CN102942498A - Ornithine aspartate compound and preparation method thereof - Google Patents
Ornithine aspartate compound and preparation method thereof Download PDFInfo
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- CN102942498A CN102942498A CN 201210495587 CN201210495587A CN102942498A CN 102942498 A CN102942498 A CN 102942498A CN 201210495587 CN201210495587 CN 201210495587 CN 201210495587 A CN201210495587 A CN 201210495587A CN 102942498 A CN102942498 A CN 102942498A
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- aspartic acid
- ornithine
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Abstract
The invention relates to an ornithine aspartate compound and a preparation method thereof. L-aspartic acid and L-ornithine acetate are used as initial raw materials, ammonium acetate serving as an intermediate product is removed by the aid of solubility difference between ornithine and the ammonium acetate in ethyl acetate to obtain free alkali of the ornithine, and then the free alkali reacts with the L-aspartic acid to generate ornithine aspartate. The compound is simple in synthetic route step, high in yield and suitable for industrial production of enterprises.
Description
Technical field
The invention belongs to the synthetic field of chemical drug, be specifically related to compound of a kind of aspartic acid ornithine and preparation method thereof.
Background technology
Aspartic acid ornithine, chemistry (S)-2 by name, the 5-Ornithine-(S)-and 2-amino-succinic acid salt, molecular formula is C
9H
19N
3O
6, molecular weight is 265.27, structural formula is:
Aspartic acid ornithine provides urea and the synthetic essential material of amide glutaminate.Glutamine is the detoxifcation product of ammonia, also is storage and the types of transportation of ammonia simultaneously; Under physiology and pathological conditions, the very one-tenth synthetic and glutamine of urea can be subject to the impact of ornithine, Aspartic Acid and other dihydroxy compound.Ornithine almost relates to the activation of ornithine cycle and the detoxifcation whole process of ammonia.The arginine that forms in this process then divides urea and forms ornithine.Aspartic Acid participates in the synthetic of the interior nucleic acid of liver cell, is beneficial to repair the liver cell that is damaged.In addition, because Aspartic Acid to the indirect promoter action of tricarboxylic acid cycle metabolic process in the liver cell, has promoted the energy in the liver cell to generate, so that the hepatocellular various functions of abducted wound is recovered.Be applicable to clinically to treat because of the hyperammonemia due to acute and chronic hepatopathy such as liver cirrhosis, fatty liver and the hepatitis, be specially adapted to the releasing of the central nervous system symptom that causes because of liver disease and the rescue of hepatic coma.
The synthetic bibliographical information of L-Orn-L-ASPARTIC ACID has following several method:
It is ornithine that the patent DE4020980 of Germany Degussan company adopts arginine to make conversion of Arginine, gets with the L-ASPARTIC ACID reaction again.Expensive by arginase, the industrialization supply bottleneck, this process costs is high, does not still have industrial value.
Japan KYOWA company and applied for English Patent GB1067741 in 1967, adopt strongly-acid (H-type) ion exchange resin to make L-Orn-L-ASPARTIC ACID salt free, again with the L-ASPARTIC ACID salify, through crystallization treatment, obtain at last the L-Orn of yield 52%-L-ASPARTIC ACID salt hydrate.This process using resin desalination, and yield is lower, and three wastes output is larger.
1992, Japan KYOWA company has applied for European patent EP 477991, first the L-Orn hydrochloride aqueous solution to be passed through Diaion SKIB resin absorption, the ammoniacal liquor desorption, with the L-ASPARTIC ACID salify, add methanol eddy and process behind the deamination, crystallization and getting, this method still have three wastes turnout large, needed the shortcomings such as resin column, high expensive.
