CN108003105A - A kind of method of synthesized micromolecule amino acid derivativges Ectoin - Google Patents
A kind of method of synthesized micromolecule amino acid derivativges Ectoin Download PDFInfo
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- CN108003105A CN108003105A CN201810002838.2A CN201810002838A CN108003105A CN 108003105 A CN108003105 A CN 108003105A CN 201810002838 A CN201810002838 A CN 201810002838A CN 108003105 A CN108003105 A CN 108003105A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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Abstract
The present invention relates to a kind of 2 methyl 1 of small molecule amino acid derivativges (S); 4; 5; the synthetic method of 6 tetrahydropyrimidine, 4 carboxylic acid (Ectoin); it is characterized in that using the L acetyl asparagine of commercialization cheap and easy to get as raw material, first pass through and be condensed into lactams, upper protection, carbonyl reduction, amide hydrolysis, cyclization obtains Ectoin molecule to the salinization of amino deprotection hydrochloric acid again.This method can easily obtain (S) 2 methyl Isosorbide-5-Nitrae of high-purity with very low cost, less step, and 5,6 tetrahydropyrimidine, 4 carboxylic acid (Ectoin) product, reaction condition is gentle, easily controllable, environmental pollution very little, is adapted to industrialized production.
Description
Technical field
The present invention relates to a kind of novel synthesis of the amino acid derivativges with physiological activity, specifically (S) -2-
Methyl isophthalic acid, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids (Ectoin).
Background technology
(S) -2- methyl isophthalic acids, 4,5,6- tetrahydropyrimidine -4- carboxylic acids (Ectoin) derive from high Halophiles (Halomonas
Elongata), it is a kind of small molecule amino acid derivativges, there is an asymmetric carbon atom.
High salt, high temperature, high ultraviolet radiation extreme condition under, Ectoin makes Halophiles escape injury.According to gram more than
Because being a kind of biological compatible solute produced in the cell to maintain osmotic balance of salt tolerant.In vivo and in vitro show (S)-
2- methyl isophthalic acids, 4,5,6- tetrahydropyrimidine -4- carboxylic acids (Ectoin) can be by synthesizing and transporting two kinds of approach in vitro thin in vivo
Intracellular accumulation, adjusts intraor extracellular osmotic balance.
(S) -2- methyl isophthalic acids, 4,5,6- tetrahydropyrimidine -4- carboxylic acids (Ectoin) are with osmotic pressure adjustment effect and surely
Determine the effect of the protein hydration large biological molecule such as layer, protective enzyme, DNA and membrane structure, cell and animals and plants can be helped
Resist the various adverse environments such as freezing, arid, high temperature, high salt, radiation.Therefore it has in medical treatment, health care and cosmetic field
It is widely applied prospect.
(S) -2- methyl isophthalic acids, 4,5,6- tetrahydropyrimidine -4- carboxylic acids (Ectoin) applying in the world in oral care
Reported disclosed in patent WO0219978.Its applying in patent DE102004016129 in skin nursing and disease prevention
Open report.Its applying in treating and preventing enterogastric diseases is reported disclosed in world patent WO2006097263.
(S) -2- methyl isophthalic acids, the initial the techniques of mass production of 4,5,6- tetrahydropyrimidine -4- carboxylic acids (Ectoin) be by into
For the biological synthesis method of " bacterial milking " technology.And also have in terms of chemical synthesis from expensive 2,4- diaminobutyric acids
Report out (patent JP-A-03031265 and patent US20110178292) for the synthetic method of raw material.
The content of the invention
It is contemplated that overcome drawbacks described above, there is provided a kind of of low cost, simple Ectoin of synthesis technique manually closes
Into new method.
