CN115124593A - Synthesis method of high-purity GHK-Cu - Google Patents
Synthesis method of high-purity GHK-Cu Download PDFInfo
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- 108010038983 glycyl-histidyl-lysine Proteins 0.000 title claims abstract description 85
- 238000001308 synthesis method Methods 0.000 title abstract description 4
- 239000000243 solution Substances 0.000 claims abstract description 66
- 239000011259 mixed solution Substances 0.000 claims abstract description 57
- 239000003957 anion exchange resin Substances 0.000 claims abstract description 54
- 239000013078 crystal Substances 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 29
- 239000000047 product Substances 0.000 claims abstract description 26
- 238000010438 heat treatment Methods 0.000 claims abstract description 24
- 238000003756 stirring Methods 0.000 claims abstract description 24
- 150000001450 anions Chemical class 0.000 claims abstract description 18
- 150000001879 copper Chemical class 0.000 claims abstract description 10
- 238000001816 cooling Methods 0.000 claims abstract description 9
- 239000006227 byproduct Substances 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 6
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000001914 filtration Methods 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 68
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 55
- 239000007864 aqueous solution Substances 0.000 claims description 25
- 238000004090 dissolution Methods 0.000 claims description 21
- 239000003513 alkali Substances 0.000 claims description 13
- 230000002194 synthesizing effect Effects 0.000 claims description 13
- 239000002585 base Substances 0.000 claims description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 7
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 229940116318 copper carbonate Drugs 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- GEZOTWYUIKXWOA-UHFFFAOYSA-L copper;carbonate Chemical compound [Cu+2].[O-]C([O-])=O GEZOTWYUIKXWOA-UHFFFAOYSA-L 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims 2
- 238000002425 crystallisation Methods 0.000 abstract description 21
- 230000008025 crystallization Effects 0.000 abstract description 21
- MVORZMQFXBLMHM-QWRGUYRKSA-N Gly-His-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CN=CN1 MVORZMQFXBLMHM-QWRGUYRKSA-N 0.000 description 78
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 61
- 239000000706 filtrate Substances 0.000 description 60
- 238000005406 washing Methods 0.000 description 60
- 238000000967 suction filtration Methods 0.000 description 59
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- 238000005303 weighing Methods 0.000 description 41
- 238000001035 drying Methods 0.000 description 39
- MPTQRFCYZCXJFQ-UHFFFAOYSA-L copper(II) chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Cu+2] MPTQRFCYZCXJFQ-UHFFFAOYSA-L 0.000 description 23
- 239000011347 resin Substances 0.000 description 20
- 229920005989 resin Polymers 0.000 description 20
- 238000002390 rotary evaporation Methods 0.000 description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 229910001431 copper ion Inorganic materials 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 241000530268 Lycaena heteronea Species 0.000 description 1
- VRBJCEAUZYHRLD-WUGLXOLRSA-N N[C@@H](CCCCN)C(=O)O.N[C@@H](CC1=CNC=N1)C(=O)O.NCC(=O)O.[Cu] Chemical compound N[C@@H](CCCCN)C(=O)O.N[C@@H](CC1=CNC=N1)C(=O)O.NCC(=O)O.[Cu] VRBJCEAUZYHRLD-WUGLXOLRSA-N 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000012609 strong anion exchange resin Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
Classifications
-
- 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
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
Abstract
The invention relates to a synthesis method of high-purity GHK-Cu, which comprises the following steps: s1, adding a copper salt into the solution of the GHK product, and uniformly stirring to obtain a mixed solution, wherein the GHK product contains by-product anions; s2, adding the mixed solution into anion exchange resin for reaction, and then filtering to obtain a reacted mixed solution; s3, concentrating the reacted mixed solution, adding an ethanol water solution, heating to 40-70 ℃, and ultrasonically dissolving to obtain a re-dissolved solution; and S4, cooling the redissolved solution to obtain a GHK-Cu crystal. The GHK-Cu product obtained by the method has the advantages of high purity, high yield, convenient crystallization, simple operation, low cost and high efficiency.
Description
Technical Field
The invention relates to synthesis of copper glycylhistidyl lysine, in particular to a method for synthesizing high-purity copper glycylhistidyl lysine, and particularly relates to a method for synthesizing copper glycylhistidyl lysine crystals.
Background
Glycylhistidyllysine (GHK) is an endogenous collagen tripeptide isolated from human plasma that has a strong affinity for the 2-valent copper ion and forms spontaneously with itThe complex GHK-Cu. The composition of GHK-Cu is as follows: glycine-histidine-lysine-copper (glycyl-L-histidyl-L-lysine-copper), copper ion Cu 2+ The yellow color of copper metal is not changed, but the copper metal is blue in aqueous solution, so GHK-Cu is also called blue copper peptide. According to the current research results, the functions mainly comprise: effectively promote the production of collagen, increase the growth of blood vessels and the oxidation resistance, stimulate the production of glucosaminoglycans and help the skin recover the self-repairing ability; promote the growth and differentiation of epithelial cells, thereby accelerating the healing of the wound surface. Has the functions of resisting oxidation, promoting collagen proliferation and assisting wound healing on the action of skin tissues. Scientists find that the wrinkle removing effect of copper ions is mainly that divalent copper ion components with biochemical effect enter cells to play physiological functions by virtue of carriers of amino acid complex (peptide). However, how to synthesize high-purity GHK-Cu more efficiently is a problem.
