CN109053580B - Synthesis method of cosmetic dipeptide - Google Patents
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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Abstract
The invention discloses a synthesis method of a cosmetic dipeptide, belonging to the technical field of polypeptide synthesis. The synthesis method comprises the following steps: alanine is protected by phthalic anhydride to prepare phthaloyl protected alanine, then the phthaloyl protected alanine reacts with acyl chlorination reagent to prepare corresponding acyl chloride product, histamine reacts with hexamethyldisilazane to obtain histamine silane protective substance, then the phthalic acyl protected dipeptide is obtained by reacting with acyl chloride product, finally deprotection is carried out under specific conditions to obtain cosmetic dipeptide, and the cosmetic dipeptide is decarboxylated carnosine. The synthesis method provided by the invention does not use a condensing agent, has cheap and easily obtained raw materials, less byproducts and high yield (the total yield is 78.6-86.4%) and is easy to obtain the dipeptide with high purity (the purity is more than 99%), thereby reducing the cost and being suitable for batch production.
Description
Technical Field
The invention belongs to the technical field of polypeptide synthesis, and particularly discloses a synthesis method of a cosmetic dipeptide.
Background
Research by eisi has noted that the formation of lipid hydroperoxide (LOOH) by reactive oxygen species plays a role in the aging process, which continues to disrupt cell membranes, causing cell death. While traditional antioxidants such as vitamin C, vitamin E, glutathione, catalase, etc. are ineffective on LOOH. The decarboxylated carnosine hydrochloride can scavenge free radicals, reduce the formation rate of LOOH and induce the transformation of the existing LOOH into harmless ethanol; protecting collagen from cross-linking caused by aldehyde toxic substances; reduce the production of AGEs, which are glycosylation end products, and reverse the collagen which has been originally glycosylated.
Decarboxylated carnosine acts on the oxidative pathway, preventing glycation in the bud. By "spoofing" advanced glycosylation end products, AGEs, in combination with induction factors other than vital collagen and elastic fibers, it becomes the first line of resistance of the skin to the hazards of glycation. The component can effectively protect fragile and healthy natural collagen and elastic fibers by synergistic action with amino guanidine of Aminoguanidine, thereby maintaining skin elasticity and softness and helping prevent the generation of future fine wrinkles.
Cosmetic products containing decarboxylated carnosine, such as alitame (decarboxylated carnosine HCl), are a multi-effect anti-aging product that is innovative in anti-aging and anti-oxidant aspects. The oxidation accumulation can cause the collapse of the skin structure, the loss of elasticity and the appearance of wrinkles, and not only can the Alistin remove free radicals, but also can reduce peroxidized cell membranes, prevent the diffusion of oxidation reaction and achieve the oxidation repair, which cannot be realized by VE and VC. Glycation can cause protein cross-linking, wrinkle generation, dull and yellowish complexion, and Alistin can not only prevent glycation, but also reverse protein glycation by competing with glycated protein. The product is recommended to be used for treating aged skin or sun-screening and after-sun repairing, detoxifying and resisting pigmentation caused by aging, and is also a preferred raw material for improving the efficacy in products such as whitening, anti-spot and anti-alopecia.
The literature reports a method for synthesizing the decarboxylated carnosine (carnine-beta-cyclodextrine derivatives of OH radicals and SOD-like properties of the pair of (II) compounds, Inorganica Chimica Acta, 361(6), 1705-1714; 2008), in which alanine is protected by boc, TBTU is used as a condensing agent to prepare the decarboxylated carnosine with histamine, the method uses a catalyst which is usually used for reaction and is more than 2 times of the main raw material, so that the cost is greatly increased, and in addition, side reactions can occur due to the fact that the imidazole ring of the histamine is not protected, so that the yield is deviated; the use of a catalyst also causes a problem of the condensation agent remaining in the product.
