CN101077863A - Modified method for chemically synthesizing N-acetyl-L-carnosine - Google Patents
Modified method for chemically synthesizing N-acetyl-L-carnosine Download PDFInfo
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- CN101077863A CN101077863A CN 200610084385 CN200610084385A CN101077863A CN 101077863 A CN101077863 A CN 101077863A CN 200610084385 CN200610084385 CN 200610084385 CN 200610084385 A CN200610084385 A CN 200610084385A CN 101077863 A CN101077863 A CN 101077863A
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- carnosine
- acetyl
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- 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 19
- 238000000034 method Methods 0.000 title claims abstract description 17
- 230000002194 synthesizing effect Effects 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 108010087806 Carnosine Proteins 0.000 claims abstract description 10
- CQOVPNPJLQNMDC-UHFFFAOYSA-N N-beta-alanyl-L-histidine Natural products NCCC(=O)NC(C(O)=O)CC1=CN=CN1 CQOVPNPJLQNMDC-UHFFFAOYSA-N 0.000 claims abstract description 10
- CQOVPNPJLQNMDC-ZETCQYMHSA-N carnosine Chemical compound [NH3+]CCC(=O)N[C@H](C([O-])=O)CC1=CNC=N1 CQOVPNPJLQNMDC-ZETCQYMHSA-N 0.000 claims abstract description 10
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000012346 acetyl chloride Substances 0.000 claims abstract description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 5
- 239000001632 sodium acetate Substances 0.000 claims abstract description 5
- 235000017281 sodium acetate Nutrition 0.000 claims abstract description 5
- 239000011230 binding agent Substances 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- 239000011259 mixed solution Substances 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- 235000017550 sodium carbonate Nutrition 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 9
- 239000012345 acetylating agent Substances 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 230000006340 racemization Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- 229960002885 histidine Drugs 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- -1 Histidine methyl esters Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- QUCHWTCTBHQQDU-BYPYZUCNSA-N (2s)-2-amino-4-oxopentanoic acid Chemical compound CC(=O)C[C@H](N)C(O)=O QUCHWTCTBHQQDU-BYPYZUCNSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- BKAYIFDRRZZKNF-SECBINFHSA-N Acetylcarnosine Chemical compound CC(=O)NCCC(=O)N[C@@H](C(O)=O)CC1=CN=CN1 BKAYIFDRRZZKNF-SECBINFHSA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- 108700016464 N-acetylcarnosine Proteins 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000008431 aliphatic amides Chemical class 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- 229910000329 aluminium sulfate Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000010960 commercial process Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000006386 memory function Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to improved chemical synthesis process of N-acetyl-L-carnosine. The main material L-carnosine is acetylated with acetyl chloride as the acetylating agent through reaction in alkaline water solution at proper temperature and pH value in the presence of sodium acetate as acid binding agent. The process has N-acetyl-L-carnosine yield of 77.5-82.0 % and no racemisation.
Description
Invention field
The present invention relates to the organic medicinal chemistry field, improve one's methods in particular to a kind of health care and medicine N-acetyl-the synthetic of L-carnosine.
Background technology
N-acetyl-L-carnosine (N-Acyl-L-Carnosine), definite is N-acetyl-Beta-alanine-L-Histidine, its chemical structural formula is:
Because N-acetyl-L-carnosine by control action kou strongly, has the raising attention to the circulation around the brain, improves memory function; Especially the aluminium salt of N-acetyl-L-carnosine can be used as the prevention and the consolidant of digestive tract ulcer, promotes it to use in nutritive health-care and medical treatment and promote.
Usually chemosynthesis is divided into two major types from structure:
(1) A.Lukton and A.Sisti, J.Org.Chem.26,617 (1961), propose L-carnosine and aceticanhydride reaction;
(2) G.Bailin and A.Lukton, J.Org.Chem.27,684 (1962), propose 3-acetylalanine and Histidine methyl esters and carry out condensation, and then, obtain N-acetyl-L-carnosine the ester hydrolysis.
As commercial process, all there is defective in aforesaid method, and first method technology relatively simply is its advantage, but has brought the racemization problem; It is too many that second method relates to Histidine methyl esters step, and use the deleterious condensing agent N to the human eye, N-dicyclohexylcarbodiimide.
