CN102976962A - L-ornithine-aspirin double salt and its preparation method and use - Google Patents
L-ornithine-aspirin double salt and its preparation method and use Download PDFInfo
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- CN102976962A CN102976962A CN2012104721486A CN201210472148A CN102976962A CN 102976962 A CN102976962 A CN 102976962A CN 2012104721486 A CN2012104721486 A CN 2012104721486A CN 201210472148 A CN201210472148 A CN 201210472148A CN 102976962 A CN102976962 A CN 102976962A
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- acetylsalicylic acid
- aspirin
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- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- 150000003839 salts Chemical class 0.000 title claims abstract description 32
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims abstract description 139
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims abstract description 103
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Abstract
The invention belongs to the field of medicines and discloses an L-ornithine-aspirin double salt and its preparation method and use. A preparation method of the L-ornithine-aspirin double salt comprises the following steps of preparing an aqueous solution of dissociative L-ornithine, adding aspirin into the aqueous solution of dissociative L-ornithine for a reaction to obtain an L-ornithine-aspirin salt solution and separating out L-ornithine-aspirin salt crystals, or comprises the following steps of mixing an ethanol solution of aspirin and an ethanol solution of dissociative L-ornithine to obtain L-ornithine-aspirin salt precipitates, carrying out precipitate dissolution and carrying out recrystallization. A mole ratio of L-ornithine to aspirin in the L-ornithine-aspirin salt crystals is 1: 1. The preparation method is easy and practicable, has a low cost and a high yield and improves the quality of the L-ornithine-aspirin double salt. An animal experiment research proves that the L-ornithine-aspirin double salt has effects of reducing fat and protecting the liver and can be used for preparation of liver-protecting drugs.
Description
Technical field
The invention belongs to field of medicaments, relate to L-Orn acetylsalicylic acid double salt and its preparation method and application.
Background technology
Hyperlipidaemia is because Human Lipid Metabolism is disorderly, the paranormal a kind of illness of blood plasma inner lipid concentration, and the protein binding in the many and blood plasma because of lipid is so claim again hyperlipoproteinemia.Main manifestations is that serum total cholesterol (TC), triglyceride level (TG) and low density lipoprotein cholesterol (LDL-C) level are too high or high density lipoprotein cholesterol (LDL-C) level is excessively low.Cholesterol in the blood plasma, triglyceride level are the main components in the atherosclerotic plaque, hyperlipidaemia is not only participated in directly and is promoted arteriosclerotic formation, and promote the formation of microthrombus by changing hemorheological property, cause microcirculation disturbance, having caused generation and the development of cardiovascular and cerebrovascular disease, is one of important risk factor of cardiovascular disorder.Therefore, regulate blood fat and to improve hemorheological property significant to the control of cardiovascular diseases.Along with the raising of people's living standard, the sickness rate of hyperlipidaemia rises year by year, has become the focus of current research.In recent years, the development of medicine and pharmacology and research, the announcement of Bloodlipid-lowering and safety results is strengthened in extensive clinical experiment, and statins becomes the effective medicine of blood fat reducing, with the basic medication as the sick control of clinical cardiovascular.Yet any medicine all can exist potential toxicity and untoward reaction, and can strengthen along with the increase of dosage, and fat-reducing medicament can not reduce the lipidosis of liver through liver, sometimes can increase the weight of hepatic injury on the contrary.Therefore, the medicine of actively seeking a kind of effective fat-reducing liver-protecting is significant.
L-Orn Main Function in vivo is to participate in ornithine cycle, can activate rapidly the ornithine cycle in the liver cell, harmful carbonic acid gas and ammonia that body is produced under morbid state excretes by ornithine cycle, so that enzymes metabolism progressively recovers in the liver, thereby so that the vigor of liver is restored, play the effect that protects the liver, protects liver.There is research data to prove, L-Orn can promote hypothalamus secretion tethelin, and tethelin can promote sugar and the metabolism of fat and synthesizing of protein, therefore, L-Orn can promote lipid metabolism and activate ornithine cycle, for body provides more multi-energy and reduces blood ammonia.And acetylsalicylic acid can make the Serine acetoxylation in PG synthetic enzyme (cyclo-oxygenase) active centre and inactivation, reduces the platelet aggregation rate that ADP, collagen and human thrombin are induced, and reduces TAX in the thrombocyte
2The generation of (thromboxane) and platelet aggregation-against and antithrombotic form, and be clinical in control thrombosis and thrombotic disease.Have no at present L-Orn acetylsalicylic acid preparation method's report both at home and abroad, also do not have the L-Orn acetylsalicylic acid for the preparation of the report of fat-reducing liver-protecting medicine.
