CN113200919A - Synthesis method of N-acetyl-carnosine - Google Patents
Synthesis method of N-acetyl-carnosine Download PDFInfo
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- CN113200919A CN113200919A CN202110546904.4A CN202110546904A CN113200919A CN 113200919 A CN113200919 A CN 113200919A CN 202110546904 A CN202110546904 A CN 202110546904A CN 113200919 A CN113200919 A CN 113200919A
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- 108700016464 N-acetylcarnosine Proteins 0.000 title claims abstract description 20
- BKAYIFDRRZZKNF-VIFPVBQESA-N N-acetylcarnosine Chemical compound CC(=O)NCCC(=O)N[C@H](C(O)=O)CC1=CN=CN1 BKAYIFDRRZZKNF-VIFPVBQESA-N 0.000 title claims abstract description 20
- 238000001308 synthesis method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 75
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims abstract description 48
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 32
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229940000635 beta-alanine Drugs 0.000 claims abstract description 24
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 21
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 21
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 17
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 8
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 8
- 238000009833 condensation Methods 0.000 claims abstract description 7
- 230000005494 condensation Effects 0.000 claims abstract description 7
- 238000005580 one pot reaction Methods 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 230000021736 acetylation Effects 0.000 claims abstract description 5
- 238000006640 acetylation reaction Methods 0.000 claims abstract description 5
- 230000008569 process Effects 0.000 claims abstract description 5
- 239000012043 crude product Substances 0.000 claims description 22
- 239000007787 solid Substances 0.000 claims description 21
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 14
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 14
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical group CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 11
- 239000012346 acetyl chloride Substances 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 11
- ZUSSTQCWRDLYJA-UHFFFAOYSA-N n-hydroxy-5-norbornene-2,3-dicarboximide Chemical compound C1=CC2CC1C1C2C(=O)N(O)C1=O ZUSSTQCWRDLYJA-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 230000002194 synthesizing effect Effects 0.000 claims description 9
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 8
- -1 PEG-500 Polymers 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 8
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 7
- 235000011009 potassium phosphates Nutrition 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 4
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 claims description 4
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000007821 HATU Substances 0.000 claims description 3
- 229920002582 Polyethylene Glycol 600 Polymers 0.000 claims description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 2
- 229920002593 Polyethylene Glycol 800 Polymers 0.000 claims description 2
- 229920002596 Polyethylene Glycol 900 Polymers 0.000 claims description 2
- 229920002523 polyethylene Glycol 1000 Polymers 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 230000000397 acetylating effect Effects 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 7
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 abstract description 6
- 239000003960 organic solvent Substances 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 abstract description 2
- 235000004279 alanine Nutrition 0.000 abstract description 2
- 235000001014 amino acid Nutrition 0.000 abstract description 2
- 150000001413 amino acids Chemical class 0.000 abstract description 2
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 231100000956 nontoxicity Toxicity 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000007858 starting material Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- 230000008034 disappearance Effects 0.000 description 8
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 238000010189 synthetic method Methods 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- NIFZMQTZQXEOQI-VIFPVBQESA-N acetylcarnosine Chemical compound CC(=O)NCCC(=O)N[C@H](C(O)=O)CC1=CN=C[N]1 NIFZMQTZQXEOQI-VIFPVBQESA-N 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000006452 multicomponent reaction Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- 239000012345 acetylating agent Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 239000000383 hazardous chemical Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- MHZDONKZSXBOGL-UHFFFAOYSA-N propyl dihydrogen phosphate Chemical compound CCCOP(O)(O)=O MHZDONKZSXBOGL-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- DFPYXQYWILNVAU-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1.C1=CC=C2N(O)N=NC2=C1 DFPYXQYWILNVAU-UHFFFAOYSA-N 0.000 description 1
