CN107936089A - A kind of method of synthetic styrene-acrylic aminoacyl lysine dipeptides - Google Patents
A kind of method of synthetic styrene-acrylic aminoacyl lysine dipeptides Download PDFInfo
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- CN107936089A CN107936089A CN201711136557.8A CN201711136557A CN107936089A CN 107936089 A CN107936089 A CN 107936089A CN 201711136557 A CN201711136557 A CN 201711136557A CN 107936089 A CN107936089 A CN 107936089A
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- lysine
- phenylalanyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P21/00—Preparation of peptides or proteins
- C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione
Abstract
A kind of method of synthetic styrene-acrylic aminoacyl lysine dipeptides, belongs to peptide symthesis technology field.The present invention is using commercially available phenylalanine and lysine as raw material, by preparing phenylalanine and lysine solution, prepare ethylene glycol non-aqueous reaction medium, prepare phenylalanyl lysine dipeptides reaction solution, prepare the resin column of purification load phenylalanyl lysine dipeptides, prepare phenylalanyl lysine dipeptides eluent, prepare two peptide freeze-dried powder of phenylalanyl lysine, the step of preparing recycling phenylalanine and lysine solution and preparing regenerating resin column, just prepares the phenylalanyl lysine dipeptides that content is 95~98%.The present invention is by the use of chymotrypsin as catalyst synthetic styrene-acrylic aminoacyl lysine dipeptides in ethylene glycol non-aqueous media, and mild condition, specificity is strong, and combined coefficient is high, is typical green production process；The phenylalanyl lysine dipeptides of preparation can be widely used for the fields such as medicine, weaving, food, have considerable social value.
Description
First, technical field
The invention belongs to peptide symthesis technology field, and in particular to a kind of method of synthetic styrene-acrylic aminoacyl-lysine dipeptides.
2nd, background technology
The chain compound that small peptide is made of the amino acid residue of 2-9, many small peptides have important biology work(
Can, it is the newcomer in biological medicine, is also widely used in the fields such as food, health products and chemical product.For example, asparagus fern ammonia
Acyl-phenylalanine dipeptide is exactly important peptides sweetener, is widely used in the fields such as food, cosmetics；In another example phenylpropyl alcohol ammonia
Acyl-lysine dipeptides, into the decomposition through protease after in vivo, generates phenylalanine and lysine, phenylalanine is required ammonia
One of base acid, is the intermediate of the amino acids cancer therapy drugs such as synthetic styrene-acrylic ammonia benzyl, formic acid sarcolycin, and production adrenal gland
The raw material of element, thyroxine and melanin, in field of food, phenylalanine is synthesis health dipeptide sweetener Aspartame
One of raw material, in daily chemicals field, phenylalanine is then as the component for absorbing ultraviolet, in skin care item；Lysine is paddy
The first limiting amino acids in thing, have and improve intelligence, improve a poor appetite, promote calcium uptake and growth, improve memory and exempt from
Epidemic disease power, build up health and other effects, is important nutritional food additive.Therefore method and the production of new synthesis small peptide are researched and developed
Product, have important economic value and application prospect.
The method of existing synthesis dipeptides, such as Application No. 200610095100.2, entitled " analogue of carnosine preparation side
The patent of invention of method ", which disclose a kind of enzymatic synthesis method of analogue of carnosine.Specific method is first to use certain pH
Phosphate buffer solution soaks the substrate l-Alanine being mixed in a certain ratio, 4,5- dicarboxylic acid imidazoles and appropriate enzyme, rear to add
Enter 10mL organic solvents, isothermal reaction is for a period of time under magnetic agitation in jacketed reactor.The defects of this method is：Select four
Hydrogen furans is non-aqueous reaction solvent, in the solvent, the dissolving of substrate l-Alanine and 4,5- dicarboxylic acid imidazole and buffer solution
Spend extremely low, therefore the efficiency of enzymatic is low, it is difficult to realizes industrialization；And tetrahydrofuran is extremely inflammable, toxicity is extremely strong, serious shadow
Health is rung, environmental pollution is also big.
3rd, the content of the invention
The purpose of the present invention is the shortcoming for enzyme' s catalysis small peptide method in existing non-aqueous media, there is provided Yi Zhong
Biological enzyme agent, the method for synthetic styrene-acrylic aminoacyl-lysine dipeptides are utilized in organic media ethylene glycol.What this method used has
Solvent ethylene glycol structure is similar to water, and hydrone can be miscible thus short to substrate amino acid and product with arbitrary proportion with it
The solubility of peptide is big, and in addition the enzyme equilibrium is partial to small peptide compound direction, thus can with high efficiency synthetic styrene-acrylic aminoacyl-
Lysine dipeptides.This method have reaction condition is gentle, easy to operate, yield is high, cost is low, green non-pollution, synthesis production
Thing dipeptides purity is high and the characteristics of easily separated purifying, can be applied to the fields such as medicine, food, weaving.
The present invention cardinal principle be：Enzymatic reaction non-aqueous media refers to organic solvent not aqueous or containing micro-moisture,
In such medium, biocatalyst enzyme can keep the specificity of catalytic reaction and reversal reaction direction under optimum conditions, because
This, the fields such as non-aqueous enzymatic reaction is gradually applied to organic synthesis, material is modified.Ethylene glycol, also known as glycol, chemical formula are
(HOCH2)2, molecular weight 62, is no color or smell, pleasantly sweet liquid, can be mixed with water with arbitrary proportion, polarity is only second to Shui Hejia
The organic solvent of alcohol.Since molecular weight glycol is small, polarity is big, can be by hydrogen bond by large quantity of moisture beamlet as organic solvent
Tie up, theoretically analyze, during used in Enzymatic Reactions in Non-aqueous Media, on the one hand keep the catalytic activity of enzyme, increase substrate and
The amount of dissolving in of product, promotes reaction balance to lift product production rate towards generation product direction；On the other hand, may diffuse to
The activated centre of enzyme, catalytic reaction is participated in the form of hydrone, therefore, high efficiency may occur in ethylene glycol non-aqueous media
Enzymic catalytic reaction.Chymotrypsin is a kind of proteolytic enzyme, in aqueous single-minded catalysis aromatic amino acid carboxylic
Base participates in the peptide bond to be formed, and in non-aqueous organic media, on the basis of still the specificity of catalytic reaction is kept, reverses catalysis anti-
Direction is answered, becomes to catalyze and synthesize the peptide bond that aromatic amino acid carboxyl participates in being formed.Therefore, using the enzyme as catalyst, in second two
, can synthetic styrene-acrylic aminoacyl-lysine dipeptides using phenylalanine and lysine as substrate in alcohol non-aqueous media.