The Chinese application with the application number of 201810868124.X discloses a method for generating GHK-Cu by directly reacting a product obtained by freeze-drying a GHK crude peptide after preparation and purification with copper acetate according to the action of 1:1 or 2: 1.
The Chinese application with the application number of 201711221991.6 discloses a method for synthesizing GHK acetate at low cost, which is a method for deprotecting Tit-Gly-His (Tit) -Lys (Trt) -OH in acetic acid and triisopropylsilane to generate GHK acetate. Although the method can reduce the cost of producing GHK acetate, excessive acetate ions in the synthesized GHK-Cu can cause that the GHK-Cu can not be crystallized and separated out.
Chinese application No. 201310751827.1 discloses a method for synthesizing GHK tripeptide, which comprises the steps of synthesizing Boc-Gly-His (Boc) -LYS (Ac) -OH, removing protection by trifluoroacetic acid to obtain trifluoroacetic acid salt of GHK, and then generating GHK acetate by reversed phase chromatography and ion exchange chromatography. The disadvantage of this method is that the deprotected trifluoroacetate needs to be purified by reverse phase chromatography to remove trifluoroacetic acid from the product and then converted to acetate by ion exchange chromatography, which is costly and not suitable for large scale production.
The existing GHK-Cu production technology basically utilizes a product obtained by reacting acetate of GHK with copper acetate at room temperature, and the method easily influences the yield of GHK-Cu due to more acetate content and poor control of acetate ion content in a reaction system.
From the above, in the process of synthesizing GHK-Cu from the conventional GHK product, it is difficult to efficiently synthesize high-purity GHK-Cu, especially GHK-Cu crystals, due to interference of anions (such as acetate and trifluoroacetate) caused by salts carried in the GHK product.
Disclosure of Invention
The invention aims to provide a method for synthesizing high-purity copper glycyl histidyl lysine GHK-Cu, which removes anions brought by salt in GHK products (such as acetate of GHK, trifluoroacetate of GHK and the like) by using anion exchange resin and then efficiently synthesizes the GHK-Cu product with higher purity and full crystal particles by adopting a recrystallization method.
Therefore, the invention provides a synthesis method of high-purity GHK-Cu, which comprises the following steps:
s1, adding a copper salt into the solution of the GHK product, and uniformly stirring to obtain a mixed solution, wherein the GHK product contains by-product anions;
s2, adding the mixed solution into anion exchange resin for reaction, and then filtering to obtain a reacted mixed solution;
s3, concentrating the mixed solution after reaction, adding an ethanol water solution, heating to 40-70 ℃, and performing ultrasonic dissolution to obtain a re-dissolved solution;
and S4, cooling the redissolved solution to obtain the GHK-Cu crystal.
In step S1, it is preferable that the copper salt is at least one selected from copper acetate, copper chloride, copper sulfate and copper carbonate, and it is further preferable that the copper salt is copper acetate and/or copper chloride.
In step S1, it is preferable that a molar ratio of the GHK in the solution of the GHK product to the copper salt is 1-2: 1.
In step S1, the byproduct anion is an anion of at least one of trifluoroacetate, acetate, hydrochloride, phosphate, and citrate, and more commonly, the byproduct anion is an anion of at least one of trifluoroacetate, acetate, and hydrochloride.
In step S1, the GHK concentration in the solution of the GHK product is preferably 50mg/ml to 500mg/ml, and more preferably 100 ± 20 mg/ml.
In step S2, it is preferable that the anion exchange resin is a strong base type anion exchange resin.
In step S2, it is preferable that the anion exchange resin has been subjected to a pretreatment comprising: the anion exchange resin is washed with alkali and then washed to neutrality.
In step S3, it is preferable that the concentration is such that 50 wt% to 100 wt% of the solvent in the mixed solution is removed by evaporation under reduced pressure.
In step S3, the concentration of ethanol in the ethanol aqueous solution is preferably 65 vol% to 85 vol%, preferably 78 vol%.
In step S3, the ethanol aqueous solution is preferably heated to 55 ℃.
In step S4, preferably, the temperature of the redissolved solution is reduced to less than or equal to 40 ℃, and the reducing is a step-by-step reducing, specifically including: cooling to 20-30 deg.C, and then cooling to 2-8 deg.C.
The invention has the following beneficial effects:
(1) according to the method, anion work of desalting the GHK product is performed by using anion exchange resin, the anion removal is favorable for the complexation of copper salt and GHK to synthesize GHK-Cu crystals, and further the recrystallization principle is combined, and the ethanol water solution is heated, dissolved and cooled to obtain GHK-Cu crystals, so that the GHK-Cu product obtained by the method has the advantages of high purity, high yield and convenience in crystallization.