- RWYHOIUBWBDNSP-UHFFFAOYSA-N 1-oxidanylpyrrolidine-2,5-dione Chemical compound ON1C(=O)CCC1=O.ON1C(=O)CCC1=O RWYHOIUBWBDNSP-UHFFFAOYSA-N 0.000 description 1
- QRYRORQUOLYVBU-VBKZILBWSA-N Carnosic acid Natural products CC([C@@H]1CC2)(C)CCC[C@]1(C(O)=O)C1=C2C=C(C(C)C)C(O)=C1O QRYRORQUOLYVBU-VBKZILBWSA-N 0.000 description 1
- 108010087806 Carnosine Proteins 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- CQOVPNPJLQNMDC-UHFFFAOYSA-N N-beta-alanyl-L-histidine Natural products NCCC(=O)NC(C(O)=O)CC1=CN=CN1 CQOVPNPJLQNMDC-UHFFFAOYSA-N 0.000 description 1
- 208000028990 Skin injury Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229940044199 carnosine Drugs 0.000 description 1
- CQOVPNPJLQNMDC-ZETCQYMHSA-N carnosine Chemical compound [NH3+]CCC(=O)N[C@H](C([O-])=O)CC1=CNC=N1 CQOVPNPJLQNMDC-ZETCQYMHSA-N 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention relates to the technical field of drug synthesis, in particular to a synthesis method of N-acetyl-carnosine. The method comprises the following steps: taking polyethylene glycol as a solvent, and carrying out a first reaction on beta-alanine and a condensation reagent; under alkaline conditions, the obtained first reaction product and histidine are subjected to a second reaction; and carrying out a third reaction on the obtained second reaction product and an acetylation reagent to obtain the N-acetyl-carnosine. The method adopts a multi-component one-pot method for reaction, is novel and simple in process, and reduces the reaction cost; the reaction solvent is polyethylene glycol, and compared with a volatile organic solvent, the polyethylene glycol has the advantages of difficult volatilization, no toxicity, biodegradability, environmental friendliness and the like; histidine and alanine are natural amino acids, the price is low, functional group protection is not carried out, direct condensation is carried out, and the synthesis cost is low; after the reaction is finished, the methyl tert-butyl ether product is added to be directly separated out, the post-treatment is simple and convenient, and the yield is high.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a synthesis method of N-acetyl-carnosine.
Background
The green chemistry principle is to avoid using toxic reagents and solvents in the synthesis, minimize waste materials, eliminate unnecessary intermediate steps, and minimize the use of energy. The significant reduction in the amount of organic solvents used has been a highly active area of research. Due to its green chemical character, organic chemists have recently achieved the efficient construction of complex molecules with bioactive structures from readily available starting materials. The transformation has the advantages of high efficiency, high yield, strong selectivity and environmental friendliness. To further achieve these goals, researchers turned to multi-component one-pot reactions. The multicomponent reactions play an important role in green chemistry development as they can be used to synthesize small molecule compounds with structural diversity and high atom economy.
Multicomponent reactions (MCRs) are synthetic methods in which three or more simple and readily available starting materials are reacted and added to one reaction, without the need for intermediate separation, molecules with complex structures are directly obtained, and the structure of the final product contains added starting material segments.
N-Acetyl-carnosine, chemical name N-Acetyl-beta-Alanyl-Histidine (N-Acetyl-beta-Alanyl-Histidine), white crystal powder, molecular formula C11H16N4O4Accurate mass 268.12, molecular weight 268.27, chemical formula:
n-acetyl-carnosine is a natural antioxidant active substance present in human muscle tissue and has been reported to be developed as eye drops for the treatment of cataract. In recent years, researches show that the N-acetyl-carnosine has the effects of resisting wrinkles, preventing aging, repairing skin injury and the like, has no toxic or side effect, and is an ideal cosmetic product. Therefore, the development of an environment-friendly synthetic method with high yield and simple purification is always a focus of attention of synthesizers.
The raw material histidine for synthesizing the acetyl carnosine has poor solubility in organic solvents, so that the method brings great challenges for synthesizing the acetyl carnosine. The currently reported main methods for synthesizing acetyl carnosine comprise two methods, wherein one method is that carnosine directly reacts with acetyl chloride or acetic anhydride to obtain a target product; one is to acetylate beta-alanine and then react with histidine to obtain the target product. The purity of the products prepared by the two methods is not high, and the industrial production is not facilitated by using hazardous chemicals such as toluene, concentrated sulfuric acid, diethyl ether and the like in the reaction process or strong acid resin in the separation process (CN101077863A, CN201610000411, CN 200910032492).