The object of the present invention is achieved like this：A kind of method of synthetic styrene-acrylic aminoacyl-lysine dipeptides, with commercially available phenylpropyl alcohol
Propylhomoserin and lysine are raw material, and using chymotrypsin as catalyst, ethylene glycol is non-aqueous media, by prepare phenylalanine and
Lysine solution, prepares ethylene glycol non-aqueous reaction medium, prepares phenylalanyl-lysine dipeptides reaction solution, prepares purification lotus
The resin column of phenylalanyl-lysine dipeptides is carried, prepares phenylalanyl-lysine dipeptides eluent, prepares phenylalanyl-bad ammonia
Sour two peptide freeze-dried powders, the step of preparing recycling phenylalanine and lysine solution and prepare regenerating resin column, are just prepared
Content is 95~98% phenylalanyl-lysine dipeptides.Its specific processing step is as follows：
(1) phenylalanine and lysine solution are prepared
Successively appropriate commercially available phenylalanine and lysine are dissolved in pure aqueous solution under agitation, just prepare phenylpropyl alcohol
Propylhomoserin concentration is 0.3~1.0mol/L, the aqueous solution of 0.3~2.0mol/L of lysine concentration；Being adjusted again with dilute sodium hydroxide should
The pH value of aqueous solution is 7.5~9.5, that is, prepares phenylalanine and lysine solution, it is non-aqueous to prepare ethylene glycol for lower step
Reaction medium.
(2) ethylene glycol non-aqueous reaction medium is prepared
After the completion of (1) step, phenylalanine and lysine solution prepared by (1) step are mixed with ethylene glycol solution,
Wherein the ratio between volume of phenylalanine and lysine solution and ethylene glycol is 1: 5~25 (L/L), and 1~3h of stir process, that is, make
For ethylene glycol non-aqueous reaction medium is gone out, phenylalanyl-lysine dipeptides reaction solution is prepared for lower step.
(3) phenylalanyl-lysine dipeptides reaction solution is prepared
After the completion of (2) step, vigor is added in ethylene glycol non-aqueous reaction medium prepared by (2) step with stirring is
The chymotrypsin of 1000~1500U/mg, wherein add chymotrypsin quality and phenylalanine and lysine it is total
Mass ratio is 1: 20~50 (kg/kg).Then controlled at 35~45 DEG C, 15~20h is reacted.After the completion of reaction, heating
To 80~90 DEG C, filtered after handling 15~20min, collect filter residue and filtrate respectively.To the filtrate of collection, that is, prepare phenylpropyl alcohol ammonia
Acyl-lysine dipeptides reaction solution, the resin column of purification load phenylalanyl-lysine dipeptides is prepared for lower step.To collection
Filter residue, is washed repeatedly with pure water, and animal feed additive is used to prepare after removing ethylene glycol.
(4) resin column of purification load phenylalanyl-lysine dipeptides is prepared
After the completion of (3) step, phenylalanyl-lysine dipeptides reaction solution prepared by (3) step pure water is first diluted 3
~6 times, then the resin column equipped with 001 × 7 cation exchange resin of activation or D0011 ion exchange resin is pumped into constant flow pump,
The ratio between volume of phenylalanyl-lysine dipeptides reaction solution that wherein prepared by the resin column and (3) step is 1: 30~60 (L/
L), the flow velocity for being pumped into the phenylalanyl-lysine dipeptides reaction solution is 2~6 times of the resin column volume (BV).It is pumped into the phenylpropyl alcohol
After the completion of aminoacyl-lysine dipeptides reaction solution, load phenylalanyl-lysine dipeptides, phenylalanine and bad ammonia is collected respectively
The resin column of acid crosses column liquid with unloading phenylalanyl-lysine dipeptides, phenylalanine and lysine.To the load benzene of collection
The resin column of alanyl-lysine dipeptides, phenylalanine and lysine, is pumped into the pure water washing of 2~6BV, and washing is completed
Collect cleaning solution respectively afterwards and remove the tree of load phenylalanyl-lysine dipeptides, phenylalanine and lysine of ethylene glycol
Fat column.To the cleaning solution of collection, mixed with the column liquid of crossing of collection, be used to prepare recycling ethylene glycol；To the removing ethylene glycol of collection
Load phenylalanyl-lysine dipeptides, phenylalanine and lysine resin column, that is, prepare purification load phenylpropyl alcohol ammonia
The resin column of acyl-lysine dipeptides, phenylalanyl-lysine dipeptides eluent is prepared for lower step.
(5) phenylalanyl-lysine dipeptides eluent is prepared
After the completion of (4) step, in the resin column of the purification load phenylalanyl-lysine dipeptides first prepared to (4) step
The sodium hydroxide solution of 0.1~0.5mol/L is pumped into, elutes phenylalanyl-lysine dipeptides, phenylalanine and lysine, institute
The flow velocity that is pumped into for stating sodium hydroxide solution is 2~4BV/h.Respectively collect 1.5~2.5BV, 3.5~4.5BV, the 5.0th~
The eluent of 6.5BV and the resin column of unloading phenylalanyl-lysine dipeptides, phenylalanine and lysine.Collection is somebody's turn to do
Resin column is unloaded, regenerating resin column is prepared for (8) step；Elution to the 1.5~2.5BV, 5.0~6.5BV of collection
Liquid, recycling phenylalanine and lysine solution are prepared for (7) step；To the eluent of 3.5~4.5BV of collection, i.e.,
Phenylalanyl-lysine dipeptides eluent is prepared, two peptide freeze-dried powder of phenylalanyl-lysine is prepared for lower step.