Summary of the invention
The objective of the invention is for above-mentioned technical problem, a kind of L-Orn acetylsalicylic acid double salt is provided.
Another object of the present invention provides the preparation method of above-mentioned L-Orn acetylsalicylic acid double salt.
A further object of the invention provides the application of above-mentioned L-Orn acetylsalicylic acid double salt in preparation fat-reducing liver-protecting medicine.
Purpose of the present invention is achieved through the following technical solutions:
A kind of L-Orn acetylsalicylic acid double salt, this double salt prepares by following method:
Method one: the aqueous solution of the free L-Orn of preparation, react to wherein adding acetylsalicylic acid again, obtain the solution of L-Orn aspirin salt, again its form with crystallization is separated out; Perhaps
Method two: the ethanolic soln of acetylsalicylic acid is mixed with the ethanolic soln of free L-Orn, obtain the precipitation of L-Orn aspirin salt, then resolution of precipitate is obtained the aqueous solution of L-Orn aspirin salt, carry out again recrystallization, and get final product.
Described L-Orn acetylsalicylic acid double salt, the mol ratio of L-Orn and acetylsalicylic acid is 1:1 in its crystal.
Described L-Orn acetylsalicylic acid double salt, salicylic acid content is below 0.2Wt% in this double salt.
The preparation method of described L-Orn acetylsalicylic acid double salt, the method comprises the following steps:
Method one: the aqueous solution of the free L-Orn of preparation, to wherein adding acetylsalicylic acid, both are fully reacted again, obtain the solution of L-Orn aspirin salt, again its form with crystallization is separated out; Perhaps
Method two: the ethanolic soln of acetylsalicylic acid is mixed with the ethanolic soln of free L-Orn, obtain the precipitation of L-Orn aspirin salt, then resolution of precipitate is obtained the aqueous solution of L-Orn aspirin salt, carry out again recrystallization, and get final product.
Described preparation method, wherein free L-Orn obtains by following method: extraction from fermented liquid, chemosynthesis, enzyme reaction or L-Orn salt obtained by desalination.
Described preparation method, wherein the mol ratio of L-Orn and acetylsalicylic acid is 0.5 ~ 2:1 in the reactant, temperature of reaction is 10 ℃-25 ℃.
The feeding mode of acetylsalicylic acid is in above-mentioned preparation method's the method one: the crystal of acetylsalicylic acid or powder or solution drop into the aqueous solution of free L-Orn.
Described preparation method, wherein crystallization method is: add the dissolved agent in the solution of L-Orn aspirin salt, perhaps reduce the temperature of solution, perhaps the solvent of evaporating solns, perhaps add crystal seed in the solution and make it crystallization, the perhaps combination of these methods.
Described preparation method, wherein L-Orn acetylsalicylic acid salts solution is its aqueous solution in the crystallization method, its mass concentration is 30% ~ 60%.
Described preparation method, temperature is controlled at-10 ℃ ~ 25 ℃ in the crystallisation process, preferred 0 ~ 20 ℃.
Described preparation method, wherein the dissolved agent is hydrophilic organic solvent, one or more in particular methanol, ethanol, propyl alcohol, Virahol, butanols, ethylene glycol, acetone, the acetonitrile; The add-on of dissolved agent is 1 ~ 8 times of L-Orn aspirin salt liquor capacity, preferred 2 ~ 5 times.