The reported synthetic method for synthesizing the N-acetyl-carnosine has the disadvantages of short synthetic steps, low yield, low purity and inconvenient post-treatment. Or the yield is high, the purity is high, but the related hazardous chemical reagents are more, the synthesis process is longer, and the industrial production is not facilitated. Therefore, the development of a green and efficient method for synthesizing N-acetyl carnosine has important market value.
Disclosure of Invention
In view of the above, the present invention provides a method for synthesizing N-acetyl-carnosine. The method is an environment-friendly, multi-component one-pot method, high in yield, low in cost and capable of industrially producing the N-acetyl-carnosine.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a synthetic method of N-acetyl-carnosine, which comprises the following steps:
step (1): taking polyethylene glycol as a solvent, and carrying out a first reaction on beta-alanine and a condensation reagent;
step (2): under alkaline conditions, the obtained first reaction product and histidine are subjected to a second reaction;
and (3): and carrying out a third reaction on the obtained second reaction product and an acetylation reagent to obtain the N-acetyl-carnosine.
Preferably, the polyethylene glycol is one or more of PEG-100, PEG-200, PEG-300, PEG-400, PEG-500, PEG-600, PEG-700, PEG-800, PEG-900 and PEG-1000.
Preferably, the polyethylene glycol is one or more of PEG-100, PEG-200, PEG-300, PEG-400, PEG-500 and PEG-600.
Preferably, the condensation reagent is one or more selected from HOSu, HONB, HOBt, HBTU, HATU, DIC, DCC, EDCI and T3P.
In particular embodiments provided herein, the condensing agent is a mixture of one of HOSu or HONB and EDCI. The amount of condensing agent is well known in the art.
Preferably, the agent for producing alkaline conditions in step (2) is selected from, but not limited to, potassium phosphate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate.
Preferably, the acetylating agent is acetyl chloride and/or acetic anhydride.
Preferably, the molar ratio of beta-alanine, histidine and acetylating agent is 10: (8-50): (1-100).
Preferably, the synthesis method is a multicomponent one-pot method.
Preferably, the reaction temperature of the synthesis method is 15-30 ℃.
Preferably, the reaction temperature of the synthesis method is room temperature.
In the present invention, the reaction time of each step is based on monitoring the completion of the reaction of the reactants.
Preferably, step (3) is followed by a crystallization purification step.
Preferably, the crystallization purification reagent is methyl tert-butyl ether.
Preferably, the crystallization purification is specifically: and (4) adjusting the pH value of the third reaction product solution obtained in the step (3) to 4-5, adding methyl tert-butyl ether to precipitate a solid, filtering to obtain a crude product, and recrystallizing the crude product.
The invention provides a synthetic method of N-acetyl-carnosine. The method comprises the following steps: taking polyethylene glycol as a solvent, and carrying out a first reaction on beta-alanine and a condensation reagent; under alkaline conditions, the obtained first reaction product and histidine are subjected to a second reaction; and carrying out a third reaction on the obtained second reaction product and an acetylation reagent to obtain the N-acetyl-carnosine. The invention has the technical effects that:
1) the method adopts a multi-component one-pot method for reaction, is novel and simple in process, and reduces the reaction cost;
2) the reaction solvent is polyethylene glycol, and compared with a volatile organic solvent, the polyethylene glycol has the advantages of difficult volatilization, no toxicity, biodegradability, environmental friendliness and the like;
3) histidine and alanine are natural amino acids, the price is low, functional group protection is not carried out, direct condensation is carried out, and the carboxyl synthesis cost is low;
4) after the reaction is finished, the methyl tert-butyl ether product is added to be directly separated out, the post-treatment is simple and convenient, and the yield is high.
