CN101735305A - Synthesizing method of L-carnosine - Google Patents
Synthesizing method of L-carnosine Download PDFInfo
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- CN101735305A CN101735305A CN201010102105A CN201010102105A CN101735305A CN 101735305 A CN101735305 A CN 101735305A CN 201010102105 A CN201010102105 A CN 201010102105A CN 201010102105 A CN201010102105 A CN 201010102105A CN 101735305 A CN101735305 A CN 101735305A
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Abstract
The invention discloses a production method of carnosine, which is characterized by comprising the following steps of: synthesizing N-acetyl cyanide-L-histidine through ammonolysis reaction by using L-histidine and ethyl cyanoacetate as raw materials and sodium alcoholate as a catalyst; and then obtaining L-carnosine through the intermediate by using stronger ammonia water and alcohol as a solvent in a high-pressure reaction kettle and using a Pd-Rh/C composite catalyst for catalytic hydrogenation under the protection of nitrogen, wherein the overall yield of two-step reaction achieves 72 percent. The invention has simple process, easy operation, low cost, and the like and is very suitable for industrialized production.
Description
Technical field
The present invention relates to foodstuff additive and field of medicaments, relate in particular to a kind of production method of L-carnosine.
Technical background
Carnosine is a kind of natural dipeptides that is present in the animal muscle, and the fats oxidn that can suppress to be caused by iron, copper, myohaemoglobin and lipoxidase reacts, because it comes from the muscle of animal, its antioxygenation has widespread use aspect Food preservation.In addition, carnosine also demonstrates various physiological actions, as anti-nerve degeneration effect, antiepileptic action, the habit-forming effect of antinarcotic thing, anti-protein crosslinked action, arteriosclerosis and antiulcer action etc., development and application values is pharmaceutically being arranged as the medicine auxiliary.
The method of existing preparation carnosine mainly contains following several:
1, carnosine is directly extracted in extraction in the animal muscle from mammiferous carnosine meat such as beef, pork, but owing to content in the animal muscle is less, has limited the production of carnosine.In addition,, influenced its antioxidant effect, limited its application owing to also contain mixtures such as the iron that can produce superoxide anion, hydroperoxide and hydroxyl radical free radical and iron protoheme in the carnosine extracting solution.
2, chemosynthesis Sifferd etc. is the earlier synthetic N-carbobenzoxy-(Cbz)-Beta-alanine of raw material with the Beta-alanine; and then produce N-carbobenzoxy-(Cbz)-β-alanyl nitrine with Sodium Nitrite reaction; with the reaction of L-Histidine methyl esters, obtain the L-carnosine through hydrolysis, hydrogenolysis more then.The intermediate of this method relates to the hydrazine compound of severe toxicity and explosive triazo-compound, and production danger is bigger, and is higher to production environment and equipment requirements.Vnick etc. are from Beta-alanine, first synthesizing dihydro-1,3-thiazoles-2,4-diketone intermediate, again with the L-histidine reaction, the L-carnosine.But this method easily generates polypeptide, and quality product is wayward, and poisonous sulfide easily causes serious environmental to pollute.Skoblik etc. are raw material with Zhang Guolin etc. with Boc-Beta-alanine or N-carbobenzoxy-(Cbz)-Beta-alanine; obtain corresponding N-maloyl hydroxyl imines ester with succinyl hydroxyl imine reaction respectively; obtain dipeptides with the L-histidine reaction again; obtain the L-carnosine after sloughing blocking group; this method complex steps; the production cost height is difficult to be fit to suitability for industrialized production equally.
Summary of the invention
The object of the present invention is to provide the synthetic method of the L-carnosine that a kind of technology is simple, production cost is low.
The synthetic method of L-carnosine of the present invention is characterized in that with L-Histidine and ethyl cyanoacetate be raw material, and sodium alkoxide is a catalyzer, by the synthetic N-cyanogen acetyl of ammonolysis reaction-L-Histidine.This intermediate is made solvent with strong aqua and ethanol in autoclave then, under nitrogen protection, with the metal catalyst Pd-Rh/C catalyst hydrogenation of carbon load, obtains the L-carnosine.The two-step reaction overall yield can be up to 72%.