For these reasons, the object of the invention provides one and improves one's methods: with the L-carnosine is starting raw material, through single step reaction, is avoiding under the condition of racemization, selects suitable acetylating agent and acid binding agent, with can suitability for industrialized production N-acetyl-L-carnosine.
Summary of the invention
One of content of the present invention: with the L-carnosine is starting raw material, carries out single step reaction with acetylizing agent under suitable alkaline condition, is characterized in that one-step synthesis keeps the L-configuration, avoids racemization.
Two of content of the present invention: being to be the N-acylating agent with the Acetyl Chloride 98Min., is the most simple and efficient method.Acetyl Chloride 98Min. is strong acylating agent, easy and aliphatic amide or aromatic amine generation N-acetylize; The assurance acetylize is complete, but owing to produce side reaction, is acid binding agent with the adding alkaline matter, just avoids N on the Histidine
2Acetylizad side reaction.
Characteristics of the present invention are that reaction improves and optimizates from the acylating agent to the reaction conditions to N-acetyl, and technology is succinct, guarantee the quality of product N-acetyl-L-carnosine, have produced industrial positively effect, have obtained economic benefit through scale production.
The invention will be further described below by embodiment.It should be understood that the described preparation method of the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, down preparation method's of the present invention simple modifications is all belonged to the scope of protection of present invention in advance in design of the present invention.Except as otherwise noted, the percentage ratio among the present invention is weight percentage.
Embodiment one:
L-carnosine 90.4g (0.40mol) is dissolved in 200ml 8% aqueous sodium hydroxide solution, stirs down, and temperature of reaction must remain on 5-10 ℃, and pH drips 95% Acetyl Chloride 98Min. 34.5g (0.44mol) and 50% sodium acetate aqueous solution 260ml simultaneously in the 13.0-13.5 scope.Dropwise, restir is 1 hour under same temperature, checks through HPLC, confirms that product N-acetyl-L-carnosine generates, and not the existing of the disappearance of raw material and by product N-acetyl-N-(imidazoles) acetyl carnosine.This reaction solution is handled through strong-acid ion exchange resin SKIB, absorption N-acetyl carnosine, with after the neutral water washing, use 1mol/L ammoniacal liquor then, former dissolution fluid is concentrated into 200ml, add acetic acid and transfer pH to 4.9, keep 50 ℃ of temperature, add Virahol 780ml, keep 50 ℃ to stir 3 hours, reduce to 20 ℃ of restir 1 hour, and separated out crude product N-acetyl-L-carnosine; Drying gets 86.6g.Specific optical rotation [α]
20 D=+26.10 ° (C=3, water)
Crude product N-acetyl-L-carnosine 86.6g is dissolved in the 104ml water, adds gac 0.8g and decolour, will add Virahol 780ml in the destainer, in 60 ℃ of stirrings 3 hours, 20 ℃ were stirred 1 hour down, separated out N-acetyl-L-carnosine, dry 83.2g, the yield 82% of getting.
De N-acetyl-L carnosine therefrom: IR.NMR analytical results and standard substance are in full accord; [α]
20 D=+26.20 ° (C=3, water) are consistent with standard substance, confirm no racemization.
Embodiment two:
L-carnosine 45.2g (0.20mol) is dissolved in 55ml 8% aqueous sodium hydroxide solution, transfers pH 13.3, drips 95% Acetyl Chloride 98Min. 20.4g (0.26mol) and 180ml50% sodium acetate solution simultaneously.1.5 hour drip off, during this period, the pH of solution is 12.5-13.5, temperature of reaction keeps 18-20 ℃.Stirred 1 hour under the same again temperature after dropwising, follow the tracks of with HPLC simultaneously, confirm the generation of reaction object, raw material and side reaction product N-acetyl-N
2-acetyl-L does not have and detects.
This reaction solution is pressed embodiment one with highly acidic resin handle, transfer PH and Virahol crystallization, obtain N-acetyl-L-carnosine 42.4g, yield 80.0%, specific optical rotation [α]
20 D=+26.10 ° (C=3, water) confirms no racemization.
Embodiment three:
L-carnosine 67.8g (0.30mol) is dissolved in 200ml water and 200ml acetone and 166ml 8% sodium hydroxide solution, and transferring pH is 12.5.With this solution stirring, temperature of reaction keeps 10 ℃, drips 95% Acetyl Chloride 98Min. 25.9g (0.33mol) simultaneously, acetone soln and 50% aqueous sodium acetate solution.The pH that reacts in the dropping process keeps 11.5-12.5.Drip and end, stirring at room 30 minutes, decompression steams acetone, adds water 200ml, handles N-acetyl-L-carnosine with embodiment one, gets crystallization 76.5g, yield 77.5%, fusing point 216-218 ℃.Specific optical rotation [α]
20 D=+26.0 ° (C=3, water) confirms no racemization.
Claims (6)
1. improving one's methods of chemosynthesis N-acetyl-L carnosine, this method is acetylization reaction in alkaline aqueous solution by L-carnosine and acetylizing agent.