(2) The method widens the source of GHK products, can be acetate of GHK, can also be trifluoroacetate of GHK and the like, and the content of anions in the GHK products does not influence the subsequent yield of GHK-Cu, thereby being beneficial to further reducing the cost and industrialization.
(3) According to the method, the high-purity GHK-Cu product is obtained by adding 65-85 vol% ethanol solution and separating out GHK-Cu from the ethanol solution by using the principle of recrystallization. The ethanol solution with the concentration of 65-85 vol% is selected, so that the granularity of the precipitated GHK-Cu crystal is larger, the yield is higher, the purity is higher, and the cost is reduced.
(4) The method of the invention raises the temperature of 65-85 vol% ethanol solution to 40-70 ℃, accelerates the dissolution rate and solubility of GHK-Cu product in ethanol, and improves the purity and yield of the product. If the temperature is not raised, the solubility of GHK-Cu in ethanol is reduced, which is not favorable for recrystallization, and the yield is reduced or GHK-Cu crystals are difficult to obtain.
Detailed Description
The following examples illustrate the invention in detail: the present example is carried out on the premise of the technical scheme of the present invention, and detailed embodiments and processes are given, but the scope of the present invention is not limited to the following examples, and experimental methods without specific conditions noted in the following examples are generally performed under conventional conditions.
In the embodiment of the invention, the acetate content of the GHK acetate sample is 10-40%, and the GHK content is 60% -75%.
Example 1: crystalline trifluoroacetate salt GHK
Weighing 4.14g of a sample of trifluoroacetic acid salt of GHK (the content of GHK is 70 vol%, and the content of the trifluoroacetic acid salt is 25 vol%), adding 20ml of pure water for dissolving, then adding 1.7g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, and standing for later use;
weighing 20g of strong base anion exchange resin in a sand core funnel, firstly washing with sodium hydroxide solution for three times, then washing with pure water until the pH value of filtrate is 7, slowly adding the mixed solution into the anion exchange resin, performing suction filtration after reacting for 5-10min, collecting filtrate, performing suction filtration again, repeating the suction filtration for three times, then washing the resin with pure water for three times, collecting filtrate, performing reduced pressure rotary drying by using a rotary evaporator, adding 20ml of prepared 78 volume percent ethanol aqueous solution into a rotary evaporation bottle, heating to 55 ℃, performing ultrasonic dissolution, placing the dissolved sample at room temperature of 25 ℃ for crystallization, placing the sample at room temperature for 12 hours after the sample is recovered to the room temperature (the purpose of sectional cooling in the embodiment is slow cooling, increasing the granularity of crystalline particles), pouring out blue solution to obtain crystals, namely GHK-Cu (1:1), drying to obtain 3.80g of GHK-Cu (1:1) with a yield of 91.8%.
Example 2: crystals of GHK acetate
Weighing 3.92g of GHK (containing 70 vol% of GHK and 25 vol% of acetate) sample of acetate, adding 40ml of pure water for dissolving, then adding 1.7g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, and standing for later use;
weighing 20g of strong alkali type anion exchange resin in a sand core funnel, firstly washing with sodium hydroxide solution for three times, then washing with pure water until the pH value of filtrate is 7, slowly adding the mixed solution into the anion exchange resin, reacting for 5-10min, carrying out suction filtration, collecting filtrate, carrying out suction filtration again, repeating the suction filtration for three times, then washing the resin with pure water for three times, collecting filtrate, carrying out reduced pressure rotary drying by using a rotary evaporator, adding 20ml of prepared 78 volume percent ethanol aqueous solution into a rotary evaporation bottle, heating to 55 ℃, carrying out ultrasonic dissolution, placing the dissolved sample at room temperature for crystallization, placing the sample at 2-8 ℃ for 12 hours after the sample is recovered to 25 ℃ at room temperature, pouring out the blue solution to obtain a crystal which is GHK-Cu (1:1), drying to obtain 3.8g of GHK-Cu (1:1), and obtaining the yield of 96.9%.
Example 3: crystals of the hydrochloride salt GHK
Weighing 3.92g of a GHK (containing 72 vol% of GHK and 25 vol% of hydrochloride) sample of hydrochloride, adding 40ml of pure water for dissolving, then adding 1.7g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, and standing for later use;
weighing 20g of strong alkali type anion exchange resin in a sand core funnel, firstly washing with sodium hydroxide solution for three times, then washing with pure water until the pH value of filtrate is 7, slowly adding the mixed solution into the anion exchange resin, reacting for 5-10min, carrying out suction filtration, collecting filtrate, carrying out suction filtration again, repeating the suction filtration for three times, then washing the resin with pure water for three times, collecting filtrate, carrying out reduced pressure rotary drying by using a rotary evaporator, adding 20ml of prepared 78 volume percent ethanol aqueous solution into a rotary evaporation bottle, heating to 55 ℃, carrying out ultrasonic dissolution, placing the dissolved sample at room temperature for crystallization, placing the sample at 2-8 ℃ for 12 hours after the sample is recovered to 25 ℃ at room temperature, pouring out the blue solution to obtain a crystal which is GHK-Cu (1:1), and drying to obtain 3.61g of GHK-Cu (1:1) with the yield of 92.1%.