Described preparation method, wherein the adding speed of dissolved agent is 0.1mL.min
-1~ 1.5mL.min
-1, preferred 0.2mL.min
-1~ 0.8mL.min
-1, 0.4mL.min more preferably
-1~ 0.6mL.min
-1
Described preparation method, wherein the crystal seed adding is period: when the volume of the hydrophilic organic solvent that stream adds is 0.1 ~ 2.5 times of L-Orn aspirin salt liquor capacity, when being preferably 0.5 ~ 1.5 times; The crystal seed add-on is: 0.1 ~ 5wt% of the amount of the L-Orn aspirin salt that contains in the relative response liquid is preferably 0.5 ~ 2.5wt%.
The application of described L-Orn acetylsalicylic acid double salt in preparation fat-reducing liver-protecting medicine.
Further, detailed technology scheme of the present invention is:
The L-Orn acetylsalicylic acid is the double salt of L-Orn and acetylsalicylic acid, and chemical structural formula is as follows, and outward appearance is white crystalline powder.
1, the preparation method of L-Orn acetylsalicylic acid composite salt.
The first step: the free L-Orn of preparation.
The method that obtains free L-Orn is a lot.Can be that L-Orn salt (comprise hydrochloride, vitriol, phosphoric acid salt, Citrate trianion etc., and the salt of other various possible forms) is obtained by desalination.Also can be from fermented liquid or other reaction solution (such as chemosynthesis and enzyme reaction solution), to obtain, as the disclosed fermented liquid of patent documentation CN101955901B is obtained after removing the art breading such as thalline, decolouring, ion-exchange.And for example adopt the preparing L-omithine through immobilized ectocellular enzyme take L-arginine as raw material of patent documentation CN1661026 report.
In certain embodiments, can be with the aqueous solution of L-Orn hydrochloride by the JK006 storng-acid cation exchange resin, L-Orn is adsorbed, and removes chlorion in the resin voids with a certain amount of washing again, use at last the ammoniacal liquor wash-out, obtain containing the aqueous solution of free L-Orn; Or process the aqueous solution of L-Orn hydrochloride with 330 weakly alkaline epoxy type anion exchange resins, chlorion is adsorbed, and removes by filter ion exchange resin wherein, and is concentrated except ammonia, obtains the aqueous solution of free L-Orn.
Second step: the reaction of free L-Orn and acetylsalicylic acid.
Stable bad in water of acetylsalicylic acid, facile hydrolysis generates Whitfield's ointment, and soda acid all has certain katalysis to hydrolysis reaction.Therefore the selection of the reaction system of the two is very important, otherwise can cause that salicylic acid content exceeds standard in the product.Reaction equation:
Can adopt following two kinds of methods to realize this reaction, for example:
(1) will dissociate first that to be concentrated to mass concentration be 36% for the aqueous solution of L-Orn, again to wherein dropping into 24g acetylsalicylic acid (existence form of acetylsalicylic acid can be crystal, powder, solution etc.) here, both are fully reacted, obtain the solution of L-Orn aspirin salt;
(2) ethanolic soln with acetylsalicylic acid mixes with the ethanolic soln of free L-Orn, obtains the precipitation of L-Orn aspirin salt.Then resolution of precipitate is obtained the solution of L-Orn aspirin salt, recrystallization.
In two kinds of methods, substrate during reaction (L-Orn and acetylsalicylic acid) mol ratio is 0.5 ~ 2:1, and temperature of reaction is controlled at 10 ℃ ~ 25 ℃.
The 3rd step: with L-Orn aspirin salt crystallization from solution.
The method that crystallization is adopted can be, adds the dissolved agent in the solution of above-mentioned L-Orn aspirin salt, perhaps reduces the temperature of mentioned solution, perhaps evaporates the solvent of mentioned solution, perhaps adds crystal seed in mentioned solution, makes it crystallization.Perhaps also can implement these methods by combination and make crystallization.In some embodiments, be preferably in the above-mentioned L-Orn acetylsalicylic acid aqueous solution and add hydrophilic organic solvent as the dissolved agent, crystal is separated out.
In some embodiments, when the agent of interpolation dissolved is separated out crystal in the solution of L-Orn aspirin salt, be preferably this concentration of polymer solution is adjusted to 30% ~ 60%.
