CN101735305B - Synthesizing method of L-carnosine - Google Patents
Synthesizing method of L-carnosine Download PDFInfo
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- CN101735305B CN101735305B CN201010102105XA CN201010102105A CN101735305B CN 101735305 B CN101735305 B CN 101735305B CN 201010102105X A CN201010102105X A CN 201010102105XA CN 201010102105 A CN201010102105 A CN 201010102105A CN 101735305 B CN101735305 B CN 101735305B
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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 working 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; Like 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 kinds:
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 with Sodium Nitrite reacted N-carbobenzoxy-(Cbz)-β-alanyl nitrine; With the reaction of L-Histidine methyl esters, obtain the L-carnosine through hydrolysis, hydrogenolysis more then.The midbody 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 midbody, again with the L-histidine reaction, the L-carnosine.But this method is prone to generate polypeptide, and quality product is wayward, and poisonous sulfide is prone to cause 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, this method complex steps after sloughing blocking group; Production cost is high, 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 compound method of the L-carnosine that a kind of technology is simple, production cost is low.
The compound 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, through the synthetic N-cyanogen acetyl of ammonolysis reaction-L-Histidine.This midbody 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.
Down in the face of further explain of the present invention:
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, under 120 ℃ condition, reacts, and 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; Said 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.
Said 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 innovation of improvement property 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 explained further details:
The following example will help to understand the present invention, but protection scope of the present invention not constituted restriction.
Step 1, N-cyanogen acetyl-L-Histidine synthesize
In reaction kettle, add sodium ethylate and the 64mol L-Histidine of 50L methyl-sulphoxide, 96mol, stir and be 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; Bullion 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 said 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 (3)
1. the working method of a carnosine 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, is reacted under 120 ℃ condition as solvent with DMSO, and 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; Said strong aqua/the mixed alkoxide solution that adds its 15 times of quality in the autoclave the inside is as solvent; The Pd-Rh/C catalyzer that adds 0.08 times of 5% carbon load of its quality, the mol ratio of Pd, Rh is 1: 1 in the said Pd-Rh/C catalyzer; 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.
2. the working method of carnosine according to claim 1 is characterized in that described sodium alkoxide is sodium methylate or sodium ethylate.
3. the working method of carnosine according to claim 1 is characterized in that the alcohol of selecting for use in described strong aqua/mixed alkoxide solution is methyl alcohol or ethanol.
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| Application Number | Priority Date | Filing Date | Title |
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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 CN101735305A (en) | 2010-06-16 |
| CN101735305B true CN101735305B (en) | 2012-05-09 |
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| 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 |
| CN107602661B (en) * | 2017-08-24 | 2020-03-17 | 烟台万润药业有限公司 | Preparation method of polaprezinc |
| 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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