CN101591271A - A kind of preparation method of crystal L-arginine alpha-ketoglutarate - Google Patents
A kind of preparation method of crystal L-arginine alpha-ketoglutarate Download PDFInfo
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- CN101591271A CN101591271A CNA2008100381173A CN200810038117A CN101591271A CN 101591271 A CN101591271 A CN 101591271A CN A2008100381173 A CNA2008100381173 A CN A2008100381173A CN 200810038117 A CN200810038117 A CN 200810038117A CN 101591271 A CN101591271 A CN 101591271A
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Abstract
The present invention relates to a kind of preparation method of crystal L-arginine alpha-ketoglutarate, this method comprises: the arginic aqueous solution of preparation L-, slowly α-Tong Wuersuan is added wherein, the mol ratio of L-arginine and α-Tong Wuersuan is 1: 1 or 2: 1; After dissolving fully, 50～80 ℃ of following concentrating under reduced pressure, the water yield of removing cumulative volume 20%～60% is cooled to 20～30 ℃; Slowly add organic hydrophilic solvent, the perhaps mixed solvent of polar hydrophilic solvent and non-polar solvent; Cooling, crystallization more after filtration, washing, vacuum-drying, obtain the crystal L-arginine alpha-ketoglutarate.Compared with prior art, technology of the present invention is reasonable, and step is simple, processing ease, the product crystal formation of gained is good, prevented from caking, be convenient to transportation and use, also have purity height (〉=98%), the yield height advantages such as (80～86%) of product simultaneously, be adapted to suitability for industrialized production.
Description
Technical field
The present invention relates to amino acid salts, relate in particular to a kind of preparation method of crystal L-arginine alpha-ketoglutarate.
Background technology
L-arginine alpha-ketoglutarate is a kind of amidates healthcare products that sales volume increases day by day on the present world market, is mainly used in raising human body protein and enhancing people's physique etc.Growing along with the international market demand amount becomes the emphasis that people pay close attention to the research of the crystallization method of L-arginic acid salt, particularly to the research of the salify crystalline method of L-arginine alpha-ketoglutarate.
At present, preparation method's complicated operation of L-arginine alpha-ketoglutarate, yield is low, is not suitable for suitability for industrialized production, can't satisfy growing demand, and product also exists shortcomings such as purity is low, crystal formation is not good simultaneously.
Summary of the invention
Purpose of the present invention is exactly the preparation method that the crystal L-arginine alpha-ketoglutarate that a kind of technology is reasonable, simple to operate, crystal formation is good is provided for the defective that overcomes above-mentioned prior art existence.
Purpose of the present invention can be achieved through the following technical solutions:
A kind of preparation method of crystal L-arginine alpha-ketoglutarate is characterized in that, this method may further comprise the steps:
(1) the arginic aqueous solution of preparation L-slowly adds α-Tong Wuersuan in the arginic aqueous solution of L-, and the mol ratio of L-arginine and α-Tong Wuersuan is 1: 1 or 2: 1;
(2) fully the dissolving after, 50～80 ℃ of following concentrating under reduced pressure, the water yield of removing cumulative volume 20%～60% is cooled to 20～30 ℃;
(3) slowly add organic hydrophilic solvent, the perhaps mixed solvent of polar hydrophilic solvent and non-polar solvent, the adding total amount is to remove 3～4 times of the volume that anhydrates in the step (2), the joining day is 0.5～2.5 hour;
(4), more after filtration, washing, vacuum-drying, obtain the crystal L-arginine alpha-ketoglutarate with system cooling, crystallization.
The concentration of the arginic aqueous solution of L-is 20%～30% (weight) in the described step (1).
In the described step (2), after dissolving fully, 55 ℃ of following concentrating under reduced pressure, the water yield of removing cumulative volume 30%～40% is cooled to 22～25 ℃.
Organic hydrophilic solvent is selected from a kind of in methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the isopropylcarbinol in the described step (3).
The volume ratio of mixed solvent Semi-polarity hydrophilic solvent and non-polar solvent is 1～5: 1 in the described step (3), described polar hydrophilic solvent is selected from a kind of in methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the isopropylcarbinol, and described non-polar solvent is selected from sherwood oil, the normal hexane a kind of.
The crystalline temperature is 5～10 ℃ in the described step (4).
Vacuum drying temperature is 50～70 ℃ in the described step (4).
The present invention adopts the α-Tong Wuersuan that adds equimolar amount or half molar weight in the L-arginine aqueous solution, at ambient temperature, the reaction salify, then under 50～80 ℃ temperature condition, concentrating under reduced pressure is removed the water that is equivalent to cumulative volume 20～60%, add hydrophilic organic solvent or mixed solvent again, obtain product 20～30 ℃ of crystallizations, reaction formula is as follows:
Wherein: n=1, m=0; Perhaps n=2, m=2.