(6) two peptide freeze-dried powder of phenylalanyl-lysine is prepared
After the completion of (5) step, phenylalanyl-lysine dipeptides eluent prepared by (5) step is pumped into molecular cut off
In the nanofiltration device of 100~200Da, first time nanofiltration to be carried out in the case where gauge pressure is the pressure of 0.1~0.5MPa, until nanofiltration retains
The ratio between volume of liquid and nanofiltration filtered solution stops nanofiltration when reaching 1: 4~5 (L/L), collect respectively first time nanofiltration filtered solution and
Nanofiltration retentate fluid.To the first time nanofiltration retentate fluid of collection, then pure water is added thereto to original volume, received for the second time
Filter, the condition of second of nanofiltration are identical with first time nanofiltration condition.After the completion of second of nanofiltration, second of nanofiltration filter is collected respectively
Cross liquid and trapped fluid.To second of nanofiltration filtered solution of collection, merge with first time nanofiltration filtered solution, adjusted with dilute hydrochloric acid
After pH value is 6.5~7.0, it is pumped into purification tank for liquid waste and carries out biochemical treatment, discharged after up to standard；Second of nanofiltration to collection retains
Liquid, is placed in low temperature refrigerator 6~12h of pre-freeze under conditions of -40~-20 DEG C, transfers in vacuum freeze drier, in temperature
Spend for -50~-40 DEG C, vacuum be 20~50Pa under conditions of carry out 24~36h of freeze-drying, that is, prepare phenylalanyl -
Two peptide freeze-dried powder of lysine, its total recovery rate reach 85~92% in terms of phenylalanine, phenylalanyl-lysine in the freeze-dried powder
Two peptide contents are 95~98%.
(7) recycling phenylalanine and lysine solution are prepared
After the completion of (5) step, 1.5~2.5BV and the eluent of 5.0~6.5BV that (5) step is collected are closed
And be first pumped into counter-osmosis device, reverse osmosis concentration is carried out under conditions of gauge pressure is 0.5~0.8MPa, up to no reverse osmosis filter
Cross when liquid occurs and stop.Reverse osmosis filtered solution and reverse osmosis trapped fluid are collected respectively, to the reverse osmosis filtered solution of collection, for washing
Regenerating resin column；To the reverse osmosis trapped fluid of collection, be reloaded into the bag filter that molecular cut off is 100Da, with pure water into
Row 6~10h of dialysis, the wherein volume of pure water are 10~20 times of reverse osmosis trapped fluid volume.After the completion of dialysis, collect respectively
Liquid and bag filter external solution in bag filter.To the bag filter external solution of collection, adjusted after pH value is 6.5~7.0 and sent to life with dilute hydrochloric acid
Change processing pond to be purified, discharged after up to standard；To liquid in the bag filter of collection, that is, prepare recycling phenylalanine and lysine water
Solution, adjusts and prepares phenylalanine and lysine available for lower batch (1) step after phenylalanine and lysine concentration therein
Aqueous solution.
(8) regenerating resin column is prepared
After the completion of (5) step, unloading phenylalanyl-lysine dipeptides, phenylalanine and the bad ammonia collected to (5) step
Pure water is pumped into the resin column of acid to be washed, until cleaning solution pH value is stopped when reaching 7.5~8.5.After collecting washing respectively
Resin column and cleaning solution, to the resin column after the washing of collection, that is, prepare regenerating resin column, available for lower batch carry out lotus
Carry phenylalanyl-lysine dipeptides, phenylalanine and lysine processing；To the cleaning solution of collection, be pumped into biochemical treatment tank into
Row processing, is discharged after up to standard.
The present invention is after adopting the above technical scheme, mainly there is following characteristics：
1st, the method for the present invention in ethylene glycol non-aqueous media by the use of enzyme as catalyst synthetic styrene-acrylic aminoacyl-lysine dipeptides,
With mild condition, specificity is strong, and combined coefficient is high, the advantage such as no side reaction, phenylalanyl-total recovery rate of lysine dipeptides with
Phenylalanine meter reaches 85~92%, and two peptide content of phenylalanyl-lysine is 95~98% in freeze-dried powder.
2nd, the raw material in process of the present invention obtains reuse, and waste liquid has carried out biochemical treatment, discharged after up to standard, without " three wastes "
Produce, be typical green production process.
3rd, the phenylalanyl-lysine dipeptides prepared can be widely used for the fields such as medicine, weaving, food, have huge
Social value and economic benefit.
4th, embodiment
With reference to embodiment, the present invention is further illustrated.
Embodiment 1
A kind of method of synthetic styrene-acrylic aminoacyl-lysine dipeptides, its concrete technology step are as follows：
(1) phenylalanine and lysine solution are prepared
Successively appropriate commercially available phenylalanine and lysine are dissolved in pure aqueous solution under agitation, just prepare phenylpropyl alcohol
Propylhomoserin concentration is 0.3mol/L, the aqueous solution of lysine concentration 0.3mol/L；The pH of the aqueous solution is adjusted with dilute sodium hydroxide again
It is worth for 7.5, that is, prepares phenylalanine and lysine solution, ethylene glycol non-aqueous reaction medium is prepared for lower step.
(2) ethylene glycol non-aqueous reaction medium is prepared
After the completion of (1) step, phenylalanine and lysine solution prepared by (1) step are mixed with ethylene glycol solution,
Wherein the ratio between volume of phenylalanine and lysine solution and ethylene glycol is 1: 5 (L/L), and stir process 1h, that is, prepare second
Glycol non-aqueous reaction medium, phenylalanyl-lysine dipeptides reaction solution is prepared for lower step.
(3) phenylalanyl-lysine dipeptides reaction solution is prepared
After the completion of (2) step, vigor is added in ethylene glycol non-aqueous reaction medium prepared by (2) step with stirring is
The chymotrypsin of 1000U/mg, wherein add chymotrypsin quality and phenylalanine and lysine gross mass it
Than for 1: 20 (kg/kg).Then controlled at 35 DEG C, 15h is reacted.After the completion of reaction, 80 DEG C are warming up to, after handling 15min
Filter, collect filter residue and filtrate respectively.To the filtrate of collection, that is, phenylalanyl-lysine dipeptides reaction solution is prepared, under being used for
Step prepares the resin column of purification load phenylalanyl-lysine dipeptides.To the filter residue of collection, washed, removed repeatedly with pure water
Animal feed additive is used to prepare after ethylene glycol.
