post processing:V)=5:1) production
Object N- bytyries-Pidolidone mono octyl ester be white solid, yield 3.54g, yield 55.70%.LC-MS(ESI,
neg.ion)m/z:328.2[M-H]-。
Embodiment 12N- bytyries-Pidolidone list lauryl
Preparation method is the same as embodiment 8.
The raw material that step 1 is put into successively be N,N-dimethylformamide 300mL, Pidolidone 50.00g (339.84mmol,
1.0eq), laruyl alcohol 75.99g (407.80mmol, 1.2eq) and concentrated sulfuric acid 46.7g (475.8mmol, 1.4eq), product L- paddy
Propylhomoserin list lauryl be faint yellow solid, yield 62.5g, yield 58.3%.LC-MS(ESI,pos.ion)m/z:316.2
[M+H]+。
The raw material that step 2 is put into successively be glacial acetic acid 20mL, Pidolidone list lauryl 5.00g (15.85mmol,
1.0eq) and butyric anhydride 3.01g (19.02mmol, 1.2eq), reversed silica gel column chromatography (methanol/water (v in post processing:V)=5:
1) product N- bytyries-Pidolidone list lauryl be white solid, yield 4.12g, yield 67.40%.LC-MS
(ESI,neg.ion)m/z:384.3[M-H]-。
Embodiment 13N- bytyries-Pidolidone list palm ester
Preparation method is the same as embodiment 8.
The raw material that step 1 is put into successively be N,N-dimethylformamide 300mL, Pidolidone 50.00g (339.84mmol,
1.0eq), palmityl alcohol 98.87g (407.80mmol, 1.2eq) and concentrated sulfuric acid 46.7g (475.8mmol, 1.4eq), product L- paddy
Propylhomoserin list palm ester be faint yellow solid, yield 76.0g, yield 60.2%.LC-MS(ESI,pos.ion)m/z:372.3
[M+H]+。
The raw material that step 2 is put into successively be glacial acetic acid 30mL, Pidolidone list palm ester 5.00g (13.46mmol,
1.0eq) and butyric anhydride 2.55g (16.15mmol, 1.2eq), reversed silica gel column chromatography (methanol/water (v in post processing:V)=6:
1) product be white solid, yield N- bytyries-Pidolidone list palm ester be 3.1g, yield 52.1%.LC-MS
(ESI,neg.ion)m/z:440.4[M-H]-。
Feeding preparation method of composition：
The butyryl glutamate derivatives of embodiment 1~13 are mixed with corresponding hybrid particle with corresponding auxiliary material respectively
Feed addictive.
1. material
Raw material：Any butyryl glutamate derivatives, butyryl glutamic acid, butyric acid, the paddy ammonia of 1~embodiment of embodiment 13
Acid；
Carrier：Cornstarch；
Adhesive：1.3% hydroxypropyl methyl cellulose aqueous solution.
2. product formula
The formula of the hybrid particle feed addictive of 1 butyryl glutamate derivatives of table
3. production technology
The production technology of hybrid particle feed addictive of the present invention is illustrated below in conjunction with Fig. 1.
Raw material supply：Research and development centre of Guangzhou Insighter Biotechnology Co., Ltd. verifies as qualified products through product control portion, pure
Degree >=99%.
Auxiliary material is purchased：Auxiliary material is purchased at qualified supplier, is sampled after auxiliary material to factory, through examining qualification that can be put in storage, is deposited
Put it is spare, this process be critical control point, it is necessary to stringent control auxiliary material quality.
Production neck material weighs：According to the ratio of product formula, raw material and auxiliary material carrier are weighed and checked successively, to production
The unified storage of raw waste (packaging bag), processing.
Mixing：Raw material and auxiliary material input mixing unit are uniformly mixed, this step is critical control point, it is necessary to stringent control
Incorporation time periodically verifies mixture homogeneity.Mixing machine reduces dust equipped with pulse dust collector.
Granulation：By raw material and the mixed product of auxiliary material and 1.3% hydroxypropyl methyl cellulose aqueous solution according to 100:35
Mass ratio input granulator in, start mixing and cutter operation 3-5min, material pelletization it is good after into fluidized bed progress
It is dry, 16 mesh screens are crossed after 30min.
Packaging and inspection：Packing of weighing is carried out according to packing specification, is stored in finished bin, identifies production batch and test status
Etc. information, each production batch at least inspect two parts of samples by random samples and laboratory sent exfactory inspection and keep sample.After the assay was approved can
Manufacture.Thus each hybrid particle feed addictive is obtained.