Example 4:
weighing 3.92g of a GHK (GHK content is 70 vol% and acetate content is 25 vol%) sample of acetate, adding 40ml of pure water for dissolving, then adding 2.1g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, and standing for later use;
weighing 20g of strong base anion exchange resin into a sand core funnel, firstly washing with a sodium hydroxide solution for three times, then washing with pure water until the pH value of the filtrate is 7, slowly adding the mixed solution into the anion exchange resin, reacting for 5-10min, carrying out suction filtration, collecting the filtrate, carrying out suction filtration again, repeating the suction filtration for three times, then washing the resin with pure water for three times, collecting the filtrate, carrying out reduced pressure rotary drying by using a rotary evaporator, adding 20ml of prepared 78 volume percent ethanol aqueous solution into a rotary evaporation bottle, heating to 55 ℃, carrying out ultrasonic dissolution, placing the dissolved sample at room temperature for crystallization, placing the sample at 2-8 ℃ for 12 hours after the sample is recovered to the room temperature of 25 ℃, pouring out the blue solution to obtain a crystal which is GHK-Cu (2:1), and drying to obtain 3.81g of GHK-Cu (2:1) with the yield of 97.1%.
Example 5
Weighing 2.01g of a GHK (GHK content is 70 vol%, acetate content is 25 vol%) sample of acetate, adding 40ml of pure water for dissolving, then adding 2.1g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, and standing for later use;
weighing 20g of strong alkali type anion exchange resin in a sand core funnel, firstly washing with sodium hydroxide solution for three times, then washing with pure water until the pH value of filtrate is 7, slowly adding the mixed solution into the anion exchange resin, reacting for 5-10min, carrying out suction filtration, collecting filtrate, carrying out suction filtration again, repeating the suction filtration for three times, then washing the resin with pure water for three times, collecting filtrate, carrying out reduced pressure rotary drying by using a rotary evaporator, adding 20ml of prepared 78 volume percent ethanol aqueous solution into a rotary evaporation bottle, heating to 55 ℃, carrying out ultrasonic dissolution, placing the dissolved sample at room temperature for crystallization, placing the sample at 2-8 ℃ for 12 hours after the sample is recovered to 25 ℃ at room temperature, pouring out the blue solution to obtain a crystal which is GHK-Cu (1:1), and drying to obtain 3.65g of GHK-Cu (1:1) with the yield of 93.1%.
Example 6
Weighing 4.00g of GHK (containing 70 vol% of GHK and 25 vol% of acetate) sample of acetate, adding 40ml of pure water for dissolving, then adding 2.10g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, and standing for later use;
weighing 20g of strong alkali type anion exchange resin in a sand core funnel, firstly washing with sodium hydroxide solution for three times, then washing with pure water until the pH value of filtrate is 7, slowly adding the mixed solution into the anion exchange resin, reacting for 5-10min, carrying out suction filtration, collecting filtrate, carrying out suction filtration again, repeating the suction filtration for three times, then washing the resin with pure water for three times, collecting filtrate, carrying out reduced pressure rotary drying by using a rotary evaporator, adding 20ml of prepared 78 volume percent ethanol aqueous solution into a rotary evaporation bottle, heating to 55 ℃, carrying out ultrasonic dissolution, placing the dissolved sample at room temperature for crystallization, placing the sample at 2-8 ℃ for 12 hours after the sample is recovered to 25 ℃ at room temperature, pouring out the blue solution to obtain a crystal which is GHK-Cu (2:1), and drying to obtain 3.81g of GHK-Cu (2:1) with the yield of 97.1%.
Example 7
Weighing 4.80g of GHK (GHK content is 70 vol% and acetate content is 25 vol%) sample of acetate, adding 40ml of pure water for dissolving, then adding 2.10g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, and standing for later use;
weighing 20g of strong base anion exchange resin into a sand core funnel, firstly washing with a sodium hydroxide solution for three times, then washing with pure water until the pH value of the filtrate is 7, slowly adding the mixed solution into the anion exchange resin, reacting for 5-10min, carrying out suction filtration, collecting the filtrate, carrying out suction filtration again, repeating the suction filtration for three times, then washing the resin with pure water for three times, collecting the filtrate, carrying out reduced pressure rotary drying by using a rotary evaporator, adding 20ml of prepared 78 volume percent ethanol aqueous solution into a rotary evaporation bottle, heating to 55 ℃, carrying out ultrasonic dissolution, placing the dissolved sample at room temperature for crystallization, placing the sample at 2-8 ℃ for 12 hours after the sample is recovered to the room temperature of 25 ℃, pouring out blue solution to obtain crystal which is GHK-Cu (2:1), drying to obtain 3.80g of GHK-Cu (2:1), and obtaining the yield of 96.9%.