Disclosure of Invention
The method provided by the invention avoids the use of a condensing agent, and the imidazole ring of histamine is also protected, so that the product generated by the reaction is single, and the purity and the yield are greatly increased. The synthesis method comprises the following steps: alanine (Ala) is protected by phthalic anhydride to obtain phthaloyl protected alanine (intermediate A), then reacts with acyl chloride reagent to obtain corresponding acyl chloride product (intermediate B), histamine reacts with hexamethyldisilazane to obtain histamine silane protecting substance (intermediate C), then reacts with acyl chloride product to obtain phthaloyl protected dipeptide (intermediate D), and finally deprotects under specific conditions to obtain cosmetic dipeptide (product E, decarboxylated carnosine). The reaction equation is as follows:
specifically, the synthesis method of the cosmetic dipeptide provided by the invention comprises the following steps:
(1) alanine and phthalic anhydride react in a nonpolar solvent 1 under the action of an acid-binding agent under the condition of reflux to divide water, the molar ratio of the phthalic anhydride to the alanine is 1.0-1.5:1, an intermediate A is obtained through reaction, and the structural formula of the intermediate A is as follows:
(2) reacting the intermediate A with an acyl chlorination reagent in a nonpolar solvent 2 at the temperature of 20-80 ℃ to obtain an intermediate B, wherein the structural formula of the intermediate B is as follows:
(3) reacting histamine with hexamethyldisilazane in a nonpolar solvent 2 at 40-130 ℃ (or reflux) under the action of a catalyst to obtain an intermediate C, wherein the molar ratio of hexamethyldisilazane to histamine is 1.0-1.5:1, and the intermediate C has the structural formula:
(4) reacting the intermediate B with the intermediate C in a nonpolar solvent 2 at 0-40 ℃, adding water to quench after the reaction is finished to obtain an intermediate D, wherein the molar ratio of the intermediate B to histamine is 1.0-1.5:1, and the structural formula of the intermediate D is as follows:
(5) reacting the intermediate D with organic amine at 20-100 ℃, wherein the organic amine is selected from n-butylamine, n-octylamine or ethylenediamine and the like, and the volume weight ratio of the organic amine to the intermediate D is 3.0-10.0: 1mL/g, concentrating to obtain oily matter after the reaction is finished, adding a polar solvent for crystallization, and filtering to obtain a product E. The step is protected under specific conditions, so that not only is a product obtained, but also the purity is very high, more than 99% of the product can be obtained through simple purification, and the structural formula of the product E is as follows:
wherein, in the step (1), after the reaction is finished until no water is produced, the temperature is reduced to 0-30 ℃ for crystallization, and the intermediate A is obtained after filtration and drying.
Specifically, in the step (1), the acid-binding agent is selected from trimethylamine, triethylamine or N, N-diisopropylethylamine and the like, and the amount of the acid-binding agent is 1% -5% of the mass of the alanine.
Among them, the step (2) is a conventional acyl chlorination method, which is well known to those skilled in the art, and thus detailed description thereof is omitted. And adding the separated intermediate B into a nonpolar solvent 2 to prepare a solvent for later use.
Wherein, in the step (3), histamine and a catalyst are added into the nonpolar solvent 2, the temperature is raised to 40-130 ℃, hexamethyldisilazane is dripped, the temperature is kept for reaction for more than 1 hour after the dripping is finished, and the temperature is lowered to 0-40 ℃ after the reaction is finished, so as to obtain an intermediate C.
Specifically, in the step (3), the catalyst is selected from concentrated sulfuric acid (more than 75%), p-toluenesulfonic acid or ammonium bisulfate, and the like, and the amount of the catalyst is 0.1-1.0% of the mass of the histamine.
Wherein, in the step (4), the reaction is carried out for more than 2 hours under the condition of heat preservation, water is added for quenching after the reaction is finished, the molar ratio of the water to the histamine is 2.0-3.0:1, and the intermediate D is obtained by filtering.
Wherein, in the step (5), the reaction is carried out for more than 2 hours, after the reaction is finished, the reaction product is concentrated to be oily, a polar solvent is added for crystallization, and a crude product of the product E is obtained by filtration, wherein the polar solvent is one or more selected from methanol, ethanol, isopropanol and the like. The crude product can be purified by simple purification methods such as recrystallization and the like to obtain a product with the purity of more than 99 percent.
Wherein, in the step (5), the organic amine is selected from n-butylamine, n-octylamine, ethylenediamine and the like. The organic amine is in a very large excess in this step, both as a starting material and as a solvent for the reaction.
