CN108840805A - Aspartic acid ornithine synthetic method - Google Patents
Aspartic acid ornithine synthetic method Download PDFInfo
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- CN108840805A CN108840805A CN201810880393.8A CN201810880393A CN108840805A CN 108840805 A CN108840805 A CN 108840805A CN 201810880393 A CN201810880393 A CN 201810880393A CN 108840805 A CN108840805 A CN 108840805A
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- ornithine
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- water
- methanol
- aspartic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
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- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of aspartic acid ornithine synthetic methods, include the following steps：The free elution of S1, ornithine, the preparation of S2, aspartic acid ornithine crude product, the purification of S3, aspartic acid ornithine；Present invention process compared with conventional aspartic acid ornithine synthetic method is simple, and safety and environmental protection, high income is at low cost, and product purity is high, is convenient for industrial production.
Description
Technical field
The invention belongs to equipment manufacturing fields, more specifically more particularly to a kind of aspartic acid ornithine synthetic method.
Background technique
Aspartic acid ornithine salt is German Maxwell（Merz）The a kind of of pharmaceutical development treats hepatic encephalopathy and other are chronic
The drug of hepatopathy is mainly used for acute and chronic hepatopathy, the blood as caused by various hepatitis, cirrhosis, fatty liver, posthepatitic syndrome
Ammonia increases and treatment hepatic encephalopathy, and such as adjoint liver secondary function of detoxification is damaged or hepatic encephalopathy stage of attack, especially uses
In the confusional state for the treatment of hepatic coma early stage or hepatic coma phase.Aspartic acid ornithine be decomposed into vivo L-aminobutanedioic acid and
Ornithine is respectively acting on urea synthesizing and glutamine synthesis --- two main ammonia detoxification pathways.The existing import product in the country
Kind, specification 10mL：The injection of 5g.Synthetic method reported in the literature is all to pass through chemistry using L-arginine as starting material
Method or bioanalysis（Fermentation or enzymatic hydrolysis）It is converted into L-Orn, or with L-Orn salt（Hydrochloride, sulfate, acetic acid
Salt etc.）Or be starting material, L-Orn is obtained by the means such as ion-exchange or acid binding agent neutralization, electroosmose process.Then
At salt by L-Orn and L-ASPARTIC ACID reaction to obtain the final product.The method production cycle for doing starting material with arginine is longer, waste water
It is more；There is also yield, quality to be difficult to control for ion-exchange, the problem more than waste water, for the ease of production, also from environmental angle
Consider, obtaining L-Orn using acid binding agent neutralisation is most convenient effective method, and aspartic acid ornithine is soluble easily in water, and
The salt formed after general neutralization is also mostly soluble easily in water, is not readily separated.In view of aspartic acid ornithine does not dissolve in organic solvent,
And ammonium acetate can be dissolved in methanol, ethyl alcohol.It is starting material that we, which select L-Orn acetate,.
There is following several method by the document report of starting material of L-Orn acetate at present：
The patent CN101798275A of Chongqing gift nation, the patent CN102942498A of general health medicine company, the patent in Datong District Changxing
CN103936611A etc., all without exception use concentrated ammonia liquor or 18% ammonium hydroxide as acid binding agent adjust pH, neutralize L-Orn
The acetate of acetate, subsequent technique is essentially identical, and buying, transport and the use of ammonium hydroxide are all inconvenient, to production environment and work
The health of people is also unfavorable.
Summary of the invention
The purpose of the present invention is to provide a kind of aspartic acid ornithine synthetic methods, to solve to mention in above-mentioned background technique
Out the problem of.