Example 8
Weighing 3.92g of acetate GHK (containing 70 vol% of GHK and 25 vol% of acetate) sample, adding 40ml of pure water for dissolving, then adding 2.10g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, standing for later use, weighing 20g of strongly basic anion exchange resin in a sand core funnel, firstly washing with sodium hydroxide solution for three times, then washing with pure water until the pH value of the filtrate is 7, slowly adding the mixed solution into the anion exchange resin, reacting for 5-10min, carrying out suction filtration, collecting the filtrate, carrying out suction filtration again, repeating suction filtration for three times, then washing the resin with pure water for three times, collecting the filtrate, carrying out reduced pressure spin drying by using a rotary evaporator, then adding 20ml of prepared 78 vol% ethanol aqueous solution into a spin-steaming bottle, heating to 55 ℃ for ultrasonic dissolution, placing the dissolved sample at room temperature for crystallization, placing the sample at 2-8 ℃ for 12 hours after the sample is recovered to 25 ℃ at room temperature, pouring out blue solution to obtain crystal which is GHK-Cu (2:1), and drying to obtain 3.7g of GHK-Cu (2:1) with the yield of 96.1%.
Example 9
Weighing 3.92g of GHK (containing 70 vol% of GHK and 25 vol% of acetate) sample of acetate, adding 8ml of pure water for dissolving, then adding 8.98g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, and standing for later use;
weighing 20g of strong alkali type anion exchange resin in a sand core funnel, firstly washing with sodium hydroxide solution for three times, then washing with pure water until the pH value of filtrate is 7, slowly adding the mixed solution into the anion exchange resin, reacting for 5-10min, carrying out suction filtration, collecting filtrate, carrying out suction filtration again, repeating the suction filtration for three times, then washing the resin with pure water for three times, collecting filtrate, carrying out reduced pressure rotary drying by using a rotary evaporator, adding 20ml of prepared 78 volume percent ethanol aqueous solution into a rotary evaporation bottle, heating to 55 ℃, carrying out ultrasonic dissolution, placing the dissolved sample at room temperature for crystallization, placing the sample at 2-8 ℃ for 12 hours after the sample is recovered to 25 ℃ at room temperature, pouring out blue solution to obtain crystal which is GHK-Cu (2:1), drying to obtain 3.75g of GHK-Cu (2:1) with yield of 95.8%.
Example 10
Weighing 3.92g of GHK (containing 70 vol% of GHK and 25 vol% of acetate) sample of acetate, adding 40ml of pure water for dissolving, then adding 2.1g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, and standing for later use;
weighing 20g of weak base type anion exchange resin in a sand core funnel, firstly washing with sodium carbonate solution for three times, then washing with pure water until the pH value of filtrate is 7, slowly adding the mixed solution into the anion exchange resin, reacting for 5-10min, carrying out suction filtration, collecting filtrate, carrying out suction filtration again, repeating the suction filtration for three times, then washing the resin with pure water for three times, collecting filtrate, carrying out reduced pressure rotary drying by using a rotary evaporator, then adding 20ml of prepared 78 volume percent ethanol aqueous solution into a rotary evaporation bottle, heating to 55 ℃ for ultrasonic dissolution, placing the dissolved sample at room temperature for crystallization, placing the sample at 2-8 ℃ for 12 hours after the sample is recovered to 25 ℃ at room temperature, pouring out the blue solution to obtain a crystal which is GHK-Cu (2:1), and drying to obtain 3.42g of GHK-Cu (2:1) with the yield of 87.2%.
Comparative example 1
Excess anions are removed without using an anion exchange resin.
Weighing 3.92g of a GHK (containing 70 vol% of GHK and 25 vol% of acetic acid) sample of acetate, adding 40ml of pure water for dissolving, then adding 2.1g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, adding 20ml of prepared 78 vol% ethanol aqueous solution, heating to 55 ℃, then placing at room temperature, after the sample is recovered to 25 ℃ at room temperature, placing at 2-8 ℃ for 12 hours, pouring out a blue solution, and not obtaining GHK-Cu crystals.
As is clear from comparative example 1, it is difficult to synthesize GHK-Cu crystals without removing excess anions using an anion exchange resin.
Example 11
Weighing 3.92g of a GHK (GHK content is 70 vol% and acetate content is 25 vol%) sample of acetate, adding 40ml of pure water for dissolving, then adding 2.1g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, and standing for later use;
weighing 20g of strong alkali type anion exchange resin in a sand core funnel, firstly washing with sodium carbonate solution for three times, then washing with pure water until the pH value of filtrate is 7, slowly adding the mixed solution into the anion exchange resin, reacting for 5-10min, carrying out suction filtration, collecting filtrate, carrying out suction filtration again, repeating the suction filtration for three times, then washing the resin with pure water for three times, collecting filtrate, carrying out reduced pressure rotary drying by using a rotary evaporator, then adding 20ml of prepared 65 volume percent ethanol aqueous solution into a rotary evaporation bottle, heating to 55 ℃ for ultrasonic dissolution, placing the dissolved sample at room temperature for crystallization, placing the sample at 2-8 ℃ for 12 hours after the sample is recovered to 25 ℃ at room temperature, pouring out the blue solution to obtain a crystal which is GHK-Cu (2:1), and drying to obtain 3.42g of GHK-Cu (2:1) with the yield of 87.2%.