The present invention provides a kind of (S) -2- methyl isophthalic acids, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, its feature to exist
In:Using the compound of such as lower structure as raw material, target product is obtained after ring-closure reaction:
The process of the ring-closure reaction is generally:By the compound of said structure, in alcohols polar solvent, it is subject to alkali
Free and then heating carries out intramolecular annulation and obtains (S) -2- methyl isophthalic acids, 4,5,6- tetrahydropyrimidine -4- carboxylic acids (according to gram
It is more because) product molecule.
In addition, present invention also offers another (S) -2- methyl isophthalic acids, the synthesis side of 4,5,6- tetrahydropyrimidine -4- carboxylic acids
Method, it is characterised in that:Using the compound of such as lower structure as raw material, hydrochloric acid is deprotected through carbonyl reduction, amide hydrolysis, amino successively
Target product is obtained after salinization, ring-closure reaction:
Wherein, Pro is amino protecting group.
Such as:Alkoxy carbonyl group class protection group:N- benzyloxycarbonyl groups, methoxycarbonyl group, carbethoxyl group, tertbutyloxycarbonyl (Boc), fluorenes
Methoxycarbonyl group (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyl ethoxycarbonyl (Teoc);
Acyl group class protection group:Phthalyl, p-toluenesulfonyl, trifluoroacetyl group, pivaloyl amine, benzamide;
Alkyls protection group:Trityl, 2,4- dimethoxy-benzyls, to methoxy-benzyl, benzyl etc..
The characteristics of such protection group is with after sloughing protection, can still revert to amino.
Specific reaction equation is as follows:
In addition, present invention also offers a kind of another (S) -2- methyl isophthalic acids, the synthesis of 4,5,6- tetrahydropyrimidine -4- carboxylic acids
Method, it is characterised in that:Using the compound of such as lower structure as raw material, successively through be condensed into lactams, upper protection, carbonyl reduction,
Target product is obtained after amide hydrolysis, the salinization of amino deprotection hydrochloric acid, ring-closure reaction:
Wherein, R is the group that can be converted into amino.Such as:All kinds of groups such as carboxyl, aldehyde radical, halogen, carboxylic acid halides, acid amides.
Specific reaction equation is as follows:
Further, (S) -2- methyl isophthalic acids provided by the invention, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, also
Have the characteristics that such:I.e. L- acetyl asparagine is raw material, obtains target product after following process successively:
S1:L- acetyl asparagine is subjected to intramolecular condensation;
S2:By L- acetyl asparagines be condensed the lactams to be formed nitrogen-atoms carry out Boc protections, and with sodium borohydride with
Triethyl group silicon hydrogen is by a carbonyl reduction of lactams into methylene;
S3:Lactams after reduction is protected to obtain with hcl reaction removing Boc again with lithium hydrate amido link
Hydrochloride intermediate;
S4:Target product is obtained through intramolecular cyclisation.
Further, (S) -2- methyl isophthalic acids provided by the invention, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, also
Have the characteristics that such:I.e., specific preparation method is as follows:
Step 1: under weak basic condition, L- acetyl asparagine is adding the bar of the condensing agents such as DCC, EDCI or HOBT
Under part, at a temperature of 10-35 DEG C, when stirring reaction 1-5 is small, lactam product is obtained;
Step 2: under the action of highly basic, the product of step 1 and Boc anhydride reactions are protected the nitrogen-atoms of lactams
Get up, more than 0 DEG C at a temperature of, with sodium borohydride, triethyl group silicon hydrogen when make reducing agent reaction 2-10 it is small when, obtain lactams
Carbonyl is reduced to the intermediate of methylene;
Step 3: the product of step 2 is protected with hcl reaction removing Boc again with lithium hydrate amido link
To hydrochloride intermediate;
Step 4: by the product of step 3, under the action of alkali, at a temperature of 50 DEG C -120 DEG C, when reaction 5-24 is small,
Obtain molecule inner ring condensation product.