Production equipment is cleaned：It is finished per a batch production, it is necessary to which production area is cleaned.Kind is produced when replacing
When, it is necessary to carrier-mediated transport removal of impurities is carried out to production equipment, prevents cross contamination.
2nd, animal-breeding is tested：
Application effect of the embodiment A different feeds additive in broiler chicken material
Experiment selects 22 ages in days, average weight 145g, three yellow-feather broilers similar in weight using single-factor Random Design
480,4 processing groups are randomly divided into, every group of 6 repetitions, male and female is fifty-fifty, each repeats 20 three yellow-feather broilers.It is right before experiment
Henhouse and utensil carry out disinfection.Experimental period, carries out carry out cage under the same feeding and management condition of same henhouse.Basal diet with
Based on Corn-soybean, entire feeding process does not add other antioxidant contents and growth accelerator additionally.Each test group is respectively pair
According to group, 1~3 group of experiment.Wherein control group only gives basal diet, and 1~3 group of experiment is added in basal diet respectively
Hybrid particle feed addictive reference substance 1 (glutamic acid) provided by the invention, reference substance 2 (butyric acid) and the product 1 of 2000ppm
(butyryl glutamic acid).Totally 20 days experimental period, test chicken free water and feeding, day feeding 2 times.As unit of each repetition, in
42 ages in days weigh and (stop expecting 12h, not cut off the water), statistical test chicken feed consumption rate, calculate the average daily gain of each group test chicken
(ADFI), average daily gain (ADG) and feedstuff-meat ratio (FCR).Test data is for statistical analysis using SPSS18 softwares, first logarithm
According to making one-way analysis of variance (ANOVA), if significant difference between processing, then carry out Multiple range test, conspicuousness with Duncan's methods
Level is 0.05.Result of the test represents that result of the test is as shown in table 3 with " average value ± standard error ".As can be known from the results, 1 is tested
The average daily gain of 2 groups of test chickens of group and experiment and average daily gain have different degrees of raising, but feedstuff-meat ratio declines
Unobvious；The average daily gain for testing 3 groups of test chicken is similar to control group, and average daily gain is improved, and feedstuff-meat ratio declines
5.26%.
3 different feeds Additive On Chickens production performance of table influences result
| Test sample | Experiment quantity | ADFI(g) | ADG(g) | FCR | |
| Control group | - | 20*6 | 623.00±9.24 | 205.00±4.80 | 3.04±0.05 |
| Test 1 group | Reference substance 1 | 20*6 | 678.50±9.14 | 226.33±2.86 | 3.00±0.03 |
| Test 2 groups | Reference substance 2 | 20*6 | 663.83±10.60 | 220.00±3.18 | 3.02±0.01 |
| Test 3 groups | Product 1 | 20*6 | 623.50±13.63 | 216.33±2.24 | 2.88±0.02 |
Application effect of the embodiment B butyryl glutamate derivatives in broiler chicken material
Experiment selects 22 ages in days, average weight 153g, three yellow-feather broilers similar in weight using single-factor Random Design
1680,14 processing groups are randomly divided into, every group of 6 repetitions, male and female is fifty-fifty, each repeats 20 three yellow-feather broilers.Before experiment
It carries out disinfection to henhouse and utensil.Experimental period, carries out carry out cage under the same feeding and management condition of same henhouse.Basal diet
Based on Corn-soybean, entire feeding process does not add other antioxidant contents and growth accelerator additionally.Each test group is respectively
Control group, 1~13 group of experiment.Wherein control group only gives basal diet, and 1~13 group of experiment is added in basal diet respectively
The hybrid particle feedstuff additive product 1~13 of the butyryl glutamate derivatives provided by the invention of 2000ppm.Experimental period, is total to
20 days, test chicken free water and feeding, day feeding 2 times.As unit of each repetition, statistical test chicken diarrhea rate；On 42nd
Age weighs and (stops expecting 12h, not cut off the water), and statistical test chicken feed consumption rate calculates the average daily gain (ADFI) of each group test chicken, puts down
Equal daily gain (ADG) and feedstuff-meat ratio (FCR).Test data is for statistical analysis using SPSS18 softwares, first makees Dan Yin to data
Plain variance analysis (ANOVA), if significant difference between processing, then Multiple range test is carried out with Duncan's methods, significance is
0.05.Result of the test represents that result of the test is as shown in table 4 with " average value ± standard error ".As can be known from the results, with blank control group
It compares, butyryl glutamic acid product can improve the feed intake of test chicken but not significantly, and butyryl glutamate derivatives are to experimental chicken
Average daily gain is without influence；Butyryl glutamic acid and its derivative on the feed intake of test chicken without influence under the premise of can be notable
Raising test chicken average daily gain and feedstuff-meat ratio is made to reduce 4.6%~13.7%, while the diarrhea rate of test chicken obtains
Effective control.