Product of the present invention can mix with acceptable carrier on one or more protective foodss according to the production method of field of health care food routine, obtains containing the various formulations of L-arginine alpha-ketoglutarate to the human body significant quantity.The protective foods acceptable carrier is meant conventional protective foods carrier, and for example: thinner, vehicle etc. can also add other assistant agent and flavouring agent, sweeting agent etc. in addition; Its dosage form comprises various solid dosages and liquid dosage form.
Product L-arginine alpha-ketoglutarate of the present invention is by the crowd by oral administration to this nutritive food of needs.Be used for when oral, can be made into conventional solid preparation such as tablet, pulvis, granule, capsule etc., also can be made into liquid preparation such as water or oiliness suspension agent etc. or other liquid preparation such as syrup etc.; Preferred form is tablet, coated tablet, capsule etc.
Compared with prior art, preparation method's technology of crystal L-arginine alpha-ketoglutarate of the present invention is reasonable, step is simple, processing ease, the product crystal formation of gained is good, and prevented from caking is convenient to transportation and use, also have purity height (〉=98%), the yield height advantages such as (80～86%) of product simultaneously, be adapted to suitability for industrialized production.
Embodiment
The invention will be further described below in conjunction with specific embodiment.
Embodiment 1
A kind of preparation method of crystal L-arginine alpha-ketoglutarate: in the 500ml reaction flask, adding 70ml (69.6g) content is the L-arginine solution (being equivalent to the 0.1molL-arginine) of 25% (weight), stir, slowly add 14.6g (0.1mol) α-Tong Wuersuan, room temperature reaction 10mins, dissolving, concentrating under reduced pressure then fully, 55 ℃ of bath temperatures, the concentration of reaction solution cumulative volume is cooled to 23 ℃ to the 56ml, slowly drips 95% ethanol while stirring when having small amount of crystalline to separate out, stir 10mins, continue then to drip 95% ethanol, the ethanol total amount is 42ml, and the dropping time is 2hr, then the crystal solution temperature is reduced to 5～10 ℃, place 30mins, make crystal structure complete, filter, crystal 95% washing with alcohol, and, obtaining white plates crystal L-arginine alpha-ketoglutarate (1: 1) 26.0g 60 ℃ of vacuum-dryings, yield is 81.4%, purity is 99.8%, [α]
D+ 14.5 ° (c=4,6N HCl).
Embodiment 2
A kind of preparation method of crystal L-arginine alpha-ketoglutarate: in the 500ml reaction flask, adding 70ml (69.6g) content is the L-arginine solution (being equivalent to the 0.08molL-arginine) of 20% (weight), stir, slowly add 5.84g (0.04mol) α-Tong Wuersuan, room temperature reaction 10mins, dissolving fully, concentrating under reduced pressure then, 50 ℃ of bath temperatures, the concentration of reaction solution cumulative volume is to the 28ml, be cooled to 20 ℃, slowly drip anhydrous methanol while stirring when having small amount of crystalline to separate out, stir 10mins, continue to drip anhydrous methanol then, the methyl alcohol total amount is 168ml, and the dropping time is 2.5hr, then the crystal solution temperature is reduced to 5～10 ℃, place 30mins, make crystal structure complete, filter, crystal washs with anhydrous methanol, and 50 ℃ of vacuum-dryings, obtain white plates crystal L-arginine alpha-ketoglutarate (2: 1) 15.89g, yield is 80.4%, and purity is 99.5%.
Embodiment 3
A kind of preparation method of crystal L-arginine alpha-ketoglutarate: in the 500ml reaction flask, adding 70ml (69.6g) content is the L-arginine solution (being equivalent to the 0.12molL-arginine) of 30% (weight), stir, slowly add 17.52g (0.12mol) α-Tong Wuersuan, room temperature reaction 10mins, dissolving, concentrating under reduced pressure then fully, 80 ℃ of bath temperatures, the concentration of reaction solution cumulative volume is cooled to 22 ℃ to the 49ml, slowly drips isopropylcarbinol while stirring when having small amount of crystalline to separate out, stir 10mins, continue then to drip isopropylcarbinol, the isopropylcarbinol total amount is 63ml, and the dropping time is 2hr, then the crystal solution temperature is reduced to 5～10 ℃, place 30mins, make crystal structure complete, filter, crystal washs with isopropylcarbinol, and, obtaining white plates crystal L-arginine alpha-ketoglutarate (1: 1) 26.5g 70 ℃ of vacuum-dryings, yield is 82.8%, purity is 98.6%, [α]
D+ 16.0 ° (c=4,6N HCl).