Further, (S) -2- methyl isophthalic acids provided by the invention, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, also
Have the characteristics that such:I.e., in step 1, the L- acetyl asparagine with, the molar ratio of DCC or EDC I or HOBT are
1:1.5;The weak base and the molar ratio of L- acetyl asparagines are 1:1.5;
Further, (S) -2- methyl isophthalic acids provided by the invention, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, also
Have the characteristics that such:I.e., in step 2, the product of the step 1 and the molar ratio of Boc acid anhydrides are 1:1-1.5;
The highly basic and the molar ratio of Boc acid anhydrides are 1:1-1.5;
The molar ratio 2-3 of the reducing agent sodium borohydride, triethyl group silicon hydrogen and step 1 product:1.
Further, (S) -2- methyl isophthalic acids provided by the invention, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, also
Have the characteristics that such:I.e., in step 3, the product of step 2 and the molar ratio of lithium hydroxide are 1:1-1.5;
Further, (S) -2- methyl isophthalic acids provided by the invention, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, also
Have the characteristics that such:I.e., in step 4, the molar ratio of the product of alkali and step 3 is 1:1-1.3.
Further, (S) -2- methyl isophthalic acids provided by the invention, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, also
Have the characteristics that such:I.e., above-mentioned steps one carry out solvent-free reaction to step 4 or have solvent reaction;
The solvent is selected from ethers, esters, alcohols, aromatics and alkanes;
The weak base is selected from triethylamine, diisopropyl ethyl amine, and highly basic is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, tertiary fourth
Potassium alcoholate, sodium hydride etc..
Further, (S) -2- methyl isophthalic acids provided by the invention, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, also
Have the characteristics that such:I.e., above-mentioned steps one to step 4 is successive reaction;I.e., the reaction without individually handling;
Or
One or multi-step reaction in above-mentioned steps one to step 4, is purified after the completion of reaction;
The process of above-mentioned purifying is as follows:
The process of the purifying is as follows:
The purification process of step 1 product is:After the pH of reaction solution is adjusted to neutrality, obtained after extracting, solvent is evaporated off
The product of step 1;
The purification process of step 2 product is:After acid elution reaction solution, through drying, solvent is evaporated off after obtain step 2
Product;
The purification process of step 3 product is:Filtering;
The purification process of step 4 product is:Target product is obtained after solvent and recrystallization is evaporated off.
The reagent for being used to extract and recrystallize can be selected from:Esters (ethyl acetate, Ethyl formate), alcohols (ethanol, first
Alcohol, propyl alcohol, isopropanol), ethers (ether, methyl tertiary butyl ether(MTBE)), ketone (acetone etc.).
Further, (S) -2- methyl isophthalic acids provided by the invention, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, also
Have the characteristics that such:I.e., in above-mentioned steps four, it also added trimethyl orthoacetate and reacted.
Further, (S) -2- methyl isophthalic acids provided by the invention, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, also
Have the characteristics that such:I.e., the molar ratio of the product of above-mentioned steps three and trimethyl orthoacetate is 1:0.1-1.5.
The function and effect of the present invention:
The present invention provides a kind of small molecule amino acid derivativges (S) -2- methyl isophthalic acids, 4,5,6- tetrahydropyrimidine -4- carboxylic acids
The synthetic method of (Ectoin), in the method for the invention, with a kind of commodity L- acetyl asparagines extremely cheap and easy to get
For raw material, first pass through that to be condensed into lactams, upper protection, carbonyl reduction, amide hydrolysis, the salinization of amino deprotection hydrochloric acid, cyclization anti-
Should after obtain Ectoin molecule.This method can easily obtain high-purity high yield with very low cost, less step
(S) -2- methyl isophthalic acids, 4,5,6- tetrahydropyrimidine -4- carboxylic acids (Ectoin) products, and the reaction condition of the reaction is gentle, easily
In control, environmental pollution is minimum, and yield improves at least 30% compared with traditional handicraft, cost then for traditional handicraft 10% less than,
Extremely suitable industrialized production.