4 butyryl glutamate derivatives of table influence result to meat chicken production performance
Application study of the embodiment C butyryl glutamate derivatives in pig feed
The miscellaneous lean meat species piggy 390 of 65 age in days Ternary Pig ternarys similar in weight, is randomly divided into 13 processing groups, every group 3
A repetition, male and female is fifty-fifty, every group 10.It carries out disinfection before experiment to pigsty and utensil.Experimental period, is in the same raising of same pigsty
Subfield stable breeding under management condition.During experiment, be freely eaten and drunk water with test pig, day feeding 2 times.Each test group is respectively pair
According to 1~12 group of group and experiment.Wherein, control group only gives basal diet, and 1~12 group of experiment is given respectively respectively in basal diet
The hybrid particle feedstuff additive product 1~13 of the butyryl glutamate derivatives provided by the invention of middle addition 2500ppm.It is whole
A each test group of feeding process does not add other antioxidant contents and growth accelerator additionally.28 days test periods, with each repetition
For unit, the production performance of statistical test pig, respectively average daily gain (ADFI), average daily gain (ADG), feedstuff-meat ratio
(FCR) and diarrhea rate.Result of the test is as shown in table 5.Test data is for statistical analysis using SPSS18 softwares, and first data are made
One-way analysis of variance (ANOVA), if significant difference between processing, then carry out Multiple range test, significance with Duncan's methods
It is 0.05.Result of the test represents that result of the test is as shown in table 5 with " average value ± standard error ".As can be known from the results, butyryl paddy is given
Compared with the control group, the feed intake of test pig does not have significantly affected, but average daily gain to the test group of threonine derivative
Feedstuff-meat ratio has dropped 7.6%~12.5% while significant raising, and in addition diarrhea rate has dropped 10.0%~30.9%.
5 butyryl glutamate derivatives of table influence the production performance of pig
| Test sample | Experiment quantity | ADFI(kg) | ADG(kg) | FCR | Diarrhea rate/% | |
| Control group | - | 10*3 | 11.87±0.32 | 4.51±0.08 | 2.63±0.02 | 32.33±1.45 |
| Test 1 group | Product 2 | 10*3 | 12.73±0.33 | 5.23±0.06 | 2.43±0.03 | 27.00±0.58 |
| Test 2 groups | Product 3 | 10*3 | 12.40±0.26 | 5.23±0.12 | 2.37±0.01 | 26.00±0.58 |
| Test 3 groups | Product 4 | 10*3 | 12.77±0.20 | 5.42±0.09 | 2.36±0.01 | 25.00±0.58 |
| Test 4 groups | Product 5 | 10*3 | 12.53±0.32 | 5.42±0.16 | 2.31±0.01 | 23.00±0.58 |
| Test 5 groups | Product 6 | 10*3 | 12.53±0.27 | 5.45±0.15 | 2.30±0.02 | 22.00±0.58 |
| Test 6 groups | Product 7 | 10*3 | 12.43±0.43 | 5.40±0.21 | 2.30±0.01 | 19.33±0.33 |
| Test 7 groups | Product 8 | 10*3 | 12.500.38 | 5.40±0.19 | 2.31±0.01 | 19.00±0.58 |
| Test 8 groups | Product 9 | 10*3 | 12.70±0.26 | 5.16±0.13 | 2.46±0.02 | 27.00±0.58 |
| Test 9 groups | Product 10 | 10*3 | 12.60±0.66 | 5.19±0.25 | 2.43±0.01 | 26.00±0.58 |
| Test 10 groups | Product 11 | 10*3 | 12.33±0.34 | 5.22±0.12 | 2.42±0.01 | 24.00±0.58 |
| Test 11 groups | Product 12 | 10*3 | 12.27±0.22 | 5.24±0.09 | 2.36±0.02 | 23.00±0.58 |
| Test 12 groups | Product 13 | 10*3 | 12.47±0.61 | 5.33±0.26 | 2.34±0.01 | 22.00±0.58 |
Application effect of the embodiment D butyryl glutamate derivatives in meat duck material
Experiment selects 20 ages in days, average weight 1300g, Cherry Village Duckss similar in weight using single-factor Random Design
1560,13 processing groups are randomly divided into, every group of 6 repetitions, male and female is fifty-fifty, each to repeat 20.To duck shed and device before experiment
Tool carries out disinfection.Experimental period, carries out carry out cage under the same feeding and management condition of same duck shed.Basal diet is with corn-cottonseed
Based on the dregs of rice, entire feeding process does not add other antioxidant contents and growth accelerator additionally.Each test group is respectively control group, examination
Test 1~12 group.Wherein control group only gives basal diet, and the sheet of 2000ppm is added in 1~12 group of experiment in basal diet respectively
The hybrid particle feedstuff additive product 2~13 of the butyryl glutamate derivatives provided is provided.Totally 28 days experimental period, tested duck