Detailed Description
The invention discloses a method for synthesizing N-acetyl-carnosine, which can be realized by appropriately improving process parameters by a person skilled in the art with reference to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
Abbreviations and english meaning:
HOSu: N-Hydroxysuccinimide (N-Hydroxysuccinimide)
HONB: n-hydroxy-5-norbornene-2, 3-dicarboximide,
(N-Hydroxy-5-norbornene-2,3-dicarboximide)
HOBt: 1-Hydroxybenzotriazole (1-Hydroxybenzotriazole)
HBTU: benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate,
(O-Benzotriazole-N,N,N',N'-tetraMethyl-uroniuM-hexafluorophosphate)
HATU: 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate,
(O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetraMethyluroniuMhexafluorophosphate)
DIC: n, N '-Diisopropylcarbodiimide (N, N' -Diisopropylcarbodiimide)
DCC: dicyclohexylcarbodiimide (Dicyclohexylcarbodiimide)
EDCI: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride,
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride
T3P: 1-Propylphosphoric acid anhydride (1-Propylphosphoric acid anhydride)
DIPEA: n, N-Diisopropylethylamine (N, N-Diisopropylethylamine)
TEA: triethylamine (Triethylamine)
The invention provides a method for synthesizing N-acetyl-carnosine by a multicomponent one-pot method in a green solvent and a purification method. The method comprises the following steps: under the condition of room temperature, sequentially adding beta-alanine, histidine and acetyl chloride (acetic anhydride) into a polyethylene glycol solvent for reaction, adjusting the pH of the solution to 4-5 after the reaction is finished, adding methyl tert-butyl ether to separate out solids, and filtering to obtain a crude product. And recrystallizing the crude product to obtain the target product. Taking acetic anhydride as an example of one of the reactants, the synthesis route of the acetyl carnosine is as follows:
polyethylene glycol (PEG) is a water-soluble polymer with good water solubility, and polyethylene glycol with low molecular weight is liquid, and polyethylene glycol with high molecular weight is solid. The liquid polyethylene glycol with low molecular weight can be mutually dissolved with water under any condition, and the solid polyethylene glycol can be well dissolved in the water. Toxicity indices of polyethylene glycol and environmental load data have been confirmed by the U.S. food and drug administration. Compared with volatile organic solvents and polyethylene glycol, the polyethylene glycol has the advantages of being difficult to volatilize, non-toxic, biodegradable, environment-friendly and the like, and is stable to acid, alkali and high temperature.
The reagents or apparatus used in the present invention are commercially available.
The invention is further illustrated by the following examples:
example 1
PEG-100(100mL), beta-alanine (8.91g, 0.1mol), N-hydroxysuccinimide (11.51g, 0.1mol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (10.74g, 0.1mol) were added to a 500mL round bottom flask and TLC monitored for complete disappearance of beta-alanine. Histidine (15.52g, 0.1mol) and potassium phosphate (42.45g, 0.2mol) were added to the above reaction, stirred, monitored by TLC for reaction, acetyl chloride (14.22mL, 0.2mol) was slowly added dropwise to the reaction mixture until the histidine was completely reacted, and monitored by HPLC for completion of the reaction of the starting materials. After the reaction is finished, adjusting the pH of the reaction solution to 4-5 by using a 2N hydrochloric acid solution, adding methyl tert-butyl ether into the reaction solution, stirring, separating out solids, and filtering to obtain a crude product. The crude product was dissolved in water and methyl tert-butyl ether was added to precipitate 52.12g of a white solid in 88.0% yield and 99.0% purity.
Example 2
PEG-200(100mL), beta-alanine (8.91g, 0.1mol), N-hydroxysuccinimide (11.51g, 0.1mol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (10.74g, 0.1mol) were added to a 500mL round bottom flask and TLC monitored for complete disappearance of beta-alanine. Histidine (15.52g, 0.1mol) and potassium phosphate (42.45g, 0.2mol) were added to the above reaction, stirred, monitored by TLC for reaction, acetyl chloride (14.22mL, 0.2mol) was slowly added dropwise to the reaction mixture until the histidine was completely reacted, and monitored by HPLC for completion of the reaction of the starting materials. After the reaction is finished, adjusting the pH of the reaction solution to 4-5 by using a 2N hydrochloric acid solution, adding methyl tert-butyl ether into the reaction solution, stirring, separating out solids, and filtering to obtain a crude product. The crude product was dissolved in water, and methyl t-butyl ether was added to precipitate 50.74g of a white solid, yield 86.0%, purity 99.2%.