Embodiment
Embodiment 1
The first step:By 500 grams of solution for being added to 300 grams of DCC and being dissolved in 3 liters of dichloromethane of raw material L- acetyl asparagine
In, then it is added dropwise to 210 grams of triethylamines.Then when reaction 2 is small at room temperature, reaction solution is adjusted to pH with hydrochloric acid after reaction
=2.After product is extracted with ethyl acetate out again, drying obtains 1 420 grams of lactams, yield 78% after solvent is evaporated off.
Second step:500 grams of 1 400 grams of lactams and BOC acid anhydrides are added in 8 liters of tetrahydrofurans, 0 DEG C of addition sodium hydride
120 grams, reacted under nitrogen protective condition.After when 0 DEG C of stirring reaction 2 is small, then 20 DEG C are added portionwise after 250 grams of sodium borohydride
React 2 it is small when.Add 400 grams of triethyl group silicon hydrogen, be heated to 60 DEG C reaction 3 it is small when.1M salt acid elutions are used after the completion of question response
Reaction solution.By solvent portions drying and it is evaporated off obtaining 3 670 grams of intermediate, yield 80% after solvent.
3rd step:The intermediate 3 of 500 grams of BOC protections is dissolved in 3 liters of ethanol and 1 liter of water, then hydrogen is added into reaction solution
Sodium oxide molybdena solid, when 40 DEG C of reactions 3 are small.After question response terminates, ethanol is steamed, is used after adding 5 liters of methyl tertiary butyl ether(MTBE)s
Clear water washes twice.Organic layer is passed through hydrogen chloride gas and obtains 4 360 grams of hydrochloride intermediate again after being dried with anhydrous sodium sulfate,
Yield 85%.
4th step:125 grams of 3360 grams of hydrochloride intermediate and sodium ethoxide are added in 5 liters of absolute ethyl alcohols, heating stirring
React 5 it is small when.Crude product is obtained after solvent is evaporated off, then crude product with methanol (60mL) and ethyl acetate (300mL) are tied again
Crystalline substance obtains 200 grams of pure product, yield 85%.
Embodiment 2
The first step:By 500 grams of solution for being added to 550 grams of EDCI and being dissolved in 4 liters of dichloromethane of raw material L- acetyl asparagine
In, then it is added dropwise to 280 grams of diisopropyl ethyl amines.Then when reaction 2 is small at room temperature, after reaction by reaction solution salt
Acid is adjusted to pH=2.After product is extracted with ethyl acetate out again, drying obtains 1 380 grams of lactams, yield after solvent is evaporated off
67%.
Second step:400 grams of 1 300 grams of lactams and BOC acid anhydrides are added in 6 liters of tetrahydrofurans, 0 DEG C of addition sodium hydride
150 grams, reacted under nitrogen protective condition.After when 0 DEG C of stirring reaction 2 is small, then 20 DEG C of reactions 3 after sodium borohydride are added portionwise
Hour.Add 400 grams of triethyl group silicon hydrogen, be heated to 60 DEG C reaction 3 it is small when.1M hydrochloric acid washing reactions are used after the completion of question response
Liquid.By solvent portions drying and it is evaporated off obtaining 3 540 grams of intermediate, yield 65% after solvent.
3rd step:The intermediate 3 of 500 grams of BOC protections is dissolved in 5 liters of methanol, then lithium hydroxide is added into reaction solution
Solid, when 40 DEG C of reactions 2 are small.After question response terminates, methanol is steamed, is washed after adding 5 liters of methyl tertiary butyl ether(MTBE)s with clear water
Wash twice.Organic layer is passed through hydrogen chloride gas and obtains 4 360 grams of hydrochloride intermediate, yield again after being dried with anhydrous sodium sulfate
85%.
4th step:130 grams of 3300 grams of hydrochloride intermediate and sodium tert-butoxide are added in 5 liters of isopropanols, heating stirring
React 4 it is small when.Crude product is obtained after solvent is evaporated off, then crude product with methanol (60mL) and ethyl acetate (300mL) are tied again
Crystalline substance obtains 200 grams of pure product, yield 89%.