Example 12
Weighing 3.92g of a GHK (GHK content is 70 vol% and acetate content is 25 vol%) sample of acetate, adding 40ml of pure water for dissolving, then adding 2.1g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, and standing for later use;
weighing 20g of strong alkali type anion exchange resin in a sand core funnel, firstly washing with sodium carbonate solution for three times, then washing with pure water until the pH value of filtrate is 7, slowly adding the mixed solution into the anion exchange resin, reacting for 5-10min, carrying out suction filtration, collecting filtrate, carrying out suction filtration again, repeating the suction filtration for three times, then washing the resin with pure water for three times, collecting filtrate, carrying out reduced pressure rotary drying by using a rotary evaporator, then adding 20ml of prepared 70 volume percent ethanol aqueous solution into a rotary evaporation bottle, heating to 55 ℃ for ultrasonic dissolution, placing the dissolved sample at room temperature for crystallization, placing the sample at 2-8 ℃ for 12 hours after the sample is recovered to 25 ℃ at room temperature, pouring out the blue solution to obtain a crystal which is GHK-Cu (2:1), and drying to obtain 3.58g of GHK-Cu (2:1) with the yield of 91.3%.
Example 13
Weighing 3.92g of GHK (containing 70 vol% of GHK and 25 vol% of acetate) sample of acetate, adding 40ml of pure water for dissolving, then adding 2.1g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, and standing for later use;
weighing 20g of strong base anion exchange resin into a sand core funnel, firstly washing with sodium carbonate solution for three times, then washing with pure water until the pH value of the filtrate is 7, slowly adding the mixed solution into the anion exchange resin, reacting for 5-10min, carrying out suction filtration, collecting the filtrate, carrying out suction filtration again, repeating the suction filtration for three times, then washing the resin with pure water for three times, collecting the filtrate, carrying out reduced pressure spin drying by using a rotary evaporator, then adding 20ml of prepared 85 volume percent ethanol aqueous solution into a spin-evaporation bottle, heating to 55 ℃, carrying out ultrasonic dissolution, placing the dissolved sample at room temperature for crystallization, placing the sample at 2-8 ℃ for 12 hours after the sample is recovered to the room temperature of 25 ℃, pouring out the blue solution to obtain a crystal which is GHK-Cu (2:1), and drying to obtain 3.78g of GHK-Cu (2:1) with the yield of 96.4%.
Comparative example 2
Weighing 3.92g of a GHK (GHK content is 70 vol% and acetate content is 25 vol%) sample of acetate, adding 40ml of pure water for dissolving, then adding 2.1g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, and standing for later use;
weighing 20g of strong base anion exchange resin in a sand core funnel, firstly washing with sodium carbonate solution for three times, then washing with pure water until the pH value of filtrate is 7, slowly adding the mixed solution into the anion exchange resin, reacting for 5-10min, carrying out suction filtration, collecting filtrate, carrying out suction filtration again, repeating the suction filtration for three times, then washing the resin with pure water for three times, collecting filtrate, carrying out reduced pressure rotary drying by using a rotary evaporator, then adding 20ml of ultrapure water into a rotary evaporation bottle, heating to 55 ℃, placing the heated sample at room temperature for crystallization, placing the sample at 2-8 ℃ for 12 hours after the temperature of the sample is recovered to 25 ℃, pouring out blue solution, and obtaining no GHK-Cu product.
As is clear from comparison of examples 11 to 13 with comparative example 2, the mixed solution from which the by-product anion is removed needs to be redissolved with an aqueous ethanol solution, otherwise it is difficult to synthesize GHK-Cu crystals.
Example 14
Weighing 3.92g of GHK (containing 70 vol% of GHK and 25 vol% of acetate) sample of acetate, adding 40ml of pure water for dissolving, then adding 2.1g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, and standing for later use;
weighing 20g of strong base anion exchange resin in a sand core funnel, firstly washing with sodium hydroxide solution for three times, then washing with pure water until the pH value of filtrate is 7, slowly adding the mixed solution into the strong anion exchange resin, reacting for 5-10min, carrying out suction filtration, collecting filtrate, carrying out suction filtration again, repeating the suction filtration for three times, then washing the resin with pure water for three times, collecting filtrate, carrying out reduced pressure rotary drying by using a rotary evaporator, adding 20ml of prepared 78 volume percent ethanol aqueous solution into a rotary evaporation bottle, heating to 40 ℃, carrying out ultrasonic dissolution, placing the dissolved sample at room temperature for crystallization, and placing the sample at 2-8 ℃ for 12 hours after the sample is recovered to 25 ℃ at room temperature, pouring out the blue solution to obtain a crystal which is GHK-Cu (2:1), drying to obtain 3.58g of GHK-Cu (2:1) with the yield of 91.3%.