Example 3
PEG-300(100mL), beta-alanine (8.91g, 0.1mol), N-hydroxysuccinimide (11.51g, 0.1mol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (10.74g, 0.1mol) were added to a 500mL round bottom flask and TLC monitored for complete disappearance of beta-alanine. Histidine (15.52g, 0.1mol) and potassium phosphate (42.45g, 0.2mol) were added to the above reaction, stirred, monitored by TLC for reaction, acetyl chloride (14.22mL, 0.2mol) was slowly added dropwise to the reaction mixture until the histidine was completely reacted, and monitored by HPLC for completion of the reaction of the starting materials. After the reaction is finished, adjusting the pH of the reaction solution to 4-5 by using a 2N hydrochloric acid solution, adding methyl tert-butyl ether into the reaction solution, stirring, separating out solids, and filtering to obtain a crude product. The crude product was dissolved in water and methyl t-butyl ether was added to precipitate 48.89g of a white solid in 82.7% yield and 99.0% purity.
Example 4
PEG-400(100mL), beta-alanine (8.91g, 0.1mol), N-hydroxysuccinimide (11.51g, 0.1mol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (10.74g, 0.1mol) were added to a 500mL round-bottomed flask, TLC was used to monitor the complete disappearance of beta-alanine, histidine (15.52g, 0.1mol) and potassium phosphate (42.45g, 0.2mol) were added to the above reaction, the reaction was monitored by TLC while stirring, acetyl chloride (14.22mL, 0.2mol) was slowly added dropwise to the reaction solution until the histidine was completely reacted, and HPLC was used to monitor that the reaction was complete. After the reaction is finished, adjusting the pH of the reaction solution to 4-5 by using a 2N hydrochloric acid solution, adding methyl tert-butyl ether into the reaction solution, stirring, separating out solids, and filtering to obtain a crude product. The crude product was dissolved in water and methyl tert-butyl ether was added to precipitate 47.61g of a white solid in 80.7% yield and 98.7% purity.
Example 5
PEG-400(100mL), beta-alanine (8.91g, 0.1mol), N-hydroxy-5-norbornene-2, 3-dicarboximide (17.91g, 0.1mol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (10.74g, 0.1mol) were added to a 500mL round bottom flask and the complete disappearance of beta-alanine was monitored by TLC. Histidine (15.52g, 0.1mol) and potassium phosphate (42.45g, 0.2mol) were added to the above reaction, stirred, monitored by TLC for reaction, acetyl chloride (14.22mL, 0.2mol) was slowly added dropwise to the reaction mixture until the histidine was completely reacted, and monitored by HPLC for completion of the reaction of the starting materials. After the reaction is finished, adjusting the pH of the reaction solution to 4-5 by using a 2N hydrochloric acid solution, adding methyl tert-butyl ether into the reaction solution, stirring, separating out solids, and filtering to obtain a crude product. The crude product was dissolved in water and methyl tert-butyl ether was added to precipitate 54.60g of a white solid in 92.5% yield and 99.5% purity.
Example 6
PEG-100(100mL), beta-alanine (8.91g, 0.1mol), N-hydroxy-5-norbornene-2, 3-dicarboximide (11.51g, 0.1mol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (10.74g, 0.1mol) were added to a 500mL round bottom flask and the complete disappearance of beta-alanine was monitored by TLC. Histidine (15.52g, 0.1mol) and sodium hydroxide (8.00g, 0.2mol) were added to the above reaction, stirred, monitored by TLC for reaction, acetyl chloride (14.22mL, 0.2mol) was slowly added dropwise to the reaction mixture until the histidine was completely reacted, and monitored by HPLC for completion of the reaction of the starting materials. After the reaction is finished, adjusting the pH of the reaction solution to 4-5 by using a 2N hydrochloric acid solution, adding methyl tert-butyl ether into the reaction solution, stirring, separating out solids, and filtering to obtain a crude product. The crude product was dissolved in water and methyl tert-butyl ether was added to precipitate 50.47g of a white solid in 85.5% yield and 99.5% purity.