Embodiment 3
The first step:By 500 grams of solution for being added to 560 grams of HOBT and being dissolved in 4 liters of dichloromethane of raw material L- acetyl asparagine
In, then it is added dropwise to 280 grams of diisopropyl ethyl amines.Then when reaction 2 is small at room temperature, after reaction by reaction solution salt
Acid is adjusted to pH=2.After product is extracted with ethyl acetate out again, drying obtains 1 400 grams of lactams, yield after solvent is evaporated off
74%.
Second step:400 grams of 1 300 grams of lactams and BOC acid anhydrides are added in 6 liters of tetrahydrofurans, 0 DEG C of addition sodium hydride
150 grams, reacted under nitrogen protective condition.After when 0 DEG C of stirring reaction 2 is small, then 20 DEG C of reactions 3 after sodium borohydride are added portionwise
Hour.Add 400 grams of triethyl group silicon hydrogen, be heated to 50 DEG C reaction 3 it is small when.1M hydrochloric acid washing reactions are used after the completion of question response
Liquid.By solvent portions drying and it is evaporated off obtaining 3 440 grams of intermediate, yield 65% after solvent.
3rd step:The intermediate 3 of 400 grams of BOC protections is dissolved in 4 liters of methanol and 1 liter of water, then hydrogen is added into reaction solution
Lithia solid, when 40 DEG C of reactions 3 are small.After question response terminates, methanol is steamed, is used after adding 5 liters of methyl tertiary butyl ether(MTBE)s
Clear water washes twice.Organic layer is passed through hydrogen chloride gas and obtains 4 320 grams of hydrochloride intermediate again after being dried with anhydrous sodium sulfate,
Yield 86%.
4th step:150 grams of 3300 grams of hydrochloride intermediate and potassium tert-butoxide are added in 5 liters of isopropanols, heating stirring
React 4 it is small when.Crude product is obtained after solvent is evaporated off, then crude product with methanol (50mL) and ethyl acetate (300mL) are tied again
Crystalline substance obtains 220 grams of pure product, yield 90%.
Claims (10)
1. a kind of (S) -2- methyl isophthalic acids, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, it is characterised in that:With such as lower structure
Compound be raw material, target product is obtained after ring-closure reaction.
2. a kind of (S) -2- methyl isophthalic acids, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, it is characterised in that:With such as lower structure
Compound be raw material, obtain target after carbonyl reduction, amide hydrolysis, amino deprotection hydrochloric acid salinization, ring-closure reaction successively
Product.
Wherein, Pro is amino protecting group.
3. a kind of (S) -2- methyl isophthalic acids, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, it is characterised in that:With such as lower structure
Compound be raw material, successively through be condensed into lactams, upper protection, carbonyl reduction, amide hydrolysis, amino be deprotected hydrochloride
Change, obtain target product after ring-closure reaction
Wherein, X is carboxyl or the group that can be converted into carboxyl.
4. one kind (S) -2- methyl isophthalic acids as claimed in claim 3, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, it is special
Sign is:L- acetyl asparagine is raw material, obtains target product after following process successively:
S1:By L- acetyl asparagine molecules internal condensations, and with protection group protection lactams nitrogen-atoms;
S2:By a carbonyl reduction of lactams, and hydrolyze, be deprotected the hydrochloride for being converted into ammonia;
S3:Target product is obtained through intramolecular cyclisation.