Embodiment 4
A kind of preparation method of crystal L-arginine alpha-ketoglutarate: in the 500ml reaction flask, adding 70ml (69.6g) content is the L-arginine solution (being equivalent to the 0.1molL-arginine) of 25% (weight), stir, slowly add 14.6g (0.1mol) α-Tong Wuersuan, room temperature reaction 10mins, dissolving fully, concentrating under reduced pressure then, 55 ℃ of bath temperatures, the concentration of reaction solution cumulative volume is to the 42ml, be cooled to 25 ℃, slowly drip the mixed solvent propyl alcohol while stirring: normal hexane (1: 1), mixed solvent total amount are 112ml, and the dropping time is 0.5hr, then the crystal solution temperature is reduced to 5～10 ℃, place 30mins, make crystal structure complete, filter, crystal washs with above-mentioned mixed solvent, and, obtaining white plates crystal L-arginine alpha-ketoglutarate (1: 1) 27.5g 60 ℃ of vacuum-dryings, yield is 86.0%, purity is 98.0%, [α]
D+ 14.9 ° (c=4,6N HCl).
Embodiment 5
A kind of preparation method of crystal L-arginine alpha-ketoglutarate: in the 500ml reaction flask, adding 70ml (69.6g) content is the L-arginine solution (being equivalent to the 0.1molL-arginine) of 25% (weight), stir, slowly add 14.6g (0.1mol) α-Tong Wuersuan, room temperature reaction 10mins, dissolving fully, concentrating under reduced pressure then, 55 ℃ of bath temperatures, the concentration of reaction solution cumulative volume is to the 42ml, be cooled to 30 ℃, slowly drip mixed solvent methyl alcohol while stirring: sherwood oil (5: 1), mixed solvent total amount are 84ml, and the dropping time is 40min, then the crystal solution temperature is reduced to 5～10 ℃, place 30mins, make crystal structure complete, filter, crystal washs with above-mentioned mixed solvent, and, obtaining white plates crystal L-arginine alpha-ketoglutarate (1: 1) 27.5g 60 ℃ of vacuum-dryings, yield is 86.0%, purity is 99.2%, [α]
D+ 14.9 ° (c=4,6N HCl).
Claims (7)
1. the preparation method of a crystal L-arginine alpha-ketoglutarate is characterized in that, this method may further comprise the steps:
(1) the arginic aqueous solution of preparation L-slowly adds α-Tong Wuersuan in the arginic aqueous solution of L-, and the mol ratio of L-arginine and α-Tong Wuersuan is 1: 1 or 2: 1;
(2) fully the dissolving after, 50～80 ℃ of following concentrating under reduced pressure, the water yield of removing cumulative volume 20%～60% is cooled to 20～30 ℃;
(3) slowly add organic hydrophilic solvent, the perhaps mixed solvent of polar hydrophilic solvent and non-polar solvent, the adding total amount is to remove 3～4 times of the volume that anhydrates in the step (2), the joining day is 0.5～2.5 hour;
(4), more after filtration, washing, vacuum-drying, obtain the crystal L-arginine alpha-ketoglutarate with system cooling, crystallization.
2. the preparation method of a kind of crystal L-arginine alpha-ketoglutarate according to claim 1 is characterized in that, the concentration of the arginic aqueous solution of L-is 20%～30% (weight) in the described step (1).
3. the preparation method of a kind of crystal L-arginine alpha-ketoglutarate according to claim 1 is characterized in that, in the described step (2), fully after the dissolving, 55 ℃ of following concentrating under reduced pressure, the water yield of removing cumulative volume 30%～40% is cooled to 22～25 ℃.
4. the preparation method of a kind of crystal L-arginine alpha-ketoglutarate according to claim 1 is characterized in that, organic hydrophilic solvent is selected from a kind of in methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the isopropylcarbinol in the described step (3).
5. the preparation method of a kind of crystal L-arginine alpha-ketoglutarate according to claim 1, it is characterized in that, the volume ratio of mixed solvent Semi-polarity hydrophilic solvent and non-polar solvent is 1～5: 1 in the described step (3), described polar hydrophilic solvent is selected from a kind of in methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the isopropylcarbinol, and described non-polar solvent is selected from sherwood oil, the normal hexane a kind of.
6. the preparation method of a kind of crystal L-arginine alpha-ketoglutarate according to claim 1 is characterized in that, the crystalline temperature is 5～10 ℃ in the described step (4).
7. the preparation method of a kind of crystal L-arginine alpha-ketoglutarate according to claim 1 is characterized in that, vacuum drying temperature is 50～70 ℃ in the described step (4).