Free water and feeding, day feeding 2 times.As unit of each repetition, weigh in 48 ages in days and (stop expecting 12h, not cut off the water), statistics examination
Duck feed consumption rate is tested, calculates average daily gain (ADFI), average daily gain (ADG) and the feedstuff-meat ratio (FCR) of each group experiment duck.Examination
It is for statistical analysis using SPSS18 softwares to test data, first data are made with one-way analysis of variance (ANOVA), if difference between processing
Significantly, then with Duncan's methods Multiple range test, significance 0.05 are carried out.Result of the test is with " average value ± standard error " table
Show, result of the test is as shown in table 6.As can be known from the results, butyryl glutamate derivatives are to living in the meat duck under identical rearing conditions
The change of production performance be very significant compared with the control group, show significantly improving and feedstuff-meat ratio for average daily gain
Aspect is remarkably decreased, illustrates that the addition of butyryl glutamate derivatives can significantly improve feed in the basal diet of meat duck
Conversion ratio.
Influence result of the 6 butyryl glutamate derivatives of table to meat duck production performance
Application of the embodiment E butyryl glutamate derivatives in aquatic products material
(1) test material
Fish is used in experiment：Test fish used be grass carp, current year fingerling, by Huizhou great Feng fish seeding grounds.Bouncing,
The consistent Grass carp of specification (4 × 2 × 1.5m in large cage3) after raising 4 weeks just for formal culture experiment, experimental system is
Buoyancy small-sized net cage (1.1 × 1.1 × 1.1m of specification3), each small-sized net cage is put there are one pneumatic head, is inflated for 24 hours daily.Small-sized net cage
One, test site 3500m is placed in temporary net cage of supporting2Pond in, the pond depth of water~1.5m, pond water for fully aeration under
Water.During experiment, 624 tail of black carp of hungry 1d is randomly divided into 13 groups, every group sets 4 repetitions, each to repeat to put 12 tail fishes, whole
It is put at random after weighing in 52 net cages, feeds different test feeds respectively.
Test feed：Experiment is matched with feed by the formula of table 7 voluntarily prepares, and different tests group is separately added into identical dose by table 8
The different butyryl glutamate derivatives of amount.Grain is made by the puffing unit of Jiangsu shepherd after ultramicro grinding in feeds utilized raw material
Diameter 3mm buoyancy expanding feeds, 130 DEG C of mold clearing temperature, by spraying 3% soya-bean oil outside fuel injection equipment, shady place is sealed spare.
7 experiment of table feed of grass carp formula and chemical composition (%wt.)
| Raw material forms | Content (%) | Raw material forms | Content (%) |
| Fish meal | 9.0 | Soya-bean oil | 3.0 |
| Casing powder | 3.0 | Phosphatide rapeseed meal | 9.0 |
| Dregs of beans | 12.0 | Gluten | 4.0 |
| Rapeseed meal | 12.0 | Blood cell powder | 2.0 |
| Monosodium glutamate albumen | 3.0 | Vc- phosphates | 0.1 |
| Wheat-middlings | 12.6 | Calcium dihydrogen phosphate | 1.8 |
| Flour | 17.0 | Choline chloride | 0.2 |
| Bentonite | 0.70 | Multidimensional | 0.1 |
| Rice bran | 10.0 | Micro- ore deposit pre-mixing agent | 0.5 |
The growth promotion experiment grouping of 8 butyryl glutamate derivatives of table
(2) test method
Trial：Experiment uses artificial limit food to feed, and feeding amount adjusts weekly once, and every group feeds horizontal (press initial
Weight) it is completely the same, twice (7 are fed daily:30 and 15:00).Experiment 8 weeks by a definite date.Water quality is supervised in timing during experiment
Control cultivates whole 26.88 ± 3.08 DEG C of water temperature, DO>5.0mg O L-1, pH 7.8, ammonia nitrogen<0.50mg N L-1, nitrite
Nitrogen<0.05mg N L-1。
Parametric statistics：During experiment, stop weighing to each net cage fish progress entirety after feeding 1d, calculate its rate of body weight gain (WG, %), raise
Expect coefficient (FCR) and survival rate (SR, %).Calculation formula is as follows：
Rate of body weight gain (WG, %)=100 × (average end weight-average initial weight)/average initial weight；
Feed coefficient (FCR)=food ration/weight gain；
Fish quantity during fish quantity/on-test during survival rate (SR, %)=100 × off-test.