5. one kind (S) -2- methyl isophthalic acids as claimed in claim 4, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, it is special
Sign is that specific preparation method is as follows:
Step 1: under weak basic condition, L- acetyl asparagine is under conditions of condensing agent is added, in 10-35 DEG C of temperature
Under, when stirring reaction 1-5 is small, obtain lactam product;
Step 2: under the action of highly basic, the product of step 1 and Boc anhydride reactions protect the nitrogen-atoms of lactams
Come, more than 0 DEG C at a temperature of, with reducing agent react 2-10 it is small when, obtain the centre that lactam carbonyl is reduced to methylene
Body;
Step 3: protect to obtain salt by the product of step 2 lithium hydrate amido link, then with hcl reaction removing Boc
Hydrochlorate intermediate;
Step 4: by the product of step 3, under the action of alkali, at a temperature of 50 DEG C -120 DEG C, when reaction 5-24 is small, obtain
Molecule inner ring condensation product.
6. one kind (S) -2- methyl isophthalic acids as claimed in claim 5, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, it is special
Sign is:
In step 1, the molar ratio of the L- acetyl asparagine and, condensing agent is 1:1.5;
The molar ratio of weak base and L- the acetyl asparagine is 1:1.5;
In step 2, the product of the step 1 and the molar ratio of Boc acid anhydrides are 1:1-1.5;
The highly basic and the molar ratio of Boc acid anhydrides are 1:1-1.5;
The molar ratio 2-3 of the reducing agent and step 1 product:1;
In step 3, the product of the step 2 and the molar ratio of lithium hydroxide are 1:1-1.5;
In step 4, the molar ratio of the product of alkali and step 3 is 1:1-1.3.
7. one kind (S) -2- methyl isophthalic acids as claimed in claim 5, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, it is special
Sign is:
The step 1 carries out solvent-free reaction to step 4 or has solvent reaction;
The solvent is selected from ethers, esters, alcohols, aromatics and alkanes;
The weak base is selected from triethylamine, diisopropyl ethyl amine, and highly basic is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, the tert-butyl alcohol
Potassium, sodium hydride etc..
8. one kind (S) -2- methyl isophthalic acids as claimed in claim 5, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, it is special
Sign is:
The step 1 to step 4 is successive reaction;
Or
One or multi-step reaction in the step 1 to step 4, is purified after the completion of reaction;
The process of the purifying is as follows:
The purification process of step 1 product is:After the pH of reaction solution is adjusted to neutrality, step is obtained after extracting, solvent is evaporated off
One product;
The purification process of step 2 product is:After acid elution reaction solution, through drying, solvent is evaporated off after obtain step 2 production
Thing;
The purification process of step 3 product is:Filtering;
The purification process of step 4 product is:Target product is obtained after solvent and recrystallization is evaporated off.
9. one kind (S) -2- methyl isophthalic acids as described in claim 5-8 is any, the synthesis side of 4,5,6- tetrahydropyrimidine -4- carboxylic acids
Method, it is characterised in that:
In the step 4, it also added trimethyl orthoacetate and reacted.
10. one kind (S) -2- methyl isophthalic acids as claimed in claim 9, the synthetic method of 4,5,6- tetrahydropyrimidine -4- carboxylic acids, it is special
Sign is:
The product of the step 3 and the molar ratio of trimethyl orthoacetate are 1:0.1-1.5.
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KR102570658B1 (en) | 2022-10-12 | 2023-08-25 | 자경케미칼 주식회사 | Preparing method of heterocyclic amino acid and Heterocyclic amino acid by manufactured the method |
KR102634384B1 (en) | 2023-03-28 | 2024-02-06 | 자경케미칼 주식회사 | Preparing method of heterocyclic amino acid and their derivatives |
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KR102481697B1 (en) | 2022-02-11 | 2022-12-27 | 주식회사 자경케미칼 | Preparing method of ectoine and Ectoine prepared by the same method |
KR102570658B1 (en) | 2022-10-12 | 2023-08-25 | 자경케미칼 주식회사 | Preparing method of heterocyclic amino acid and Heterocyclic amino acid by manufactured the method |
KR102634384B1 (en) | 2023-03-28 | 2024-02-06 | 자경케미칼 주식회사 | Preparing method of heterocyclic amino acid and their derivatives |
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