The Chinese patent CN101100435A of Shanghai Yi Furui corporation in 2006 application, the method that adopts is: L-Orn vitriol is dissolved in the distilled water, add L-ASPARTIC ACID, after the heating for dissolving, use the hydrated barta neutralisation of sulphuric acid, filter, barium ion with D403 resin chelating remnants removes by filter resin, and solution decompression is concentrated, activated carbon decolorizing, add absolute ethyl alcohol and stirring, heating, the barium ion of severe toxicity is used in crystallization under the reflux state, the method, and still need resin column to remove heavy metal ion and remove barium ion after solution adopt vacuum-concentrcted, length consuming time, operation industry is complicated.
Chinese patent CN101798275A discloses a kind of preparation method of ornithine Aspartic Acid, after the method is water-soluble with L-Orn acetate, add L-ASPARTIC ACID, then transfer pH to 6-9 with ammonia, activated carbon decolorizing, the polar organic solvent recrystallization, the method is because directly additive polarity organic solvent crystallization in reacted reaction solution, in suitability for industrialized production, need to expend so a large amount of organic solvents and carry out, cost also improves relatively, and since wherein reacted salt for sloughing, during recrystallization, these salt can be brought in the crystallization unavoidably.
In sum, in the prior art, when the preparation aspartic acid ornithine, perhaps introduce ion exchange method and remove some inorganic salt impurity in the reaction solution, and then carry out crystallisation step, this technique length consuming time, and follow-up when carrying out crystallization, the gained effluent volume is large, directly adds when alcohol carries out crystallization to expend a large amount of alcohol, and cost is high; Perhaps reaction solution carry out preliminary rotating pressure-decreasing concentrated after, concentrated solution carries out crystallization treatment again, the time that this concentration method needs is long, it is also large to consume energy.It is simple how to work out synthetic route, and yield is high, and cost is low, the aspartic acid ornithine preparation method of non-environmental-pollution is extremely urgent.
Summary of the invention
The present invention aims to provide compound of a kind of aspartic acid ornithine and preparation method thereof, solves the needs of problems of present suitability for industrialized production.
For achieving the above object, compound of a kind of aspartic acid ornithine of the present invention and preparation method thereof, its specific embodiments is:
Compound of a kind of aspartic acid ornithine of the present invention and preparation method thereof is characterized in that this aspartic acid-ornithine compound chemical formula is:
1) L-Orn acetate is dissolved in the water, then uses the pH=7-9 of ammoniacal liquor regulation system, add ethyl acetate, 25-40 ℃ was stirred 2-8 hour, made the ammonium acetate precipitation fully;
2) filter, with 50 ℃ of concentrating under reduced pressure of filtrate, then add ASPARTIC ACID, stir and be warmed up to 55-85 ℃, slowly add alcohol solvent, it is muddy that solution begins to become, then reflux 0.5-2h;
3) be cooled to 0-30 ℃, filter to get white solid;
4) white solid is added in the solvent, be heated to backflow 1-1.5h after, be cooled to again 10-20 ℃;
5) filter, 40-50 ℃ of vacuum-drying obtains aspartic acid ornithine.
The method of the invention is characterized in that solvent is selected from ethyl acetate, tetrahydrofuran (THF), ethyl acetate.Ammoniacal liquor is regulated pH=8-10, preferred pH=9-10.Whipping temp 25-40 ℃, preferred 30 ℃.Churning time 2-8 hour, preferred 4-6 hour.
The method of the invention is characterized in that whipping temp 25-90 ℃, preferred 65-75 ℃, and reflux 0.5-2h, preferred 1-1.5h.
The method of the invention is characterized in that cooling temperature 0-30 ℃, preferred 10-20 ℃.
The method of the invention is characterized in that drying temperature 40-50 ℃, preferred 45 ℃.
Compared with prior art, the present invention has the following advantages:
The selected solvent of the present invention, toxicity is low, and environmental pollution is little; Synthetic route is simple, and workload is little, and is with low cost; Product yield is high, and the cycle is short, is fit to industrial mass production.
Embodiment
Below enforcement only for more detailed description the present invention, but do not limit in any form the present invention.