Wherein, in the step (1), the nonpolar solvent 1 is selected from toluene. Since this reaction is very slow at temperatures below 100 ℃ and above 100 ℃ it is possible to carry out the water diversion under reflux and the toluene which is commonly used.
Wherein, in the steps (2), (3) and (4), the nonpolar solvent 2 is selected from dichloromethane, trichloromethane or toluene, etc. The solvents used in the three steps may be the same or different, and are preferably the same for ease of handling.
Preferably, the synthesis method of the cosmetic dipeptide provided by the invention comprises the following steps:
(1) in toluene, alanine and phthalic anhydride react by water under reflux condition under the action of an acid-binding agent until no water is produced, the temperature is reduced to 0-30 ℃ for crystallization, and an intermediate A is obtained after filtration and drying; wherein the molar ratio of phthalic anhydride to alanine is 1.0-1.5: 1; the acid-binding agent is selected from trimethylamine, triethylamine or N, N-diisopropylethylamine and the like, and the dosage of the acid-binding agent is 1-5% of the alanine by mass.
(2) The intermediate A reacts with acyl chloride reagent in nonpolar solvent 2 at 20-80 ℃ to obtain intermediate B.
(3) Adding histamine and a catalyst into the nonpolar solvent 2, heating to 40-130 ℃, then dropwise adding hexamethyldisilazane, keeping the temperature for reaction for more than 1 hour after dropwise adding, and cooling to 0-40 ℃ after the reaction is finished to obtain an intermediate C; wherein the molar ratio of hexamethyldisilazane to histamine is 1.0-1.5: 1; the catalyst is selected from concentrated sulfuric acid, p-toluenesulfonic acid or ammonium bisulfate and the like, and the dosage of the catalyst is 0.1-1.0 percent of the mass of the histamine.
(4) Reacting the intermediate B with the intermediate C in a nonpolar solvent 2 at 0-40 ℃, preserving the temperature for more than 2 hours, adding water for quenching after the reaction is finished, and filtering to obtain an intermediate D; wherein the molar ratio of the intermediate B to the histamine is 1.0-1.5:1, and the molar ratio of the water to the histamine is 2.0-3.0: 1.
(5) Reacting the intermediate D with organic amine at 20-100 ℃ for more than 2 hours, concentrating to obtain an oily substance after the reaction is finished, adding a polar solvent for crystallization, filtering to obtain a crude product of the product E, and recrystallizing the crude product to obtain a product; wherein the organic amine is selected from n-butylamine, n-octylamine or ethylenediamine and the like, and the volume weight ratio of the organic amine to the intermediate D is 3.0-10.0: 1mL/g, and the polar solvent is one or more selected from methanol, ethanol, isopropanol and the like.
Wherein the nonpolar solvent 2 is selected from dichloromethane, chloroform or toluene.
The synthesis method provided by the invention does not use a condensing agent, has cheap and easily obtained raw materials, less byproducts and high yield (the total yield is 78.6-86.4%) and is easy to obtain the dipeptide with high purity (the purity is more than 99%), thereby reducing the cost and being suitable for batch production.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention are described in further detail below.
Example 1:
1. synthesizing phthalic anhydride alanine:
100g (1.12 mol) of alanine, 170g (1.15 mol) of phthalic anhydride, 5g of triethylamine and 650mL of toluene are added into a 1000mL three-necked bottle, the temperature is raised to reflux reaction, water is separated in the reaction process, the temperature is reduced to 20 ℃ until no water is dropped, the temperature is kept for 2 hours, the filtration is carried out, and the filter cake is dried to obtain 240.2g of phthalic anhydride alanine, the HPLC purity is 99.1%, and the yield is 97.7%.
2. Synthesizing acyl chloride:
240g (1.09 mol) of phthalic anhydride alanine and 700mL of chloroform are added into a 1000mL reaction bottle, the temperature is raised to 60 ℃, 135g (1.13 mol) of thionyl chloride is added dropwise, the reaction is kept for 3 hours after the dropwise addition, the reaction is carried out under reduced pressure and concentrated to dryness, and 400mL of chloroform is added for dissolving for standby.