To achieve the above object, the present invention provides the following technical solutions：
A kind of aspartic acid ornithine synthetic method, includes the following steps：
The free elution of S1, ornithine：The free of ornithine is divided into two resin columns while carrying out, and is added to 500L reaction kettle
140kg purified water, 14kg ornithine hydrochloride, are stirred at room temperature 30 min, make to be completely dissolved, by ornithine hydrochloride aqueous solution
It is gradually pumped into, flows through the good resin column equipped with 140L of regeneration treatment, adjustment drain age velocity is 20kg/h, complete to solution pump
Afterwards, with purifying water washing resin column, stopped when no white precipitate after washing to neutrality with 5% silver nitrate detection chloride ion
It only elutes, is then eluted with 5% ammonium hydroxide with 20kg/h speed, when eluent pH > 7,5% ammonium hydroxide 90-110L starts to receive
Collect eluent, collect 140L, and 10ml is taken to be diluted to 100ml, as the concentrations control product of TLC, rear every 15minTLC detection is washed
Ornithine concentration is primary in de- liquid, when observing that collecting sample concentration is less than comparison liquid concentration, stops collecting, merges two resins
The eluent that column elutes, weighing, is transferred in reaction kettle, and control solution temperature is concentrated under reduced pressure at 50 DEG C ± 5 DEG C, to
70% ± 5% water is boiled off, distillation is stopped, weighing steams water, calculates remaining concentrate weight；
The preparation of S2, aspartic acid ornithine crude product：L-aminobutanedioic acid is added into above-mentioned concentrate, adjusts pH to 6.5 ± 0.2, stirs
About 30min is mixed, 0.44kg active carbon, stirring decoloration 30min is added, filtering calculates L-aminobutanedioic acid according to the meter of L-aminobutanedioic acid
The amount and water weight of ornithine；Filtrate is transferred in reaction kettle, lower heating is stirred, maintaining reaction temperature starts to drip at 65 ± 5 DEG C
Add methanol, when solution has muddiness to occur, stops being added dropwise, crystal seed is added, after continuing insulated and stirred 0.5h~1h, secondary dropwise addition first
Alcohol when occurring obvious milky turbidity again, stops being added dropwise after solution clarification, and dripping quantity is 0.5~0.6 times of water weight, control
It is dripped in 1.5h ± 0.5h processed, continues at 65 DEG C of ± 5 DEG C of heat preservation 30min, be cooled to 40 ± 5 DEG C, filtered, each filter cake first
After alcohol/aqueous solution washing, again with methanol 10kg washing, filtering obtain filter cake, are dried under reduced pressure 6~8h at 65 ± 5 DEG C, obtain thick
Product, calculated yield, yield spectra are 87 ± 5%；
The purification of S3, aspartic acid ornithine：The purified water of 80kg is added to reaction kettle, 40kg L-aminobutanedioic acid bird ammonia is then added
Filtrate is transferred in reaction kettle by acid crude, stirring and dissolving, addition 0.4kg active carbon room temperature decoloration 30min, filtering, and stirring is lower to be added
Heat, maintaining reaction temperature at 65 ± 5 DEG C starts that methanol is added dropwise, and when solution has muddiness to occur, stops being added dropwise, dripping quantity 1.0
~1.2 times of water weight, control are dripped in 0.5h~1.0h, and crystal seed is added.After continuing insulated and stirred 0.5h~1h, secondary dropwise addition
Methanol when occurring obvious milky turbidity again, stops being added dropwise after solution clarification, and dripping quantity is 0.5~0.6 times of water weight,
It is dripped in control 1.5h ± 0.5h, continues at 65 DEG C of ± 5 DEG C of heat preservation 30min, be cooled to 40 ± 5 DEG C, filtered, filter cake first
After alcohol/aqueous solution washing, again with methanol 10kg washing, filtering obtain filter cake, are dried under reduced pressure 6~8h in 65 ± 5 DEG C, obtain finished product,
Calculated yield, yield spectra are 87 ± 5%.
Compared with prior art, the beneficial effects of the invention are as follows：The present invention and conventional aspartic acid ornithine synthetic method
Simple compared to process, safety and environmental protection, high income is at low cost, and product purity is high, is convenient for industrial production.