The present invention can represent with following reaction formula:
Wherein, RONa is sodium methylate or sodium ethylate.
Below the present invention is described in more detail:
Step 1) intermediate N cyanogen acetyl-L-Histidine preparation: with the L-Histidine is raw material, mole number is the ethyl cyanoacetate of 1.5 times of L-Histidines, the adding mole number is that the sodium alkoxide of 1.5 times of L-Histidines is made catalyzer, reaction solvent selects DMSO, react under 120 ℃ condition, the reaction times is 12 hours.After reaction finished, the abstraction reaction thing obtained N-cyanogen acetyl-L-Histidine.
As solvent, the mutual solubility of reactant is better with DMSO in the present invention, and the efficient of reaction is higher, and the toxicity of DMSO is little, is suitable for the production of additive kind material.
Described sodium alkoxide is preferably sodium methylate or sodium ethylate.
Step 2) the L-carnosine is synthetic: according to mass ratio is 3: 2 configuration strong aqua/mixed alkoxide solutions, the N-cyanogen acetyl-L-Histidine that obtains with step 1) is a raw material, described strong aqua/the mixed alkoxide solution that adds its 15 times of quality in the autoclave the inside, the metal catalyst Pd-Rh/C catalyzer that adds 0.08 times of 5% carbon load of its quality is earlier 4 * 10
6Pa feeds nitrogen down, gets rid of the oxygen in the reaction system, again 4 * 10
6Under the hydrogen pressure of Pa, 80 ℃ are reacted, and the reaction times is 8 hours.After reaction finished, the abstraction reaction product obtained the L-carnosine.
Described metal catalyst uses the Pd-Rh/C catalyzer, and catalytic efficiency is better, and productive rate is higher.The mol ratio of Pd, Rh is 1: 1 in the Pd-Rh/C catalyzer.
The alcohol of selecting for use in described strong aqua/pure system is methyl alcohol or ethanol.
The present invention has carried out the improvement innovation to reaction solvent and catalyzer on existing technology basis, it is simple to have technology, easy handling, and advantage such as production cost is low is more suitable in suitability for industrialized production.
Embodiment
Below in conjunction with embodiment content of the present invention is described in further details:
The following example will help to understand the present invention, but protection scope of the present invention will not be construed as limiting.
Step 1, N-cyanogen acetyl-L-Histidine synthesize
The sodium ethylate and the 64mol L-Histidine that in reactor, add 50L methyl-sulphoxide, 96mol, stirring also is warmed up to 60 ℃, controlled temperature, slowly drip the ethyl cyanoacetate of 96mol, be warming up to 120 ℃ after adding, stirring reaction 5h under this temperature, stopped reaction postcooling to 50 ℃ slowly adds concentrated hydrochloric acid to pH=2 ~ 3, is evaporated to the about 15L of reaction solution again, in enriched material, add 50L acetone again after being chilled to room temperature, cool to-10 ℃ of thick product crystallizations and separate out, filter, crude product is soluble in water, regulate pH=5, acetone recrystallization gets white solid 12.1kg.
This step adopts sodium methylate also can.
Synthesizing of step 2, L-carnosine
According to mass ratio is 3: 2 configuration strong aqua/alcohol mixed solutions, in autoclave, add the described strong aqua/ethanolic soln of 75kg and 5kg N-cyanogen acetyl-L-Histidine, add the 0.4kg massfraction then and be 5% Pd-Rh/C catalyzer (mol ratio of Pd, Rh is 1: 1 in the Pd-Rh/C catalyzer).Feed 4 * 10 earlier
6Pa N
2Get rid of the O in the solution
2, feed 4 * 10 again
6The H of Pa
2, heat to 80 ℃, insulation reaction 8h, cool to room temperature removes by filter catalyzer, and concentrating under reduced pressure, ethyl alcohol recrystallization get 4.4kg carnosine white solid.Carnosine content 99%, 252 ~ 255 ℃ of fusing points.