3. Protection of histamine silane:
adding 115.4g (1.03 mol) of histamine, 250mL of chloroform and 0.2g of concentrated sulfuric acid into a 1000mL reaction bottle, heating to reflux, dropwise adding 169.5g (1.05 mol) of hexamethyldisilazane, heating to 100 ℃ after dropwise adding, reacting for 4 hours, and cooling to 20 ℃ for later use.
4. Preparation of creatinine decarboxylated carnosine:
cooling the histamine silane protective solution prepared in the step 3 to 0-10 ℃, dropwise adding acyl chloride prepared in the step 2, keeping the temperature for reaction for 4 hours after dropwise adding, dropwise adding 40g (2.22 mol) of water for quenching reaction, performing suction filtration, and drying the solid to obtain phthalic anhydride decarboxylated carnosine: 304.4g, HPLC purity: 97.5%, yield: 94.0 percent.
5. Preparation of cosmetic dipeptide:
adding 300g (0.95 mol) of phthalic anhydride decarboxylated carnosine and 1200mL of n-butylamine into a 2000mL reaction bottle, heating to 60 ℃, reacting for more than 3 hours, concentrating to dryness after the reaction is finished (the distilled n-butylamine can be recovered for ammonolysis in the step), obtaining an oily substance, then dropwise adding 800mL of methanol for crystallization, performing suction filtration, and drying a solid to obtain 143.8g of crude product of the decarboxylated carnosine, wherein the HPLC purity: 96.7%, 136.6g of cosmetic dipeptide was obtained by one-time refining, HPLC purity: 99.7%, yield: 78.6 percent.
Example 2:
1. synthesizing phthalic anhydride alanine:
adding 800g (8.98 mol) of alanine, 1983.6g (10.77 mol) of phthalic anhydride, 80g of N, N-diisopropylethylamine and 7.5L of toluene into a 10L three-necked flask, heating to reflux reaction, separating water in the reaction process, reacting until no water drops, cooling to 10 ℃, preserving heat for 3 hours, performing suction filtration, drying a filter cake to obtain 1903.4g of phthalic anhydride alanine, wherein the HPLC purity is 98.7%, and the yield is 96.7%.
2. Synthesizing acyl chloride:
1900g (8.67 mol) of phthalic anhydride alanine and 6L of toluene are added into a 10L reaction bottle, the temperature is raised to 70 ℃, 1186.2g (9.97 mol) of thionyl chloride is added dropwise, the reaction is kept for 3 hours after the dropwise addition, the reaction is carried out under reduced pressure and concentrated to be dry, and 5L of toluene is added for dissolving for standby.
3. Protection of histamine silane:
876.5g (7.88 mol) of histamine, 2.5L of toluene and 8.7g of ammonium bisulfate are added into a 10L reaction bottle, the temperature is raised to 100 ℃, 1271.8g (7.88 mol) of hexamethyldisilazane is dropwise added, the reaction is carried out for 5 hours after the dropwise addition, and the temperature is reduced to 30 ℃ for standby
4. Preparation of creatinine decarboxylated carnosine:
and (3) dropwise adding the acyl chloride prepared in the step (2) into the glutamic acid silane protective solution prepared in the step (3) at the temperature of 25-35 ℃, preserving heat, reacting for 2 hours, dropwise adding 150g (8.33 mol) of water, quenching, reacting, filtering after dropwise adding, and drying the solid to obtain 2259.5g of phthalic anhydride decarboxylated carnosine, wherein the HPLC purity is as follows: 97.1%, yield: 91.2 percent.