Detailed description of the invention
Fig. 1 is synthesis process flow diagram of the invention；
Fig. 2 is chemical reaction route map of the invention.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, below in conjunction with specific embodiment, to this
Invention is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, not
For limiting the present invention.
A kind of aspartic acid ornithine synthetic method, includes the following steps：
1 title of starting material：L-aminobutanedioic acid
Molecular formula：C4H7NO4
Molecular weight：133.10
No. CAS：1783-96-6
Structural formula：
2 title of starting material：Ornithine hydrochloride
Molecular formula： C5H12N2O2 . HCl
Molecular weight：168.62
No. CAS：3184-13-2
Structural formula：
The free elution of S1, ornithine：
| Material name | Standard number | Material rank | Inventory | Ingredient proportion（In terms of ornithine hydrochloride） |
| Ornithine hydrochloride | SOP-QC-022024-01 | Technical grade | 28kg | 1 |
| Purified water | SOP-QC-140001-02 | —— | 280kg | 10 |
| Ammonium hydroxide（25%-28%） | SOP-QC-040005-02 | Technical grade | 120kg | 4.29 |
| H-type strong-acid ion exchange resin | SOP-QC-040054-01 | Technical grade | 240kg | 8.57 |
By taking the ornithine hydrochloride 28kg that feeds intake as an example：
The free of ornithine is divided into two resin columns while carrying out, and 140kg purified water, 14kg bird ammonia is added to 500L reaction kettle
30 min are stirred at room temperature in acid hydrochloride, make to be completely dissolved, and ornithine hydrochloride aqueous solution is gradually pumped into, is flowed through at regeneration
The resin column equipped with 140L managed, adjustment drain age velocity be 20kg/h, after solution pump is complete, with purifying water washing resin column,
After washing to neutrality with 5% silver nitrate detect chloride ion, when no white precipitate, that is, stop elution, then with 5% ammonium hydroxide with
20kg/h speed is eluted, and when eluent pH > 7,5% ammonium hydroxide 90-110L starts to collect eluent, collects 140L, and take
10ml is diluted to 100ml, and as the concentrations control product of TLC, ornithine concentration is primary in rear every 15minTLC detection eluent, sees
When observing collection sample concentration less than comparison liquid concentration, stops collecting, merge the eluent that two resin columns elute, claim
Weight, is transferred in reaction kettle, and control solution temperature is concentrated under reduced pressure at 50 DEG C ± 5 DEG C, wait boil off 70% ± 5% water, stops steaming
It evaporates, weighing steams water, calculates remaining concentrate weight；
The preparation of S2, aspartic acid ornithine crude product：
| Material name | Standard number | Material rank | Inventory | Ingredient proportion（In terms of ornithine hydrochloride） |
| Ornithine hydrochloride | SOP-QC-022024-01 | Technical grade | 28kg | 1 |
| L-aminobutanedioic acid | SOP-QC-022023-01 | Pharmaceutical grade | 19.88kg~22kg | 0.71~0.79 |
| Active carbon | SOP-QC-040065-02 | Pharmaceutical grade | 0.44kg | 0.0157 |
| Methanol | SOP-QC-040028-02 | Technical grade | 140kg~182kg | 5~6.5 |
| Crystal seed | —— | Self-control | 0.044kg | 0.00157 |
By taking the ornithine hydrochloride 28kg that feeds intake as an example：
L-aminobutanedioic acid is added into above-mentioned concentrate, adjusts pH to 6.5 ± 0.2, stir about 30min, 0.44kg active carbon is added, stirs
Decoloration 30min is mixed, filtering calculates the amount and water weight of aspartic acid ornithine according to the meter of L-aminobutanedioic acid；Filtrate is transferred to
In reaction kettle, lower heating is stirred, maintaining reaction temperature starts dropwise addition methanol and stop when solution has muddiness to occur at 65 ± 5 DEG C
Only it is added dropwise（The amount that methanol is added dropwise at this time is the weight of 1.0~1.2 times of water, and control is dripped in 0.5h~1.0h）, crystal seed is added,