(4) resin column of purification load phenylalanyl-lysine dipeptides is prepared
After the completion of (3) step, phenylalanyl-lysine dipeptides reaction solution prepared by (3) step pure water is first diluted 3
Times, then it is pumped into the resin column equipped with 001 × 7 cation exchange resin of activation, the wherein resin column and (3) step system with constant flow pump
The ratio between volume of standby phenylalanyl-lysine dipeptides reaction solution is 1: 30 (L/L), is pumped into the phenylalanyl-lysine dipeptides
The flow velocity of reaction solution is 2 times of the resin column volume (BV).It is pumped into after the completion of the phenylalanyl-lysine dipeptides reaction solution, point
Shou Ji not load phenylalanyl-lysine dipeptides, the resin column of phenylalanine and lysine and unloading phenylalanyl-lysine
The column liquid excessively of dipeptides, phenylalanine and lysine.To load phenylalanyl-lysine dipeptides of collection, phenylalanine and
The resin column of lysine, is pumped into the pure water washing of 2BV, collects cleaning solution after the completion of washing respectively and removes the load of ethylene glycol
The resin column of phenylalanyl-lysine dipeptides, phenylalanine and lysine.To the cleaning solution of collection, the column liquid excessively with collection
Mixing, is used to prepare recycling ethylene glycol；To load phenylalanyl-lysine dipeptides, the phenylalanine of the removing ethylene glycol of collection
And the resin column of lysine, that is, the resin column of purification load phenylalanyl-lysine dipeptides is prepared, benzene is prepared for lower step
Alanyl-lysine dipeptides eluent.
(5) phenylalanyl-lysine dipeptides eluent is prepared
After the completion of (4) step, in the resin column of the purification load phenylalanyl-lysine dipeptides first prepared to (4) step
The sodium hydroxide solution of 0.1mol/L is pumped into, elutes phenylalanyl-lysine dipeptides, phenylalanine and lysine, the hydrogen
The flow velocity that is pumped into of sodium hydroxide solution is 2BV/h.1.5~2.5BV, 3.5~4.5BV, 5.0~6.5BV are collected respectively
The resin column of eluent and unloading phenylalanyl-lysine dipeptides, phenylalanine and lysine.To the unloading resin of collection
Column, regenerating resin column is prepared for (8) step；The eluent of 1.5~2.5BV, 5.0~6.5BV to collection, for
(7) step prepares recycling phenylalanine and lysine solution；To the eluent of 3.5~4.5BV of collection, that is, prepare phenylpropyl alcohol
Aminoacyl-lysine dipeptides eluent, two peptide freeze-dried powder of phenylalanyl-lysine is prepared for lower step.
(6) two peptide freeze-dried powder of phenylalanyl-lysine is prepared
After the completion of (5) step, phenylalanyl-lysine dipeptides eluent prepared by (5) step is pumped into molecular cut off
In the nanofiltration device of 100Da, first time nanofiltration to be carried out in the case where gauge pressure is the pressure of 0.1MPa, until nanofiltration retentate fluid is filtered with nanofiltration
Cross when the ratio between volume of liquid reaches 1: 4 (L/L) and stop nanofiltration, collect first time nanofiltration filtered solution and nanofiltration retentate fluid respectively.It is right
The first time nanofiltration retentate fluid of collection, then pure water is added thereto to original volume, second of nanofiltration is carried out, second of nanofiltration
Condition is identical with first time nanofiltration condition.After the completion of second of nanofiltration, second of nanofiltration filtered solution and trapped fluid are collected respectively.It is right
Second of the nanofiltration filtered solution collected, merges with first time nanofiltration filtered solution, after being 6.5 with dilute hydrochloric acid adjusting pH value, pump
Enter purification tank for liquid waste and carry out biochemical treatment, discharged after up to standard；To second of nanofiltration retentate fluid of collection, it is placed in low temperature refrigerator
The pre-freeze 6h under conditions of -40 DEG C, transfers in vacuum freeze drier, in the bar that temperature is -50 DEG C, vacuum is 20Pa
Freeze-drying 24h is carried out under part, that is, prepares two peptide freeze-dried powder of phenylalanyl-lysine, its total recovery rate is in terms of phenylalanine
Reach 85~92%, two peptide content of phenylalanyl-lysine is 95~98% in the freeze-dried powder.
(7) recycling phenylalanine and lysine solution are prepared
After the completion of (5) step, 1.5~2.5BV and the eluent of 5.0~6.5BV that (5) step is collected are closed
And be first pumped into counter-osmosis device, reverse osmosis concentration is carried out under conditions of gauge pressure is 0.5MPa, until going out without reverse osmosis filtered solution
It is current to stop.Reverse osmosis filtered solution and reverse osmosis trapped fluid are collected respectively, to the reverse osmosis filtered solution of collection, for regenerated from washing tree
Fat column；To the reverse osmosis trapped fluid of collection, it is reloaded into the bag filter that molecular cut off is 100Da, is dialysed with pure water
The volume of 6h, wherein pure water are 10 times of reverse osmosis trapped fluid volume.After the completion of dialysis, respectively collect bag filter in liquid and thoroughly
Analyse bag external solution.To the bag filter external solution of collection, send to biochemical treatment tank and purified after being 6.5 with dilute hydrochloric acid adjusting pH value, reached
Discharged after mark；To liquid in the bag filter of collection, that is, recycling phenylalanine and lysine solution are prepared, adjusts phenylpropyl alcohol therein
After propylhomoserin and lysine concentration phenylalanine and lysine solution are prepared available for lower batch (1) step.
(8) regenerating resin column is prepared
After the completion of (5) step, unloading phenylalanyl-lysine dipeptides, phenylalanine and the bad ammonia collected to (5) step
Pure water is pumped into the resin column of acid to be washed, until cleaning solution pH value is stopped when reaching 7.5.The resin after washing is collected respectively
Column and cleaning solution, to the resin column after the washing of collection, that is, prepare regenerating resin column, and load phenylpropyl alcohol is carried out available for lower batch
Aminoacyl-lysine dipeptides, phenylalanine and lysine processing；To the cleaning solution of collection, it is pumped into biochemical treatment tank and is handled,
Discharge after up to standard.