5. Preparation of cosmetic dipeptide:
2259g (7.18 mol of anhydro-decacarnosine and 8L of n-octylamine) are added into a 10L reaction bottle, the temperature is raised to 55 ℃ for reaction for more than 4 hours, after the reaction is finished, the mixture is concentrated to be dry (the recovered n-octylamine can be used for ammonolysis in the step), an oily substance is obtained, 9L of ethanol is added dropwise for crystallization, the mixture is filtered and dried, 1256.3g of crude decacarnosine is obtained, the HPLC purity is 97.3%, 1130.3g of cosmetic dipeptide is obtained after one-time refining, the HPLC purity is 99.8%, and the yield is 86.4%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. A method for synthesizing cosmetic dipeptide, comprising the steps of:
(1) alanine and phthalic anhydride are subjected to water diversion reaction in a nonpolar solvent 1 under the action of an acid binding agent under the reflux condition, the molar ratio of the phthalic anhydride to the alanine is 1.0-1.5:1, an intermediate A is obtained through the reaction, and the structural formula of the intermediate A is as follows:
(2) reacting the intermediate A with an acyl chlorination reagent in a nonpolar solvent 2 at the temperature of 20-80 ℃ to obtain an intermediate B, wherein the structural formula of the intermediate B is as follows:
(3) reacting histamine with hexamethyldisilazane in a nonpolar solvent 2 at 40-130 ℃ under the action of a catalyst to obtain an intermediate C, wherein the molar ratio of hexamethyldisilazane to histamine is 1.0-1.5:1, and the intermediate C has the structural formula:
(4) reacting the intermediate B with the intermediate C in a nonpolar solvent 2 at 0-40 ℃, adding water for quenching after the reaction is finished, and filtering to obtain an intermediate D, wherein the molar ratio of the intermediate B to histamine is 1.0-1.5:1, the molar ratio of water to histamine is 2.0-3.0:1, and the structural formula of the intermediate D is as follows:
(5) reacting the intermediate D with organic amine at 20-100 ℃, wherein the volume weight ratio of the organic amine to the intermediate D is 3.0-10.0: 1mL/g, concentrating after the reaction is finished, adding a polar solvent for crystallization, and filtering to obtain a product E, wherein the structural formula of the product E is as follows:
2. the method for synthesizing cosmetic dipeptide according to claim 1, wherein in step (1), after the reaction is completed without water production, the temperature is reduced to 0-30 ℃ for crystallization, and the intermediate A is obtained after filtration and drying.
3. The method for synthesizing cosmetic dipeptide according to claim 1, wherein in step (1), the acid scavenger is selected from trimethylamine, triethylamine or N, N-diisopropylethylamine, and the amount of the acid scavenger is 1% -5% of the alanine by mass.
4. The method for synthesizing cosmetic dipeptide according to claim 1, wherein in step (3), histamine and a catalyst are added to the nonpolar solvent 2, the temperature is raised to 40 to 130 ℃, hexamethyldisilazane is added dropwise, the reaction is kept at an incubation temperature for more than 1 hour after the addition is completed, and the temperature is lowered to 0 to 40 ℃ after the reaction is completed to obtain the intermediate C.
5. The method for synthesizing cosmetic dipeptide according to claim 1, wherein in step (3), the catalyst is selected from concentrated sulfuric acid, p-toluenesulfonic acid or ammonium bisulfate, and the amount of the catalyst is 0.1% to 1.0% by mass of histamine.
6. The method for synthesizing cosmetic dipeptide according to claim 1, wherein the reaction is carried out in step (4) with an incubation time of 2 hours or more.
7. The method for synthesizing cosmetic dipeptide according to claim 1, wherein in step (5), the reaction is carried out for 2 hours or more, and the polar solvent is one or more selected from methanol, ethanol and isopropanol.
8. The method for synthesizing cosmetic dipeptide according to claim 1, wherein in step (5), the organic amine is selected from n-butylamine, n-octylamine, or ethylenediamine.
9. The process for the synthesis of cosmetic dipeptide according to claim 1, wherein in step (1), the non-polar solvent 1 is selected from toluene.
10. The process for the synthesis of cosmetic dipeptide according to claim 1, wherein in steps (2), (3) and (4) the non-polar solvent 2 is selected from dichloromethane, trichloromethane or toluene.
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| CN112341475B (en) * | 2020-12-02 | 2023-02-21 | 烟台万润药业有限公司 | Preparation method of clopidogrel hydrogen sulfate |
| CN114213336A (en) * | 2021-12-24 | 2022-03-22 | 深圳瑞德林生物技术有限公司 | Process for producing beta-alanyl-L-histidine |
| CN114736162A (en) * | 2022-03-04 | 2022-07-12 | 深圳市迪克曼生物科技有限公司 | Crystalline form of decarboxylated carnosine and process for preparing same |
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| CN101284862B (en) * | 2008-05-26 | 2011-04-13 | 常熟富士莱医药化工有限公司 | Synthetic method of L-carnosine |
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