After continuing insulated and stirred 0.5h~1h, secondary dropwise addition methanol when occurring obvious milky turbidity again, stops after solution clarification
It is only added dropwise, dripping quantity is 0.5~0.6 times of water weight, controls and drips in 1.5h ± 0.5h, continues at 65 DEG C of ± 5 DEG C of heat preservations
30min is cooled to 40 ± 5 DEG C, filters, each filter cake methanol/water solution（Methanol：Water=7kg：4.4kg）After washing, then use
Methanol 10kg washing, filtering, obtain filter cake, are dried under reduced pressure 6~8h at 65 ± 5 DEG C, obtain crude product, calculated yield, yield spectra
It is 87 ± 5%；
The purification of S3, aspartic acid ornithine：
| Material name | Standard number | Material rank | Inventory | Ingredient proportion |
| Aspartic acid ornithine crude product | SOP-QC-022024-01 | Self-control | 40kg | 1 |
| Purified water | SOP-QC-140001-02 | —— | 80kg | 2 |
| Active carbon | SOP-QC-040065-02 | Pharmaceutical grade | 0.4kg | 0.01 |
| Crystal seed | —— | Self-control | 0.04kg | 0.001 |
| Methanol | SOP-QC-040028-02 | Technical grade | 140kg~160kg | 3.5~4 |
By taking the aspartic acid ornithine crude product 40kg that feeds intake as an example：
The purified water of 80kg is added to reaction kettle, 40kg aspartic acid ornithine crude product is then added, stirring and dissolving is added
Filtrate is transferred in reaction kettle by 0.4kg active carbon room temperature decoloration 30min, filtering, stirs lower heating, maintaining reaction temperature is 65
± 5 DEG C, start that methanol is added dropwise, when solution has muddiness to occur, stop being added dropwise, dripping quantity is 1.0~1.2 times of water weight, control
It is dripped in 0.5h~1.0h, crystal seed is added.After continuing insulated and stirred 0.5h~1h, secondary dropwise addition methanol, after solution clarification,
When occurring obvious milky turbidity again, stop being added dropwise, dripping quantity is 0.5~0.6 times of water weight, drop in control 1.5h ± 0.5h
It adds, continues at 65 DEG C of ± 5 DEG C of heat preservation 30min, be cooled to 40 ± 5 DEG C, filter, filter cake methanol/water solution（Methanol/water=
7kg/4.4kg）After washing, again with methanol 10kg washing, filtering obtain filter cake, are dried under reduced pressure 6~8h in 65 ± 5 DEG C, obtain finished product,
Calculated yield, yield spectra are 87 ± 5%.
The present invention and routine
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto, and it is any
Those familiar with the art in the technical scope disclosed by the present invention, according to the technique and scheme of the present invention and its invents
Design is subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (2)
1. a kind of aspartic acid ornithine synthetic method, which is characterized in that include the following steps：
The free elution of S1, ornithine：The free of ornithine is divided into two resin columns while carrying out, and is added to 500L reaction kettle
140kg purified water, 14kg ornithine hydrochloride, are stirred at room temperature 30 min, make to be completely dissolved, by ornithine hydrochloride aqueous solution
It is gradually pumped into, flows through the good resin column equipped with 140L of regeneration treatment, adjustment drain age velocity is 20kg/h, complete to solution pump
Afterwards, with purifying water washing resin column, stopped when no white precipitate after washing to neutrality with 5% silver nitrate detection chloride ion
It only elutes, is then eluted with 5% ammonium hydroxide with 20kg/h speed, when eluent pH > 7,5% ammonium hydroxide 90-110L starts to receive
Collect eluent, collect 140L, and 10ml is taken to be diluted to 100ml, as the concentrations control product of TLC, rear every 15minTLC detection is washed
Ornithine concentration is primary in de- liquid, when observing that collecting sample concentration is less than comparison liquid concentration, stops collecting, merges two resins