Embodiment
The aspartic acid-ornithine compound synthetic method:
L-Orn acetate is dissolved in the water, then uses the ammoniacal liquor regulation system
The pH value, add ethyl acetate, 30 ℃ of stirrings
4-6 hour, make the ammonium acetate precipitation fully, filter, with 50 ℃ of concentrating under reduced pressure of filtrate, then add ASPARTIC ACID, stirring is warmed up to
65-75 ℃, slowly add
Alcohol solvent, it is muddy that solution begins to become, then reflux
1-1.5h, then be cooled to
10-20 ℃, filter to get white solid, then white solid is added in the solvent reflux
1-1.5h, be cooled to again 10-20 ℃, to filter, 40-50 ℃ of vacuum-drying obtains aspartic acid ornithine.
Claims (6)
1. compound of an aspartic acid ornithine and preparation method thereof is characterized in that this aspartic acid-ornithine compound chemical formula is:
2. compound of described a kind of aspartic acid ornithine and preparation method thereof according to claim 1 is characterized in that the method is specially:
1) L-Orn acetate is dissolved in the water, then uses the pH=7-9 of ammoniacal liquor regulation system, add ethyl acetate, 25-40 ℃ was stirred 2-8 hour, made the ammonium acetate precipitation fully;
Filter, with 50 ℃ of concentrating under reduced pressure of filtrate, then add ASPARTIC ACID, stir and be warmed up to 55-85 ℃, slowly add alcohol solvent, it is muddy that solution begins to become, then reflux 0.5-2h;
Be cooled to 0-30 ℃, filter to get white solid;
White solid is added in the solvent, be heated to backflow 1-1.5h after, be cooled to again 10-20 ℃;
Filter, 40-50 ℃ of vacuum-drying obtains aspartic acid ornithine.
3. described method according to claim 2 is characterized in that solvent is selected from ethyl acetate, tetrahydrofuran (THF), and ethyl acetate, ammoniacal liquor is regulated pH=7-9, preferred pH=7-8; Whipping temp 25-40 ℃, preferred 30 ℃; Churning time 2-8 hour, preferred 4-6 hour.
4. described method according to claim 2 is characterized in that whipping temp 55-85 ℃, preferred 65-75 ℃, and reflux 0.5-2h, preferred 1-1.5h.
5. described method according to claim 2 is characterized in that cooling temperature 0-30 ℃, preferred 10-20 ℃.
6. described method according to claim 2 is characterized in that drying temperature 40-75 ℃, preferred 45 ℃.
Priority Applications (1)
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| CN 201210495587 CN102942498A (en) | 2012-11-29 | 2012-11-29 | Ornithine aspartate compound and preparation method thereof |
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| CN 201210495587 CN102942498A (en) | 2012-11-29 | 2012-11-29 | Ornithine aspartate compound and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699586A (en) * | 2016-12-08 | 2017-05-24 | 陕西天宇制药有限公司 | Preparation method of ornithine aspartate |
| CN110317144A (en) * | 2018-03-28 | 2019-10-11 | 上海贵之言医药科技有限公司 | A kind of aspartic acid ornithine Crystal form of double salt compound and preparation method thereof |
| CN110317145A (en) * | 2018-03-28 | 2019-10-11 | 上海贵之言医药科技有限公司 | A kind of preparation method of aspartic acid ornithine compound salt |
-
2012
- 2012-11-29 CN CN 201210495587 patent/CN102942498A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699586A (en) * | 2016-12-08 | 2017-05-24 | 陕西天宇制药有限公司 | Preparation method of ornithine aspartate |
| CN106699586B (en) * | 2016-12-08 | 2019-01-25 | 陕西天宇制药有限公司 | The preparation method of aspartic acid ornithine |
| CN110317144A (en) * | 2018-03-28 | 2019-10-11 | 上海贵之言医药科技有限公司 | A kind of aspartic acid ornithine Crystal form of double salt compound and preparation method thereof |
| CN110317145A (en) * | 2018-03-28 | 2019-10-11 | 上海贵之言医药科技有限公司 | A kind of preparation method of aspartic acid ornithine compound salt |
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Application publication date: 20130227 |