Example 15
Weighing 3.92g of GHK (containing 70 vol% of GHK and 25 vol% of acetate) sample of acetate, adding 40ml of pure water for dissolving, then adding 2.1g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, and standing for later use;
weighing 20g of strong alkali type anion exchange resin in a sand core funnel, firstly washing with sodium hydroxide solution for three times, then washing with pure water until the pH value of filtrate is 7, slowly adding the mixed solution into the anion exchange resin, reacting for 5-10min, carrying out suction filtration, collecting filtrate, carrying out suction filtration again, repeating the suction filtration for three times, then washing the resin with pure water for three times, collecting filtrate, carrying out reduced pressure rotary drying by using a rotary evaporator, adding 20ml of prepared 78 volume percent ethanol aqueous solution into a rotary evaporation bottle, heating to 45 ℃ for ultrasonic dissolution, placing the dissolved sample at room temperature for crystallization, placing the sample at 2-8 ℃ for 12 hours after the sample is recovered to 25 ℃ at room temperature, pouring out the blue solution to obtain a crystal which is GHK-Cu (2:1), and drying to obtain 3.77g of GHK-Cu (2:1) with the yield of 96.1%.
Example 16
Weighing 3.92g of GHK (containing 70 vol% of GHK and 25 vol% of acetate) sample of acetate, adding 40ml of pure water for dissolving, then adding 2.1g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, and standing for later use;
weighing 20g of strong alkali type anion exchange resin in a sand core funnel, firstly washing with sodium hydroxide solution for three times, then washing with pure water until the pH value of filtrate is 7, slowly adding the mixed solution into the anion exchange resin, reacting for 5-10min, carrying out suction filtration, collecting filtrate, carrying out suction filtration again, repeating the suction filtration for three times, then washing the resin with pure water for three times, collecting filtrate, carrying out reduced pressure rotary drying by using a rotary evaporator, adding 20ml of prepared 78 volume percent ethanol aqueous solution into a rotary evaporation bottle, heating to 50 ℃ for ultrasonic dissolution, placing the dissolved sample at room temperature for crystallization, placing the sample at 2-8 ℃ for 12 hours after the sample is recovered to 25 ℃ at room temperature, pouring out the blue solution to obtain a crystal which is GHK-Cu (2:1), and drying to obtain 3.79g of GHK-Cu (2:1) with the yield of 96.6%.
EXAMPLE 17
Weighing 3.92g of GHK (containing 70 vol% of GHK and 25 vol% of acetate) sample of acetate, adding 40ml of pure water for dissolving, then adding 2.1g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, and standing for later use;
weighing 20g of strong alkali type anion exchange resin in a sand core funnel, firstly washing with sodium hydroxide solution for three times, then washing with pure water until the pH value of filtrate is 7, slowly adding the mixed solution into the anion exchange resin, reacting for 5-10min, carrying out suction filtration, collecting filtrate, carrying out suction filtration again, repeating the suction filtration for three times, then washing the resin with pure water for three times, collecting filtrate, carrying out reduced pressure rotary drying by using a rotary evaporator, adding 20ml of prepared 78 volume percent ethanol aqueous solution into a rotary evaporation bottle, heating to 65 ℃ for ultrasonic dissolution, placing the dissolved sample at room temperature for crystallization, placing the sample at 2-8 ℃ for 12 hours after the sample is recovered to 25 ℃ at room temperature, pouring out the blue solution to obtain a crystal which is GHK-Cu (2:1), and drying to obtain 3.77g of GHK-Cu (2:1) with the yield of 96.1%.
EXAMPLE 18
Weighing 3.92g of GHK (containing 70 vol% of GHK and 25 vol% of acetate) sample of acetate, adding 40ml of pure water for dissolving, then adding 2.1g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, and standing for later use;
weighing 20g of strong alkali type anion exchange resin in a sand core funnel, firstly washing with sodium hydroxide solution for three times, then washing with pure water until the pH value of filtrate is 7, slowly adding the mixed solution into the anion exchange resin, reacting for 5-10min, carrying out suction filtration, collecting filtrate, carrying out suction filtration again, repeating the suction filtration for three times, then washing the resin with pure water for three times, collecting filtrate, carrying out reduced pressure rotary drying by using a rotary evaporator, adding 20ml of prepared 78 volume percent ethanol aqueous solution into a rotary evaporation bottle, heating to 70 ℃, carrying out ultrasonic dissolution, placing the dissolved sample at room temperature for crystallization, placing the sample at 2-8 ℃ for 12 hours after the sample is recovered to 25 ℃ at room temperature, pouring out the blue solution to obtain a crystal which is GHK-Cu (2:1), and drying to obtain 3.77g of GHK-Cu (2:1) with the yield of 96.1%.