The eluent that column elutes, weighing, is transferred in reaction kettle, and control solution temperature is concentrated under reduced pressure at 50 DEG C ± 5 DEG C, to
70% ± 5% water is boiled off, distillation is stopped, weighing steams water, calculates remaining concentrate weight；
The preparation of S2, aspartic acid ornithine crude product：L-aminobutanedioic acid is added into above-mentioned concentrate, adjusts pH to 6.5 ± 0.2, stirs
About 30min is mixed, 0.44kg active carbon, stirring decoloration 30min is added, filtering calculates L-aminobutanedioic acid according to the meter of L-aminobutanedioic acid
The amount and water weight of ornithine；Filtrate is transferred in reaction kettle, lower heating is stirred, maintaining reaction temperature starts to drip at 65 ± 5 DEG C
Add methanol, when solution has muddiness to occur, stops being added dropwise, crystal seed is added, after continuing insulated and stirred 0.5h~1h, secondary dropwise addition first
Alcohol when occurring obvious milky turbidity again, stops being added dropwise after solution clarification, and dripping quantity is 0.5~0.6 times of water weight, control
It is dripped in 1.5h ± 0.5h processed, continues at 65 DEG C of ± 5 DEG C of heat preservation 30min, be cooled to 40 ± 5 DEG C, filtered, each filter cake first
After alcohol/aqueous solution washing, again with methanol 10kg washing, filtering obtain filter cake, are dried under reduced pressure 6~8h at 65 ± 5 DEG C, obtain thick
Product, calculated yield, yield spectra are 87 ± 5%；
The purification of S3, aspartic acid ornithine：The purified water of 80kg is added to reaction kettle, 40kg L-aminobutanedioic acid bird ammonia is then added
Filtrate is transferred in reaction kettle by acid crude, stirring and dissolving, addition 0.4kg active carbon room temperature decoloration 30min, filtering, and stirring is lower to be added
Heat, maintaining reaction temperature at 65 ± 5 DEG C starts that methanol is added dropwise, and when solution has muddiness to occur, stops being added dropwise, dripping quantity 1.0
~1.2 times of water weight, control are dripped in 0.5h~1.0h, and crystal seed is added.
2. after continuing insulated and stirred 0.5h~1h, there is obvious milky turbidity after solution clarification again in secondary dropwise addition methanol
When, stop being added dropwise, dripping quantity is 0.5~0.6 times of water weight, controls and drips in 1.5h ± 0.5h, continues at 65 DEG C of ± 5 DEG C of guarantors
Warm 30min is cooled to 40 ± 5 DEG C, and filtering, after filter cake is washed with methanol/water solution, again with methanol 10kg washing, filtering must be filtered
Cake is dried under reduced pressure 6~8h in 65 ± 5 DEG C, obtains finished product, calculated yield, and yield spectra is 87 ± 5%.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114349652A (en) * | 2021-12-10 | 2022-04-15 | 汕头市佳禾生物科技有限公司 | Preparation method of L-lysine aspartate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864634A (en) * | 2014-03-27 | 2014-06-18 | 常州兰陵制药有限公司 | Method for preparing ornithine aspartate |
| CN107522629A (en) * | 2017-10-12 | 2017-12-29 | 福建金山生物制药股份有限公司 | A kind of preparation method of aspartic acid ornithine |
-
2018
- 2018-08-03 CN CN201810880393.8A patent/CN108840805A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864634A (en) * | 2014-03-27 | 2014-06-18 | 常州兰陵制药有限公司 | Method for preparing ornithine aspartate |
| CN107522629A (en) * | 2017-10-12 | 2017-12-29 | 福建金山生物制药股份有限公司 | A kind of preparation method of aspartic acid ornithine |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114349652A (en) * | 2021-12-10 | 2022-04-15 | 汕头市佳禾生物科技有限公司 | Preparation method of L-lysine aspartate |
| CN114349652B (en) * | 2021-12-10 | 2024-03-29 | 汕头市佳禾生物科技有限公司 | Preparation method of L-lysine aspartate |
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