Embodiment 2
A kind of method of synthetic styrene-acrylic aminoacyl-lysine dipeptides, its concrete technology step are as follows：
(1) phenylalanine and lysine solution are prepared
Successively appropriate commercially available phenylalanine and lysine are dissolved in pure aqueous solution under agitation, just prepare phenylpropyl alcohol
Propylhomoserin concentration is 0.6mol/L, the aqueous solution of lysine concentration 1.2mol/L；The pH of the aqueous solution is adjusted with dilute sodium hydroxide again
It is worth for 8.5, that is, prepares phenylalanine and lysine solution, ethylene glycol non-aqueous reaction medium is prepared for lower step.
(2) ethylene glycol non-aqueous reaction medium is prepared
After the completion of (1) step, phenylalanine and lysine solution prepared by (1) step are mixed with ethylene glycol solution,
Wherein the ratio between volume of phenylalanine and lysine solution and ethylene glycol is 1: 15 (L/L), and stir process 2h, that is, prepare second
Glycol non-aqueous reaction medium, phenylalanyl-lysine dipeptides reaction solution is prepared for lower step.
(3) phenylalanyl-lysine dipeptides reaction solution is prepared
After the completion of (2) step, vigor is added in ethylene glycol non-aqueous reaction medium prepared by (2) step with stirring is
The chymotrypsin of 1200U/mg, wherein add chymotrypsin quality and phenylalanine and lysine gross mass it
Than for 1: 35 (kg/kg).Then controlled at 40 DEG C, 18h is reacted.After the completion of reaction, 85 DEG C are warming up to, after handling 18min
Filter, collect filter residue and filtrate respectively.To the filtrate of collection, that is, phenylalanyl-lysine dipeptides reaction solution is prepared, under being used for
Step prepares the resin column of purification load phenylalanyl-lysine dipeptides.To the filter residue of collection, washed, removed repeatedly with pure water
Animal feed additive is used to prepare after ethylene glycol.
(4) resin column of purification load phenylalanyl-lysine dipeptides is prepared
After the completion of (3) step, phenylalanyl-lysine dipeptides reaction solution prepared by (3) step pure water is first diluted 5
Times, then the resin column equipped with activation D0011 ion exchange resin is pumped into constant flow pump, it is prepared by wherein resin column and (3) step
The ratio between the volume of phenylalanyl-lysine dipeptides reaction solution be 1: 50 (L/L), it is anti-to be pumped into the phenylalanyl-lysine dipeptides
The flow velocity for answering liquid is 4 times of the resin column volume (BV).It is pumped into after the completion of the phenylalanyl-lysine dipeptides reaction solution, respectively
Collect load phenylalanyl-lysine dipeptides, the resin column of phenylalanine and lysine and unloading phenylalanyl-lysine two
The column liquid excessively of peptide, phenylalanine and lysine.To load phenylalanyl-lysine dipeptides of collection, phenylalanine and rely
The resin column of propylhomoserin, is pumped into the pure water washing of 4BV, collects cleaning solution after the completion of washing respectively and removes the load benzene of ethylene glycol
The resin column of alanyl-lysine dipeptides, phenylalanine and lysine.To the cleaning solution of collection, mixed with the column liquid of crossing of collection
Close, be used to prepare recycling ethylene glycol；Removing load phenylalanyl-lysine dipeptides of ethylene glycol, phenylalanine to collection with
And the resin column of lysine, that is, the resin column of purification load phenylalanyl-lysine dipeptides is prepared, phenylpropyl alcohol is prepared for lower step
Aminoacyl-lysine dipeptides eluent.
(5) phenylalanyl-lysine dipeptides eluent is prepared
After the completion of (4) step, in the resin column of the purification load phenylalanyl-lysine dipeptides first prepared to (4) step
The sodium hydroxide solution of 0.3mol/L is pumped into, elutes phenylalanyl-lysine dipeptides, phenylalanine and lysine, the hydrogen
The flow velocity that is pumped into of sodium hydroxide solution is 3BV/h.1.5~2.5BV, 3.5~4.5BV, 5.0~6.5BV are collected respectively
The resin column of eluent and unloading phenylalanyl-lysine dipeptides, phenylalanine and lysine.To the unloading resin of collection
Column, regenerating resin column is prepared for (8) step；The eluent of 1.5~2.5BV, 5.0~6.5BV to collection, for
(7) step prepares recycling phenylalanine and lysine solution；To the eluent of 3.5~4.5BV of collection, that is, prepare phenylpropyl alcohol
Aminoacyl-lysine dipeptides eluent, two peptide freeze-dried powder of phenylalanyl-lysine is prepared for lower step.
(6) two peptide freeze-dried powder of phenylalanyl-lysine is prepared
After the completion of (5) step, phenylalanyl-lysine dipeptides eluent prepared by (5) step is pumped into molecular cut off
In the nanofiltration device of 200Da, first time nanofiltration to be carried out in the case where gauge pressure is the pressure of 0.3MPa, until nanofiltration retentate fluid is filtered with nanofiltration
Cross when the ratio between volume of liquid reaches 1: 4.5 (L/L) and stop nanofiltration, collect first time nanofiltration filtered solution and nanofiltration retentate fluid respectively.
To the first time nanofiltration retentate fluid of collection, then pure water is added thereto to original volume, carry out second of nanofiltration, second of nanofiltration
Condition it is identical with first time nanofiltration condition.After the completion of second of nanofiltration, second of nanofiltration filtered solution and trapped fluid are collected respectively.
To second of nanofiltration filtered solution of collection, merged with first time nanofiltration filtered solution, after being 6.8 with dilute hydrochloric acid adjusting pH value,
It is pumped into purification tank for liquid waste and carries out biochemical treatment, is discharged after up to standard；To second of nanofiltration retentate fluid of collection, it is placed in low temperature refrigerator
The pre-freeze 9h under conditions of -30 DEG C, transfers in vacuum freeze drier, in the bar that temperature is -45 DEG C, vacuum is 35Pa
Freeze-drying 30h is carried out under part, that is, prepares two peptide freeze-dried powder of phenylalanyl-lysine, its total recovery rate is in terms of phenylalanine
Reach 85~92%, two peptide content of phenylalanyl-lysine is 95~98% in the freeze-dried powder.