The dissolved agent can be hydrophilic organic solvent, includes but not limited to methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, ethylene glycol, acetone, acetonitrile etc., or the combination of these materials.
The consumption of dissolved agent can for 1 ~ 8 times of the volume of the solution of L-Orn aspirin salt, be preferably 2 ~ 5 times.The adding mode of dissolved agent can be under 0 ~ 25 ℃, and slowly stream adds in the solution of the L-Orn aspirin salt that is adjusted to above-mentioned concentration.The flow acceleration of dissolved agent is: for the solution of 20mL, dissolved agent stream rate of acceleration can be controlled at 0.1mL.min
-1~ 1.5mL.min
-1, preferred 0.2mL.min
-1~ 0.8mL.min
-1, 0.4mL.min more preferably
-1~ 0.6mL.min
-1
Crystal seed adds mode: when dissolved agent volume is 0.1 ~ 2.5 times of L-Orn aspirin salt liquor capacity, when being preferably 0.5 ~ 1.5 times, add a certain amount of crystal seed.
Seed load: 0.1 ~ 5.0wt% of the amount of the L-Orn aspirin salt that relatively contains in this reaction solution is preferably 0.5 ~ 2.5wt%.
The L-Orn acetylsalicylic acid is hydrolyzed into L-Orn and acetylsalicylic acid after entering human body, has the effect of reducing blood-fat, can be used for preparing blood lipid-lowering medicine.
Beneficial effect of the present invention:
Preparation method of the present invention has the advantages such as simple possible, production cost are low, constant product quality, and the L-Orn acetylsalicylic acid can be used for preparing blood lipid-lowering medicine, for the hypolipidemic research and development provide new selection.
Embodiment
The invention will be further elaborated below by embodiment.
Embodiment 1: preparation L-Orn aspirin salt.
The first step: the free L-Orn of preparation;
Example 1:
The L-Orn hydrochloride of 30g is dissolved in the 1000mL water, regulates pH to 2.0, flow through the pillar that has loaded the JK006 storng-acid cation exchange resin.With 300mL water flushing pillar, the flush away impurity such as chlorion wherein, use again the ammoniacal liquor wash-out L-Orn of the 2mol/L of 400mL, concentrated except ammonia, the L-Orn aqueous solution that obtains dissociating.
Example 2:
The L-Orn vitriol of 30g is dissolved in the 1000mL water, regulates pH to 2.0, flow through the pillar that has loaded the JK006 storng-acid cation exchange resin.With 300mL water flushing pillar, the flush away impurity such as sulfate radical wherein, use again the ammoniacal liquor wash-out L-Orn of the 2mol/L of 400mL, concentrated except ammonia, the L-Orn aqueous solution that obtains dissociating.
Example 3:
Adopt the chlorion in the anionite-exchange resin Static Adsorption L-Orn hydrochloride aqueous solution, concrete operations are as follows: the L-Orn hydrochloride of 30g is dissolved in the 1000mL water, add 330 weakly alkaline epoxy type anion exchange resins, stir 1.5h under the room temperature, detect wherein chloride ion content with Silver Nitrate, remove by filter resin, the L-Orn aqueous solution that obtains dissociating.
Example 4:
According to the disclosed method of patent documentation CN101955901B, obtain containing the fermented liquid of L-Orn, fermented liquid obtains containing the aqueous solution of free L-Orn after removing thalline, pigment processing.
Second step: free L-Orn and acetylsalicylic acid react, and obtain L-Orn acetylsalicylic acid salts solution, and adjust its concentration.
Example 1:
It is under 36%, 20 ℃ of water-bath that the free L-Orn aqueous solution that the first step is obtained is concentrated to mass concentration, stir, and to wherein adding the 24g acetylsalicylic acid, the L-Orn acetylsalicylic acid salt content that obtains is about 55%.
Example 2:
The free L-Orn aqueous solution that the first step obtains is concentrated, use again the 25mL dissolve with ethanol.Water-bath control temperature is 20 ℃, stirs, and the ethanolic soln stream of free L-Orn is added in the ethanolic soln of acetylsalicylic acid that 120mL concentration is 200gL, filters, and drying obtains the white solid of L-Orn aspirin salt.Above-mentioned white solid (41.6g) is dissolved in an amount of water, and making its mass concentration is 55%.