(3) result of the test
The growth promotion result of the test of butyryl glutamate derivatives is shown in Table 9.As a result display is added to butyryl glutamate derivatives
Test group increase weight and feed coefficient in terms of be superior to not add the blank control groups of butyryl glutamate derivatives, have apparent
Growth enhancing effect.
Application test result of the 9 butyryl glutamate derivatives of table in aquatic products material
Embodiment described above only expresses the several embodiments of the present invention, and also other modes are used for implementing this hair
It is bright.Correspondingly, the embodiment of the present invention is illustratively to illustrate, but can not be therefore interpreted as to the special of the present invention
The limitation of sharp range, it is also possible to the modification made or in the claims within the scope of the present invention and in same inventive concept
The equivalents added.
Claims (10)
1. a kind of butyryl glutamate derivatives or its raceme, stereoisomer, geometrical isomerism of structure as shown in below general formula
Body, tautomer, solvate or the acceptable salt of feed：
Substituent group A and B in formula are each independently H or alkyl, and the alkyl is n-propyl, isopropyl, C5-C20Straight chain
Or branched alkyl, C1-C8Linear chain or branch chain halogenated alkyl or C3-C7Cycloalkyl.
2. butyryl glutamate derivatives according to claim 1 or its raceme, stereoisomer, geometric isomer, mutually
Tautomeric, solvate or the acceptable salt of feed, which is characterized in that the substituent group A and B is simultaneously alkyl.
3. butyryl glutamate derivatives according to claim 1 or its raceme, stereoisomer, geometric isomer, mutually
Tautomeric, solvate or the acceptable salt of feed, which is characterized in that be H during described substituent group A and B differences.
4. butyryl glutamate derivatives according to claim 1 or its raceme, stereoisomer, geometric isomer, mutually
One of tautomeric, solvate or the acceptable salt of feed, which is characterized in that have following structure：
5. claim 1-4 any one of them butyryl glutamate derivatives or its raceme, stereoisomer, geometrical isomerism
The application of body, tautomer, solvate or the acceptable salt of feed in animal feed additive is prepared.
6. application according to claim 5, which is characterized in that the animal includes poultry, domestic animal, aquiculture animal
Or pet.
7. claim 1-4 any one of them butyryl glutamate derivatives or its raceme, stereoisomer, geometrical isomerism
The application of body, tautomer, solvate or the acceptable salt of feed in animal feed is prepared.
8. a kind of feeding composition, which is characterized in that comprising claim 1-4 any one of them butyryl glutamate derivatives,
Or in its raceme, stereoisomer, geometric isomer, tautomer, solvate or the acceptable salt of feed at least
It is a kind of and can feeding auxiliary material.
9. feeding composition according to claim 8, which is characterized in that also comprising feedstuff.
10. feeding composition according to claim 8 or claim 9, which is characterized in that also added comprising additional animal feed
Agent, the additional animal feed additive add selected from nutritional feed additive, general feeds additive or pharmaceutical feed
Add agent.
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| CN111132962A (en) * | 2019-01-11 | 2020-05-08 | 黄华成 | Tryptophan derivative and application thereof |
| CN111629602A (en) * | 2018-11-13 | 2020-09-04 | 黄华成 | Application of acylated derivative of amino acid in preparation of animal feed additive |
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| CN101440042A (en) * | 2008-12-29 | 2009-05-27 | 北京龙科方舟生物工程技术中心 | Preparation of N-carbamylglutamic |
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| CN101440042A (en) * | 2008-12-29 | 2009-05-27 | 北京龙科方舟生物工程技术中心 | Preparation of N-carbamylglutamic |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111629602A (en) * | 2018-11-13 | 2020-09-04 | 黄华成 | Application of acylated derivative of amino acid in preparation of animal feed additive |
| CN111132962A (en) * | 2019-01-11 | 2020-05-08 | 黄华成 | Tryptophan derivative and application thereof |
| CN111132962B (en) * | 2019-01-11 | 2023-09-08 | 彭险峰 | Tryptophan derivative and application thereof |
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