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102020593A (en) * | 2010-11-29 | 2011-04-20 | 广东环西生物科技股份有限公司 | Process for preparing L-arginine-alpha-ketoglutarate (AAKG) from fermentation liquor through direct crystallization |
| CN102028230A (en) * | 2010-12-08 | 2011-04-27 | 江南大学 | Health care product auxiliary material and application thereof |
| CN102058890A (en) * | 2010-12-08 | 2011-05-18 | 江南大学 | Sustained release medicinal auxiliary material for improving stability of basic remedy |
| GB2485862A (en) * | 2010-11-29 | 2012-05-30 | Guangdong Huanxi Biolog Technology Co Ltd | Preparation process of L-arginine-alpha-ketoglutarate by direct crystallisation from fermentation broth |
| CN102531968A (en) * | 2010-10-13 | 2012-07-04 | 张国基 | Process for preparation of l-arginine alpha-ketoglutarate 1:1 and 2:1 |
| CN105036330A (en) * | 2015-07-02 | 2015-11-11 | 山东阜丰发酵有限公司 | Preparation method of crystalline L-arginine alpha-ketoglutarate (AAKG) |
| CN106350547A (en) * | 2016-08-24 | 2017-01-25 | 天津科技大学 | Preparation method of L-arginine-alpha-ketoglutaric acid |
| CN111925305A (en) * | 2020-08-25 | 2020-11-13 | 精晶药业股份有限公司 | Method for preparing arginine ketoglutaric acid by spraying method |
| WO2023131142A1 (en) * | 2022-01-04 | 2023-07-13 | 成都夸常奥普医疗科技有限公司 | Stable solution, preparation method, use, pharmaceutical composition and kit |
Citations (1)
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| CN101011372A (en) * | 2007-02-02 | 2007-08-08 | 北京和为康医药科技有限公司 | Preparing method of alpha-ketoglutaric acid-arginine salt and its use for treating hepatic disease |
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2008
- 2008-05-27 CN CNA2008100381173A patent/CN101591271A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101011372A (en) * | 2007-02-02 | 2007-08-08 | 北京和为康医药科技有限公司 | Preparing method of alpha-ketoglutaric acid-arginine salt and its use for treating hepatic disease |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102531968A (en) * | 2010-10-13 | 2012-07-04 | 张国基 | Process for preparation of l-arginine alpha-ketoglutarate 1:1 and 2:1 |
| GB2485862B (en) * | 2010-11-29 | 2013-09-04 | Guangdong Huanxi Biolog Technology Co Ltd | Preparation process of L-arginine-alpha-ketoglutarate by direct crystallization from fermentation broth |
| CN102020593A (en) * | 2010-11-29 | 2011-04-20 | 广东环西生物科技股份有限公司 | Process for preparing L-arginine-alpha-ketoglutarate (AAKG) from fermentation liquor through direct crystallization |
| GB2485862A (en) * | 2010-11-29 | 2012-05-30 | Guangdong Huanxi Biolog Technology Co Ltd | Preparation process of L-arginine-alpha-ketoglutarate by direct crystallisation from fermentation broth |
| WO2012071766A1 (en) * | 2010-11-29 | 2012-06-07 | 广东环西生物科技股份有限公司 | Preparation method of l-arginine-α-ketoglutarate by direct crystallization from zymotic fluid |
| CN102028230B (en) * | 2010-12-08 | 2014-12-10 | 江南大学 | Health care product auxiliary material and application thereof |
| CN102028230A (en) * | 2010-12-08 | 2011-04-27 | 江南大学 | Health care product auxiliary material and application thereof |
| CN102058890B (en) * | 2010-12-08 | 2014-11-12 | 江南大学 | Sustained release medicinal auxiliary material for improving stability of basic remedy |
| CN102058890A (en) * | 2010-12-08 | 2011-05-18 | 江南大学 | Sustained release medicinal auxiliary material for improving stability of basic remedy |
| CN105036330A (en) * | 2015-07-02 | 2015-11-11 | 山东阜丰发酵有限公司 | Preparation method of crystalline L-arginine alpha-ketoglutarate (AAKG) |
| CN105036330B (en) * | 2015-07-02 | 2017-04-12 | 山东阜丰发酵有限公司 | Preparation method of crystalline L-arginine alpha-ketoglutarate (AAKG) |
| CN106350547A (en) * | 2016-08-24 | 2017-01-25 | 天津科技大学 | Preparation method of L-arginine-alpha-ketoglutaric acid |
| CN111925305A (en) * | 2020-08-25 | 2020-11-13 | 精晶药业股份有限公司 | Method for preparing arginine ketoglutaric acid by spraying method |
| WO2023131142A1 (en) * | 2022-01-04 | 2023-07-13 | 成都夸常奥普医疗科技有限公司 | Stable solution, preparation method, use, pharmaceutical composition and kit |
| WO2023130205A1 (en) * | 2022-01-04 | 2023-07-13 | 成都夸常奥普医疗科技有限公司 | Stabilizing solution, preparation method, application, pharmaceutical composition, and kit |
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