(7) recycling phenylalanine and lysine solution are prepared
After the completion of (5) step, 1.5~2.5BV and the eluent of 5.0~6.5BV that (5) step is collected are closed
And be first pumped into counter-osmosis device, reverse osmosis concentration is carried out under conditions of gauge pressure is 0.6MPa, until going out without reverse osmosis filtered solution
It is current to stop.Reverse osmosis filtered solution and reverse osmosis trapped fluid are collected respectively, to the reverse osmosis filtered solution of collection, for regenerated from washing tree
Fat column；To the reverse osmosis trapped fluid of collection, it is reloaded into the bag filter that molecular cut off is 100Da, is dialysed with pure water
The volume of 8h, wherein pure water are 15 times of reverse osmosis trapped fluid volume.After the completion of dialysis, respectively collect bag filter in liquid and thoroughly
Analyse bag external solution.To the bag filter external solution of collection, send to biochemical treatment tank and purified after being 6.8 with dilute hydrochloric acid adjusting pH value, reached
Discharged after mark；To liquid in the bag filter of collection, that is, recycling phenylalanine and lysine solution are prepared, adjusts phenylpropyl alcohol therein
After propylhomoserin and lysine concentration phenylalanine and lysine solution are prepared available for lower batch (1) step.
(8) regenerating resin column is prepared
After the completion of (5) step, unloading phenylalanyl-lysine dipeptides, phenylalanine and the bad ammonia collected to (5) step
Pure water is pumped into the resin column of acid to be washed, until cleaning solution pH value is stopped when reaching 8.0.The resin after washing is collected respectively
Column and cleaning solution, to the resin column after the washing of collection, that is, prepare regenerating resin column, and load phenylpropyl alcohol is carried out available for lower batch
Aminoacyl-lysine dipeptides, phenylalanine and lysine processing；To the cleaning solution of collection, it is pumped into biochemical treatment tank and is handled,
Discharge after up to standard.
Embodiment 3
A kind of method of synthetic styrene-acrylic aminoacyl-lysine dipeptides, its concrete technology step are as follows：
(1) phenylalanine and lysine solution are prepared
Successively appropriate commercially available phenylalanine and lysine are dissolved in pure aqueous solution under agitation, just prepare phenylpropyl alcohol
Propylhomoserin concentration is 1.0mol/L, the aqueous solution of lysine concentration 2.0mol/L；The pH of the aqueous solution is adjusted with dilute sodium hydroxide again
It is worth for 9.5, that is, prepares phenylalanine and lysine solution, ethylene glycol non-aqueous reaction medium is prepared for lower step.
(2) ethylene glycol non-aqueous reaction medium is prepared
After the completion of (1) step, phenylalanine and lysine solution prepared by (1) step are mixed with ethylene glycol solution,
Wherein the ratio between volume of phenylalanine and lysine solution and ethylene glycol is 1: 25 (L/L), and stir process 3h, that is, prepare second
Glycol non-aqueous reaction medium, phenylalanyl-lysine dipeptides reaction solution is prepared for lower step.
(3) phenylalanyl-lysine dipeptides reaction solution is prepared
After the completion of (2) step, vigor is added in ethylene glycol non-aqueous reaction medium prepared by (2) step with stirring is
The chymotrypsin of 1500U/mg, wherein add chymotrypsin quality and phenylalanine and lysine gross mass it
Than for 1: 50 (kg/kg).Then controlled at 45 DEG C, 20h is reacted.After the completion of reaction, 90 DEG C are warming up to, after handling 20min
Filter, collect filter residue and filtrate respectively.To the filtrate of collection, that is, phenylalanyl-lysine dipeptides reaction solution is prepared, under being used for
Step prepares the resin column of purification load phenylalanyl-lysine dipeptides.To the filter residue of collection, washed, removed repeatedly with pure water
Animal feed additive is used to prepare after ethylene glycol.
(4) resin column of purification load phenylalanyl-lysine dipeptides is prepared
After the completion of (3) step, phenylalanyl-lysine dipeptides reaction solution prepared by (3) step pure water is first diluted 6
Times, then it is pumped into the resin column equipped with 001 × 7 cation exchange resin of activation, the wherein resin column and (3) step system with constant flow pump
The ratio between volume of standby phenylalanyl-lysine dipeptides reaction solution is 1: 60 (L/L), is pumped into the phenylalanyl-lysine dipeptides
The flow velocity of reaction solution is 6 times of the resin column volume (BV).It is pumped into after the completion of the phenylalanyl-lysine dipeptides reaction solution, point
Shou Ji not load phenylalanyl-lysine dipeptides, the resin column of phenylalanine and lysine and unloading phenylalanyl-lysine
The column liquid excessively of dipeptides, phenylalanine and lysine.To load phenylalanyl-lysine dipeptides of collection, phenylalanine and
The resin column of lysine, is pumped into the pure water washing of 6BV, collects cleaning solution after the completion of washing respectively and removes the load of ethylene glycol
The resin column of phenylalanyl-lysine dipeptides, phenylalanine and lysine.To the cleaning solution of collection, the column liquid excessively with collection
Mixing, is used to prepare recycling ethylene glycol；To load phenylalanyl-lysine dipeptides, the phenylalanine of the removing ethylene glycol of collection
And the resin column of lysine, that is, the resin column of purification load phenylalanyl-lysine dipeptides is prepared, benzene is prepared for lower step
Alanyl-lysine dipeptides eluent.
(5) phenylalanyl-lysine dipeptides eluent is prepared
After the completion of (4) step, in the resin column of the purification load phenylalanyl-lysine dipeptides first prepared to (4) step
The sodium hydroxide solution of 0.5mol/L is pumped into, elutes phenylalanyl-lysine dipeptides, phenylalanine and lysine, the hydrogen
The flow velocity that is pumped into of sodium hydroxide solution is 4BV/h.1.5~2.5BV, 3.5~4.5BV, 5.0~6.5BV are collected respectively
The resin column of eluent and unloading phenylalanyl-lysine dipeptides, phenylalanine and lysine.To the unloading resin of collection
Column, regenerating resin column is prepared for (8) step；The eluent of 1.5~2.5BV, 5.0~6.5BV to collection, for
(7) step prepares recycling phenylalanine and lysine solution；To the eluent of 3.5~4.5BV of collection, that is, prepare phenylpropyl alcohol
Aminoacyl-lysine dipeptides eluent, two peptide freeze-dried powder of phenylalanyl-lysine is prepared for lower step.