2. according to the method for claims 1, wherein acetylizing agent is an Acetyl Chloride 98Min., and acid binding agent is respectively: the aqueous solution of sodium acetate, sodium hydroxide, yellow soda ash, triethylamine and pyridine or both mixed solutions.
3. according to the method for claims 1-2, Acetyl Chloride 98Min. wherein feeds intake: L-carnosine (mol ratio) is: 1～1.3: 1, preferred (mol ratio) 1.1: 1.
4. according to the method for claims 1-3, wherein alkaline aqueous solution is an aqueous sodium hydroxide solution, and concentration is 4-12%, preferred 8%.
5. according to the method for claims 1-4, wherein temperature of reaction is at 0-25 ℃, preferred 5-10 ℃.
6. according to the method for claims 1-5, the pH value of reaction solution is controlled at 10.0-13.5, preferred 11.0-13.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610084385 CN101077863A (en) | 2006-05-24 | 2006-05-24 | Modified method for chemically synthesizing N-acetyl-L-carnosine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610084385 CN101077863A (en) | 2006-05-24 | 2006-05-24 | Modified method for chemically synthesizing N-acetyl-L-carnosine |
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| Publication Number | Publication Date |
|---|---|
| CN101077863A true CN101077863A (en) | 2007-11-28 |
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| CN 200610084385 Pending CN101077863A (en) | 2006-05-24 | 2006-05-24 | Modified method for chemically synthesizing N-acetyl-L-carnosine |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101585813B (en) * | 2009-06-17 | 2011-04-13 | 常熟富士莱医药化工有限公司 | Prepartion method of N-acetyl-L-carnosine |
| CN105153038A (en) * | 2014-06-11 | 2015-12-16 | 上海予利化学科技有限公司 | Synthetic method for N-acetyl carnosine |
| CN105461632A (en) * | 2016-01-04 | 2016-04-06 | 湖北泓肽生物科技有限公司 | Preparing method for N-acetyl-L-carnosine |
| CN106083992A (en) * | 2016-06-17 | 2016-11-09 | 四川松麒医药科技有限公司 | Preparation method, product and the application of a kind of carnosine derivant |
| CN116496221A (en) * | 2023-04-28 | 2023-07-28 | 精晶药业股份有限公司 | A kind of refining method of acetylcarnosine |
-
2006
- 2006-05-24 CN CN 200610084385 patent/CN101077863A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101585813B (en) * | 2009-06-17 | 2011-04-13 | 常熟富士莱医药化工有限公司 | Prepartion method of N-acetyl-L-carnosine |
| CN105153038A (en) * | 2014-06-11 | 2015-12-16 | 上海予利化学科技有限公司 | Synthetic method for N-acetyl carnosine |
| CN105153038B (en) * | 2014-06-11 | 2017-07-04 | 上海予利化学科技有限公司 | A kind of synthetic method of N acetyl carnosines |
| CN105461632A (en) * | 2016-01-04 | 2016-04-06 | 湖北泓肽生物科技有限公司 | Preparing method for N-acetyl-L-carnosine |
| CN105461632B (en) * | 2016-01-04 | 2018-01-09 | 湖北泓肽生物科技有限公司 | A kind of preparation method of N acetyl L carnosines |
| CN106083992A (en) * | 2016-06-17 | 2016-11-09 | 四川松麒医药科技有限公司 | Preparation method, product and the application of a kind of carnosine derivant |
| CN106083992B (en) * | 2016-06-17 | 2019-08-20 | 四川松麒医药科技有限公司 | A kind of preparation method, product and the application of carnosine derivative |
| CN116496221A (en) * | 2023-04-28 | 2023-07-28 | 精晶药业股份有限公司 | A kind of refining method of acetylcarnosine |
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