The 3rd step: the crystallization of L-Orn aspirin salt
Crystallization can be adopted several different methods, can adopt and add the dissolved agent in the solution of L-Orn aspirin salt, perhaps reduces the temperature of solution, and the perhaps solvent of evaporating solns perhaps adds crystal seed in the solution and makes it crystallization, the perhaps combination of these methods.Temperature is controlled at-10 ℃ ~ 25 ℃ in the crystallisation process, and the add-on of dissolved agent is controlled at 1 ~ 8 times of L-Orn aspirin salt liquor capacity, and the adding rate-controlling of dissolved agent is at 0.1mL.min
-1~ 1.5mL.min
-1, the crystal seed adding is period: when the volume of the hydrophilic organic solvent that stream adds was 0.1 ~ 2.5 times of L-Orn aspirin salt liquor capacity, the crystal seed add-on was: 0.1 ~ 5wt% of the amount of the L-Orn aspirin salt that contains in the relative response liquid.
Example 1:
Under 25 ℃ and the condition that stirs, speed stream with 1.5mL/min in the L-Orn acetylsalicylic acid salts solution that obtains to second step example 1 adds dehydrated alcohol, adds 4.5g crystal seed, stirring and crystallizing 30min behind about 30min, continue stream and add the dissolved agent, stop stream behind about 100min and add.Filter, drying, obtain the crystal of the L-Orn aspirin salt of white needles, yield is 80.5%, product purity is 97.6%.
Example 2:
Under 10 ℃ and the condition that stirs, speed stream with 1.0mL/min in the L-Orn acetylsalicylic acid salts solution that obtains to second step example 1 adds dehydrated alcohol, adds 4.5g crystal seed, stirring and crystallizing 30min behind about 45min, continue stream and add the dissolved agent, stop stream behind about 150min and add.Filter, drying, obtain the crystal of the L-Orn aspirin salt of white needles, yield is 85.5%, product purity is 96.9%.
Example 3:
Under 25 ℃ and the condition that stirs, speed stream with 1.5mL/min in the L-Orn acetylsalicylic acid salts solution that obtains to second step example 1 adds dehydrated alcohol, adds 9.0g crystal seed, stirring and crystallizing 30min behind about 30min, continue stream and add the dissolved agent, stop stream behind about 100min and add.Filtration, drying, the crystal yield that obtains the L-Orn aspirin salt of white needles is 81.2%, product purity is 97.8%.
The accent blood fat hepatoprotective effect research of embodiment 2, L-Orn acetylsalicylic acid double salt
2.1 experiment material: 60 of healthy Wistar big white mouse, body weight (269.2 ± 50.9) g male and female dual-purpose.
Feed: normal diet; The high lipid food prescription is: basal feed 72.7%, cholesterol 2%, yolk powder 5%, lard 10%, propylthiouracil 0.2%, sucrose 10%, Sodium cholic acid 0.1%.(mass percent)
2.2 animal grouping and administration: the experimental rat of buying adapts in the laboratory raised for 1 week, pressing the order of weighing compiles original number, look into table of random number and be divided at random blank group, model control group, L-Orn acetylsalicylic acid 2mg/kg low dose group, dosage group among the 4mg/kg, the 8mg/kg high dose group, positive drug (Simvastatin 1.5mg/kg) control group.Every group 10.Blank group, model control group gavage distilled water from the experiment, administration group gavage relative medicine, 1 time/d, volume is 10ml/kg, claims weekly body weight 1 time, adjusts dosage according to body weight.The blank group is fed and is raised normal diet, and all the other each groups are fed and raised high lipid food, and duration of test is freely ingested, freely drunk water, and continuous modeling also prevents 8 weeks of administration.
2.3 observation index: fasting 12h after the last administration, can't help water.3% vetanarcol anesthetized rat, abdominal aortic blood, centrifugation serum, survey serum total cholesterol (TC), triacylglycerol (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), superoxide-dismutase (SOD), mda (MDA),
Gpt (ALT), glutamic-oxal(o)acetic transaminase (AST) value.