(6) two peptide freeze-dried powder of phenylalanyl-lysine is prepared
After the completion of (5) step, phenylalanyl-lysine dipeptides eluent prepared by (5) step is pumped into molecular cut off
In the nanofiltration device of 100Da, first time nanofiltration to be carried out in the case where gauge pressure is the pressure of 0.5MPa, until nanofiltration retentate fluid is filtered with nanofiltration
Cross when the ratio between volume of liquid reaches 1: 5 (L/L) and stop nanofiltration, collect first time nanofiltration filtered solution and nanofiltration retentate fluid respectively.It is right
The first time nanofiltration retentate fluid of collection, then pure water is added thereto to original volume, second of nanofiltration is carried out, second of nanofiltration
Condition is identical with first time nanofiltration condition.After the completion of second of nanofiltration, second of nanofiltration filtered solution and trapped fluid are collected respectively.It is right
Second of the nanofiltration filtered solution collected, merges with first time nanofiltration filtered solution, after being 7.0 with dilute hydrochloric acid adjusting pH value, pump
Enter purification tank for liquid waste and carry out biochemical treatment, discharged after up to standard；To second of nanofiltration retentate fluid of collection, it is placed in low temperature refrigerator
The pre-freeze 12h under conditions of -20 DEG C, transfers in vacuum freeze drier, temperature be -40 DEG C, vacuum be 50Pa's
Under the conditions of carry out freeze-drying 36h, that is, prepare two peptide freeze-dried powder of phenylalanyl-lysine, its total recovery rate is with phenylalanine
Meter reaches 85~92%, and two peptide content of phenylalanyl-lysine is 95~98% in the freeze-dried powder.
(7) recycling phenylalanine and lysine solution are prepared
After the completion of (5) step, 1.5~2.5BV and the eluent of 5.0~6.5BV that (5) step is collected are closed
And be first pumped into counter-osmosis device, reverse osmosis concentration is carried out under conditions of gauge pressure is 0.8MPa, until going out without reverse osmosis filtered solution
It is current to stop.Reverse osmosis filtered solution and reverse osmosis trapped fluid are collected respectively, to the reverse osmosis filtered solution of collection, for regenerated from washing tree
Fat column；To the reverse osmosis trapped fluid of collection, it is reloaded into the bag filter that molecular cut off is 100Da, is dialysed with pure water
The volume of 10h, wherein pure water are 20 times of reverse osmosis trapped fluid volume.After the completion of dialysis, respectively collect bag filter in liquid and
Bag filter external solution.To the bag filter external solution of collection, send to biochemical treatment tank and purified after being 7.0 with dilute hydrochloric acid adjusting pH value,
Discharge after up to standard；To liquid in the bag filter of collection, that is, recycling phenylalanine and lysine solution are prepared, adjusts benzene therein
After alanine and lysine concentration phenylalanine and lysine solution are prepared available for lower batch (1) step.
(8) regenerating resin column is prepared
After the completion of (5) step, unloading phenylalanyl-lysine dipeptides, phenylalanine and the bad ammonia collected to (5) step
Pure water is pumped into the resin column of acid to be washed, until cleaning solution pH value is stopped when reaching 8.5.The resin after washing is collected respectively
Column and cleaning solution, to the resin column after the washing of collection, that is, prepare regenerating resin column, and load phenylpropyl alcohol is carried out available for lower batch
Aminoacyl-lysine dipeptides, phenylalanine and lysine processing；To the cleaning solution of collection, it is pumped into biochemical treatment tank and is handled,
Discharge after up to standard.
Claims (1)
- A kind of 1. method of synthetic styrene-acrylic aminoacyl-lysine dipeptides, it is characterised in that specific processing step is as follows：(1) phenylalanine and lysine solution are preparedSuccessively appropriate commercially available phenylalanine and lysine are dissolved in pure aqueous solution under agitation, just prepare phenylalanine Concentration is 0.3~1.0mol/L, the aqueous solution of 0.3~2.0mol/L of lysine concentration；This to be adjusted with dilute sodium hydroxide water-soluble again The pH value of liquid is 7.5~9.5, that is, prepares phenylalanine and lysine solution, ethylene glycol non-aqueous reaction is prepared for lower step Medium；(2) ethylene glycol non-aqueous reaction medium is preparedAfter the completion of (1) step, phenylalanine and lysine solution prepared by (1) step are mixed with ethylene glycol solution, wherein The ratio between volume of phenylalanine and lysine solution and ethylene glycol is 1: 5~25 (L/L), and 1~3h of stir process, that is, prepare Ethylene glycol non-aqueous reaction medium, phenylalanyl-lysine dipeptides reaction solution is prepared for lower step；(3) phenylalanyl-lysine dipeptides reaction solution is preparedAfter the completion of (2) step, added with stirring in ethylene glycol non-aqueous reaction medium prepared by (2) step vigor for 1000~ The chymotrypsin of 1500U/mg, wherein add chymotrypsin quality and phenylalanine and lysine gross mass it Than for 1: 20~50 (kg/kg), then controlled at 35~45 DEG C, reacting 15~20h, after the completion of reaction, it is warming up to 80~ 90 DEG C, filtered after handling 15~20min, collect filter residue and filtrate respectively, to the filtrate of collection, that is, prepare phenylalanyl-rely Propylhomoserin dipeptides reaction solution, the resin column of purification load phenylalanyl-lysine dipeptides is prepared for lower step, to the filter residue of collection, Washed repeatedly with pure water, animal feed additive is used to prepare after removing ethylene glycol；(4) resin column of purification load phenylalanyl-lysine dipeptides is preparedAfter the completion of (3) step, phenylalanyl-lysine dipeptides reaction solution prepared by (3) step pure water is first diluted 3~6 Times, then the resin column equipped with 001 × 7 cation exchange resin of activation or D0011 ion exchange resin is pumped into constant flow pump, wherein The ratio between volume of phenylalanyl-lysine dipeptides reaction solution prepared by the resin column and (3) step is 1: 30~60 (L/L), pump The flow velocity for entering the phenylalanyl-lysine dipeptides reaction solution is 2~6 times of the resin column volume (BV), be pumped into the phenylalanyl- After the completion of lysine dipeptides reaction solution, the tree of load phenylalanyl-lysine dipeptides, phenylalanine and lysine