This step also can adopt strong aqua/methanol mixed solution.
Claims (5)
1. the production method of a carnosine, it is characterized in that: with L-Histidine and ethyl cyanoacetate is raw material, sodium alkoxide is a catalyzer, by the synthetic N-cyanogen acetyl of ammonolysis reaction-L-Histidine; N-cyanogen acetyl-L-Histidine is made solvent with strong aqua/mixed alkoxide solution in autoclave then, under oxygen-free environment, with the metal catalyst Pd-Rh/C catalyst hydrogenation of carbon load, obtains the L-carnosine.
2. as the synthetic method in the claim 1, it is characterized in that, may further comprise the steps:
1) N-cyanogen acetyl-L-Histidine is synthetic: with the L-Histidine is raw material, adding mole number is the ethyl cyanoacetate of 1.5 times of L-Histidines, the sodium alkoxide that adds mole number again and be 1.5 times of L-Histidines is made catalyzer, reaction with DMSO as solvent, react under 120 ℃ condition, the reaction times is 5 hours; After reaction finished, the abstraction reaction product obtained N-cyanogen acetyl-L-Histidine;
2) the L-carnosine is synthetic: according to mass ratio is 3: 2 configuration strong aqua/mixed alkoxide solutions, the N-cyanogen acetyl-L-Histidine that obtains with step 1) is a raw material, add the described strong aqua/mixed alkoxide solution of its 15 times of quality as solvent in the autoclave the inside, the Pd-Rh/C catalyzer that adds 0.08 times of 5% carbon load of its quality, under the oxygen free condition, 4 * 10
6Under the hydrogen pressure of Pa, react under 80 ℃, the reaction times is 8 hours; After reaction finished, the abstraction reaction product obtained the L-carnosine.
3. synthetic method according to claim 1 and 2 is characterized in that described sodium alkoxide is sodium methylate or sodium ethylate.
4. according to claim 1 and 2 described synthetic methods, it is characterized in that the alcohol of selecting for use in described strong aqua/mixed alkoxide solution is methyl alcohol or ethanol.
5. according to claim 1 and 2 described synthetic methods, it is characterized in that the mol ratio of Pd, Rh in the Pd-Rh/C catalyzer of described 5% carbon load is 1: 1.
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| CN201010102105XA CN101735305B (en) | 2010-01-25 | 2010-01-25 | Synthesizing method of L-carnosine |
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| CN201010102105XA CN101735305B (en) | 2010-01-25 | 2010-01-25 | Synthesizing method of L-carnosine |
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| CN101735305A true CN101735305A (en) | 2010-06-16 |
| CN101735305B CN101735305B (en) | 2012-05-09 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN107602661A (en) * | 2017-08-24 | 2018-01-19 | 烟台万润药业有限公司 | A kind of preparation method of Polaprezinc |
| CN114213335A (en) * | 2021-12-23 | 2022-03-22 | 浙江湃肽生物有限公司 | Carnosine intermediate and preparation and application of carnosine |
| CN117164519A (en) * | 2023-08-18 | 2023-12-05 | 杭州小蓓医药科技有限公司 | Synthesis method of L-carnosine |
-
2010
- 2010-01-25 CN CN201010102105XA patent/CN101735305B/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN107602661A (en) * | 2017-08-24 | 2018-01-19 | 烟台万润药业有限公司 | A kind of preparation method of Polaprezinc |
| CN114213335A (en) * | 2021-12-23 | 2022-03-22 | 浙江湃肽生物有限公司 | Carnosine intermediate and preparation and application of carnosine |
| CN114213335B (en) * | 2021-12-23 | 2023-08-15 | 浙江湃肽生物股份有限公司 | Carnosine intermediate and preparation and application of carnosine thereof |
| CN117164519A (en) * | 2023-08-18 | 2023-12-05 | 杭州小蓓医药科技有限公司 | Synthesis method of L-carnosine |
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| CN101735305B (en) | 2012-05-09 |
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