2.4 result
A) the L-Orn acetylsalicylic acid is on the impact of Serum Lipids in Experimental HypercholesterolemicRats
By as seen from Table 1, to compare with normal group, the level of TC, TG, LDL-C obviously raises (P＜0.05) in the model group rat blood serum, presents typical lipid metabolism disorders, shows the success of Experimental Hyperlipemia model copy.Compare with model group, treatment group can obviously reduce serum TC, TG, LDL-C content (P＜0.05), and remarkable elevating HDL-C content (P＜0.01) and present dose-dependently.
Table 1 respectively organize rat fat change (
N=10)
B) the L-Orn acetylsalicylic acid is on the impact of Liver Function
Serum alt and AST can react liver function.High lipid food group ALT and AST illustrate that apparently higher than basal feed group (P＜0.05) liver has certain infringement.And each administration group has obvious reduction, and compares with Normal group, and difference is very significant (P＜0.01); L-Orn acetylsalicylic acid group can reduce ALT and the AST of Rats with Fatty Liver, and with the model group contrast, difference has utmost point significant (P＜0.01), and it the results are shown in Table 2.
Table 2 respectively organize the Liver Function changing conditions (
N=10)
C) the L-Orn acetylsalicylic acid is on the impact of rat model hepatic tissue SOD, MDA content
With the blank group relatively, model group rat blood serum SOD is active significantly to reduce (P＜0.01), MDA content obviously raise (P＜0.01).Compare with model group, each administration group liver injury model rat blood serum SOD activity all has rising in various degree, with L-Orn acetylsalicylic acid high dose group significantly (P＜0.05), MDA content obviously reduces (P＜0.01), the result shows that the L-Orn acetylsalicylic acid has preferably lipoid peroxidization resistant to hyperlipemia rat.It the results are shown in Table 3.
Table 3 respectively organize activity of SOD in serum, MDA content relatively (
N=10)
During hyperlipidaemia, the Radical Metabolism balance in the body in the liver cell will be lacked of proper care, also can descend to the defence capability of free radical, too much free radical can with cytolemma in lipoids generation peroxidation, the destruction that causes cytolemma causes necrocytosis; The degradation production (MDA) of lipid peroxide also can be combined with materials such as protein and phosphatide simultaneously, is deposited on histocyte, and the damaging cells film causes that cell function is disorderly, causes at last cell can't keep eubolism and death.Above-mentioned test-results shows, SOD activity in the model group rat blood serum significantly is lower than normal group, MDA content is then apparently higher than normal group, rising and lipid peroxidation that blood fat is described are proportionate, after hyperlipidemia rats gavages the L-Orn acetylsalicylic acid, its TC, TG, LDL-C content obviously reduce, and HDL-C content raises; MDA content obviously reduces in the serum, and SOD is active obviously to raise; Serum alt and increasing of AST that high lipid food is caused have restraining effect.Illustrate that the L-Orn acetylsalicylic acid can regulate and improve the Radical Metabolism balance, promoted fatty acid metabolism, certain accent fat liver protection effect is arranged, and it transfers blood fat certain relation to be arranged with its interior antioxidation action, but its concrete blood fat mechanism of regulating remains further research.
In addition, L-Orn acetylsalicylic acid double salt water-soluble fine, the pH of its aqueous solution is neutral meta-acid, can be used for intramuscular injection and quiet notes, avoided oral administration to GI stimulation, can reduce to a certain extent hepatotoxic incidence, especially higher to liver function damage risk level hyperlipemic patients.
Claims (14)
1. L-Orn acetylsalicylic acid double salt, this double salt prepares by following method:
Method one: the aqueous solution of the free L-Orn of preparation, react to wherein adding acetylsalicylic acid again, obtain the solution of L-Orn aspirin salt, again its form with crystallization is separated out; Perhaps
Method two: the ethanolic soln of acetylsalicylic acid is mixed with the ethanolic soln of free L-Orn, obtain the precipitation of L-Orn aspirin salt, then resolution of precipitate is obtained the aqueous solution of L-Orn aspirin salt, carry out again recrystallization, and get final product.