is collected respectively Fat column crosses column liquid with unloading phenylalanyl-lysine dipeptides, phenylalanine and lysine, to the load phenylpropyl alcohol ammonia of collection The resin column of acyl-lysine dipeptides, phenylalanine and lysine, is pumped into the pure water washing of 2~6BV, divides after the completion of washing Not Shou Ji cleaning solution and remove ethylene glycol load phenylalanyl-lysine dipeptides, phenylalanine and lysine resin column, To the cleaning solution of collection, mixed with the column liquid of crossing of collection, be used to prepare recycling ethylene glycol；To the load of the removing ethylene glycol of collection The resin column of phenylalanyl-lysine dipeptides, phenylalanine and lysine, that is, prepare purification load phenylalanyl-bad ammonia The resin column of sour dipeptides, phenylalanyl-lysine dipeptides eluent is prepared for lower step；(5) phenylalanyl-lysine dipeptides eluent is preparedAfter the completion of (4) step, it is pumped into the resin column of the purification load phenylalanyl-lysine dipeptides first prepared to (4) step The sodium hydroxide solution of 0.1~0.5mol/L, elutes phenylalanyl-lysine dipeptides, phenylalanine and lysine, the hydrogen The flow velocity that is pumped into of sodium hydroxide solution is 2~4BV/h, collects 1.5~2.5BV, 3.5~4.5BV, 5.0~6.5BV respectively Eluent and unloading phenylalanyl-lysine dipeptides, phenylalanine and lysine resin column, to the unloading tree of collection Fat column, regenerating resin column is prepared for (8) step；The eluent of 1.5~2.5BV, 5.0~6.5BV to collection, are used for (7) step prepares recycling phenylalanine and lysine solution；To the eluent of 3.5~4.5BV of collection, that is, prepare benzene Alanyl-lysine dipeptides eluent, two peptide freeze-dried powder of phenylalanyl-lysine is prepared for lower step；(6) two peptide freeze-dried powder of phenylalanyl-lysine is preparedAfter the completion of (5) step, phenylalanyl-lysine dipeptides eluent prepared by (5) step is pumped into molecular cut off as 100 In the nanofiltration device of~200Da, gauge pressure be 0.1~0.5MPa pressure under carry out first time nanofiltration, until nanofiltration retentate fluid with The ratio between volume of nanofiltration filtered solution stops nanofiltration when reaching 1: 4~5 (L/L), collect first time nanofiltration filtered solution and nanofiltration respectively Trapped fluid, to the first time nanofiltration retentate fluid of collection, then adds pure water to original volume, carries out second of nanofiltration thereto, the The condition of secondary nanofiltration is identical with first time nanofiltration condition, after the completion of second of nanofiltration, collects second of nanofiltration filtered solution respectively And trapped fluid, to second of nanofiltration filtered solution of collection, merged with first time nanofiltration filtered solution, pH value is adjusted with dilute hydrochloric acid After 6.5~7.0, it is pumped into purification tank for liquid waste and carries out biochemical treatment, discharged after up to standard；To second of nanofiltration retentate fluid of collection, 6~12h of pre-freeze under conditions of -40~-20 DEG C is placed in low temperature refrigerator, is transferred in vacuum freeze drier, in temperature Carry out 24~36h of freeze-drying under conditions of being 20~50Pa for -50~-40 DEG C, vacuum, that is, prepare phenylalanyl-rely Two peptide freeze-dried powder of propylhomoserin, its total recovery rate reach 85~92% in terms of phenylalanine, phenylalanyl-lysine two in the freeze-dried powder Peptide content is 95~98%；(7) recycling phenylalanine and lysine solution are preparedAfter the completion of (5) step, 1.5~2.5BV and the eluent of 5.0~6.5BV that (5) step is collected are merged, First it is pumped into counter-osmosis device, reverse osmosis concentration is carried out under conditions of gauge pressure is 0.5~0.8MPa, until without reverse osmosis filtered solution Stop during appearance, collect reverse osmosis filtered solution and reverse osmosis trapped fluid respectively, to the reverse osmosis filtered solution of collection, for regenerated from washing Resin column；To the reverse osmosis trapped fluid of collection, it is reloaded into the bag filter that molecular cut off is 100Da, is carried out with pure water 6~10h is analysed, the wherein volume of pure water is 10~20 times of reverse osmosis trapped fluid volume, after the completion of dialysis, collects dialysis respectively Liquid and bag filter external solution in bag, to the bag filter external solution of collection, are adjusted after pH value is 6.5~7.0 with dilute hydrochloric acid and sent to biochemistry Reason pond is purified, and is discharged after up to standard；To liquid in the bag filter of collection, that is, prepare recycling phenylalanine and lysine water-soluble Liquid, adjusts and prepares phenylalanine and lysine water available for lower batch (1) step after phenylalanine and lysine concentration therein Solution；(8) regenerating resin column is preparedAfter the completion of (5) step, to unloading phenylalanyl-lysine dipeptides of (5) step collection, phenylalanine and lysine Pure water is pumped into resin column to be washed, until cleaning solution pH value is stopped when reaching 7.5~8.5, collects the tree after washing respectively Fat column and cleaning solution, to the resin column after the washing of collection, that is, prepare regenerating resin column, and load benzene is carried out available for lower batch Alanyl-lysine dipeptides, phenylalanine and lysine processing；To the cleaning solution of collection, it is pumped at biochemical treatment tank Reason, is discharged after up to standard.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108794570A (en) * | 2018-06-15 | 2018-11-13 | 华南理工大学 | A kind of xanthine oxidase inhibitor and application thereof containing phenylalanine |
| CN110627865A (en) * | 2019-09-29 | 2019-12-31 | 南京益唯森生物科技有限公司 | Metronidazole-phenylalanyl-lysine dipeptide compound and preparation and application thereof |
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| CN108794570A (en) * | 2018-06-15 | 2018-11-13 | 华南理工大学 | A kind of xanthine oxidase inhibitor and application thereof containing phenylalanine |
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| CN110627865A (en) * | 2019-09-29 | 2019-12-31 | 南京益唯森生物科技有限公司 | Metronidazole-phenylalanyl-lysine dipeptide compound and preparation and application thereof |
| CN110627865B (en) * | 2019-09-29 | 2023-03-31 | 南京益唯森生物科技有限公司 | Metronidazole-phenylalanyl-lysine dipeptide compound and preparation and application thereof |
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