Comparative example 3
Weighing 3.92g of GHK (containing 70 vol% of GHK and 25 vol% of acetate) sample of acetate, adding 40ml of pure water for dissolving, then adding 2.1g of copper chloride dihydrate, stirring uniformly to obtain a mixed solution, and standing for later use;
weighing 20g of strong base anion exchange resin in a sand core funnel, firstly washing with sodium hydroxide solution for three times, then washing with pure water until the pH value of filtrate is 7, slowly adding the mixed solution into the strong base anion exchange resin, reacting for 5-10min, carrying out suction filtration, collecting filtrate, carrying out suction filtration for three times, then washing the resin with pure water for three times, collecting filtrate, carrying out reduced pressure rotary drying by using a rotary evaporator, adding 20ml of prepared 78 volume percent ethanol aqueous solution into a rotary evaporation bottle, directly placing for 12 hours at the temperature of 2-8 ℃ without heating, pouring out blue solution to obtain crystals, namely GHK-Cu (2:1), drying to obtain 2.57g of GHK-Cu (2:1), and obtaining the yield of 65.6%.
As is clear from comparison of examples 14 to 18 with comparative example 3, the mixed solution from which the by-product anion was removed was heated to 40 to 65 ℃ when redissolved with an aqueous ethanol solution, otherwise it was difficult to synthesize GHK-Cu crystals.
The present invention is capable of other embodiments, and various changes and modifications can be made by one skilled in the art without departing from the spirit and scope of the invention.
Claims (10)
1. A method for synthesizing high-purity GHK-Cu is characterized by comprising the following steps:
s1, adding a copper salt into the solution of the GHK product, and uniformly stirring to obtain a mixed solution, wherein the GHK product contains by-product anions;
s2, adding the mixed solution into anion exchange resin for reaction, and then filtering to obtain a reacted mixed solution;
s3, concentrating the mixed solution after reaction, adding an ethanol water solution, heating to 40-70 ℃, and performing ultrasonic dissolution to obtain a re-dissolved solution;
and S4, cooling the redissolved solution to obtain the GHK-Cu crystal.
2. The method for synthesizing high purity GHK-Cu as claimed in claim 1, wherein the copper salt is at least one selected from copper acetate, copper chloride, copper sulfate and copper carbonate, and further preferably the copper salt is copper acetate and/or copper chloride.
3. The method for synthesizing high-purity GHK-Cu as claimed in claim 1, wherein the molar ratio of GHK in the solution of GHK product to the copper salt is 1-2: 1.
4. The method of synthesizing high purity GHK-Cu as in claim 1, wherein the byproduct anion is an anion of at least one of trifluoroacetate, acetate, hydrochloride, phosphate, and citrate.
5. The method for synthesizing high purity GHK-Cu as claimed in claim 1, wherein the concentration of GHK in the solution of GHK product is 50mg/ml-500mg/ml, more preferably 100 ± 20 mg/ml.
6. The method as claimed in claim 1, wherein the anion exchange resin is a strong base anion exchange resin in step S2.
7. The method as claimed in claim 1, wherein the anion exchange resin has been pretreated in step S2, the pretreatment comprising: the anion exchange resin is washed with alkali and then washed to neutrality.
8. The method as claimed in claim 1, wherein the concentration is such that 50 wt% to 100 wt% of the solvent in the mixed solution is removed by evaporation under reduced pressure in step S3.
9. The method for synthesizing high purity GHK-Cu as claimed in claim 1, wherein the concentration of ethanol in the ethanol aqueous solution is 65 vol% to 85 vol%, preferably 78 vol% in step S3.
10. The method as claimed in claim 1, wherein the ethanol aqueous solution is heated to 55-65 ℃ in step S3; in step S4, cooling the redissolved solution to less than or equal to 40 ℃; the cooling is sectional cooling.
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| WO2007087738A1 (en) * | 2006-02-03 | 2007-08-09 | Pentapharm Ag | Biologically active tripeptides and copper complexes and salts thereof |
| CN108276455A (en) * | 2017-01-05 | 2018-07-13 | 西南化工研究设计院有限公司 | A kind of synthetic method of L- xyloses |
| CN111690037A (en) * | 2020-07-31 | 2020-09-22 | 广州赛莱拉干细胞科技股份有限公司 | Method for synthesizing GHK acetate |
| CN111808165A (en) * | 2020-06-24 | 2020-10-23 | 浙江天台药业有限公司 | Synthetic method of GHK copper peptide |
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| WO2007087738A1 (en) * | 2006-02-03 | 2007-08-09 | Pentapharm Ag | Biologically active tripeptides and copper complexes and salts thereof |
| CN108276455A (en) * | 2017-01-05 | 2018-07-13 | 西南化工研究设计院有限公司 | A kind of synthetic method of L- xyloses |
| CN111808165A (en) * | 2020-06-24 | 2020-10-23 | 浙江天台药业有限公司 | Synthetic method of GHK copper peptide |
| CN111690037A (en) * | 2020-07-31 | 2020-09-22 | 广州赛莱拉干细胞科技股份有限公司 | Method for synthesizing GHK acetate |
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