2. L-Orn acetylsalicylic acid double salt according to claim 1 is characterized in that the mol ratio of L-Orn and acetylsalicylic acid is 1:1 in the described crystal.
3. L-Orn acetylsalicylic acid double salt according to claim 1 is characterized in that salicylic acid content is below 0.2wt% in the described double salt.
4. the preparation method of the described L-Orn acetylsalicylic acid of claim 1 double salt is characterized in that the method comprises the following steps:
Method one: the aqueous solution of the free L-Orn of preparation, to wherein adding acetylsalicylic acid, both are fully reacted again, obtain the solution of L-Orn aspirin salt, again its form with crystallization is separated out; Perhaps
Method two: the ethanolic soln of acetylsalicylic acid is mixed with the ethanolic soln of free L-Orn, obtain the precipitation of L-Orn aspirin salt, then resolution of precipitate is obtained the aqueous solution of L-Orn aspirin salt, carry out again recrystallization, and get final product.
5. preparation method according to claim 4 is characterized in that free L-Orn obtains by following method: extraction from fermented liquid, chemosynthesis, enzyme reaction or L-Orn salt obtained by desalination.
6. preparation method according to claim 4 is characterized in that the mol ratio of L-Orn and acetylsalicylic acid is 0.5 ~ 2:1 in the reactant, and temperature of reaction is 10 ℃-25 ℃.
7. preparation method according to claim 4 is characterized in that the feeding mode of acetylsalicylic acid in the method one is: the aqueous solution of the crystal of acetylsalicylic acid or powder or the free L-Orn of solution input.
8. preparation method according to claim 4, it is characterized in that, described crystallization method is: add the dissolved agent in the solution of L-Orn aspirin salt, perhaps reduce the temperature of solution, the perhaps solvent of evaporating solns, perhaps add crystal seed in the solution and make it crystallization, the perhaps combination of these methods.
9. preparation method according to claim 8 is characterized in that L-Orn acetylsalicylic acid salts solution is its aqueous solution in the described crystallization method, and its mass concentration is 30% ~ 60%.
10. preparation method according to claim 8 is characterised in that temperature is controlled in the crystallisation process-10 ℃ ~ 25 ℃, preferred 0 ~ 20 ℃.
11. preparation method according to claim 8 is characterized in that described dissolved agent is hydrophilic organic solvent, one or more in particular methanol, ethanol, propyl alcohol, Virahol, butanols, ethylene glycol, acetone, the acetonitrile; The add-on of dissolved agent is 1 ~ 8 times of L-Orn aspirin salt liquor capacity, preferred 2 ~ 5 times.
12. preparation method according to claim 8, the adding speed that it is characterized in that described dissolved agent is 0.1mL.min
-1~ 1.5mL.min
-1, preferred 0.2mL.min
-1~ 0.8mL.min
-1, 0.4mL.min more preferably
-1~ 0.6mL.min
-1
13. described preparation method according to claim 8 is characterized in that described crystal seed adding is period: when the volume of the hydrophilic organic solvent that stream adds is 0.1 ~ 2.5 times of L-Orn aspirin salt liquor capacity, when being preferably 0.5 ~ 1.5 times; The crystal seed add-on is: 0.1 ~ 5wt% of the amount of the L-Orn aspirin salt that contains in the relative response liquid is preferably 0.5 ~ 2.5wt%.
14. the application of L-Orn acetylsalicylic acid double salt claimed in claim 1 in preparation fat-reducing liver-protecting medicine.
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| CN104829476A (en) * | 2015-05-18 | 2015-08-12 | 万红贵 | Preparation method and application of L-ornithine succinate neutral salt |
| CN106309457A (en) * | 2016-11-03 | 2017-01-11 | 福州大学 | Application of ursolic acid-aspirin conjugate in preparing liver-protecting drug |
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Application publication date: 20130320 Assignee: Nanjing Siddartha medical science and Technology Co.,Ltd. Assignor: Nanjing Tech University Contract record no.: 2017320000159 Denomination of invention: L-ornithine-aspirin double salt and its preparation method and use Granted publication date: 20150204 License type: Exclusive License Record date: 20170711 |