Example 7
PEG-100(100mL), beta-alanine (8.91g, 0.1mol), N-hydroxy-5-norbornene-2, 3-dicarboximide (11.51g, 0.1mol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (10.74g, 0.1mol) were added to a 500mL round bottom flask and the complete disappearance of beta-alanine was monitored by TLC. Histidine (15.52g, 0.1mol) and potassium hydroxide (11.22g, 0.2mol) were added to the above reaction, stirred, monitored by TLC, after completion of the reaction of histidine, acetyl chloride (14.22mL, 0.2mol) was slowly added dropwise to the reaction mixture, and monitored by HPLC, to complete the reaction of the starting materials. After the reaction is finished, adjusting the pH of the reaction solution to 4-5 by using a 2N hydrochloric acid solution, adding methyl tert-butyl ether into the reaction solution, stirring, separating out solids, and filtering to obtain a crude product. The crude product was dissolved in water and methyl t-butyl ether was added to precipitate 50.11g of a white solid in 84.9% yield and 99.7% purity.
Example 8
PEG-100(100mL), beta-alanine (8.91g, 0.1mol), N-hydroxy-5-norbornene-2, 3-dicarboximide (11.51g, 0.1mol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (10.74g, 0.1mol) were added to a 500mL round bottom flask and the complete disappearance of beta-alanine was monitored by TLC. Histidine (15.52g, 0.1mol) and triethylamine (27.79mL, 0.2mol) were added to the reaction, stirred, monitored by TLC for reaction, acetic anhydride (18.19mL, 0.2mol) was slowly added dropwise to the reaction mixture until the histidine was completely reacted, and monitored by HPLC for completion of the starting material reaction. After the reaction is finished, adjusting the pH of the reaction solution to 4-5 by using a 2N hydrochloric acid solution, adding methyl tert-butyl ether into the reaction solution, stirring, separating out solids, and filtering to obtain a crude product. The crude product was dissolved in water and methyl t-butyl ether was added to precipitate 53.46g of a white solid in 90.61% yield and 99.7% purity.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A method for synthesizing N-acetyl-carnosine, which is characterized by comprising the following steps:
step (1): taking polyethylene glycol as a solvent, and carrying out a first reaction on beta-alanine and a condensation reagent;
step (2): under alkaline conditions, the obtained first reaction product and histidine are subjected to a second reaction;
and (3): and carrying out a third reaction on the obtained second reaction product and an acetylation reagent to obtain the N-acetyl-carnosine.
2. The synthesis method of claim 1, wherein the polyethylene glycol is one or more selected from the group consisting of PEG-100, PEG-200, PEG-300, PEG-400, PEG-500, PEG-600, PEG-700, PEG-800, PEG-900, and PEG-1000.
3. The method of claim 1, wherein the condensing agent is one or more of HOSu, HONB, HOBt, HBTU, HATU, DIC, DCC, EDCI, and T3P.
4. The synthesis method according to claim 1, wherein the reagent for producing the alkaline condition in step (2) is selected from, but not limited to, potassium phosphate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate.
5. The synthesis process according to claim 1, characterized in that the acetylating reagent is acetyl chloride and/or acetic anhydride.
6. The synthesis method according to claim 1, wherein the molar ratio of the beta-alanine to the histidine to the acetylation reagent is 10: (8-50): (1-100).
7. The synthesis method according to claim 1, wherein the synthesis method is a multi-component one-pot method, and the reaction temperature of the synthesis method is 15-30 ℃.
8. The synthesis method according to any one of claims 1 to 7, characterized in that step (3) is followed by a crystallization purification step.
9. The synthesis method according to claim 8, wherein the crystallization purification reagent is methyl tert-butyl ether.
10. The synthesis method according to claim 9, characterized in that the crystallization purification is in particular: and (4) adjusting the pH value of the third reaction product solution obtained in the step (3) to 4-5, adding methyl tert-butyl ether to precipitate a solid, filtering to obtain a crude product, and recrystallizing the crude product.
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| CN113801190A (en) * | 2020-06-12 | 2021-12-17 | 深圳瑞德林生物技术有限公司 | Method for preparing oligopeptide-1 hydrochloride |
| CN113801190B (en) * | 2020-06-12 | 2023-07-07 | 深圳瑞德林生物技术有限公司 | Preparation method of oligopeptide-1 hydrochloride |
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