CN101463075A - Preparation of N(2)-L-alanyl-L-glutamine - Google Patents
Preparation of N(2)-L-alanyl-L-glutamine Download PDFInfo
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- CN101463075A CN101463075A CNA2007101511080A CN200710151108A CN101463075A CN 101463075 A CN101463075 A CN 101463075A CN A2007101511080 A CNA2007101511080 A CN A2007101511080A CN 200710151108 A CN200710151108 A CN 200710151108A CN 101463075 A CN101463075 A CN 101463075A
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Abstract
The invention discloses a method for preparing N(2)-L-alanyl-L-glutamine, belonging to a method for preparing dipeptide containing four amino acids at most. The method comprises the following steps: (1) inorganic base is added into the solution of toluene and water which contains L-glutamine; then the mixture of D-alpha-chloropropionyl chloride and toluene is added and the pH value of reaction solution is controlled between 9.5 and 10.5 by the inorganic base; the reaction temperature is maintained between 0-5 DEG C; the reaction solution is quiescent so that a toluene layer is separated; sodium chloride is added into the remaining solution at room temperature and N(2)-D-alpha-chloropropionyl-L-glutamine is obtained after filtration and drying; ammonia is added into the N (2)-D-alpha-chloropropionyl-L-glutamine, and concentrated solution after concentration under reduced pressure is transferred to a crystallizer; methanol is added and a crude product is obtained after filtration and drying; a refined product of the N (2)-L-alanyl-L-glutamine is obtained by refining.
Description
Technical field
The present invention relates to the preparation method of a kind of preparation method who contains maximum 4 amino acid whose dipeptides, particularly N (2)-L-alanyl-L-glutamine.
Background technology
Amidoamino acid is the exceedingly useful amino acid of a class.For example glutamine just has many important physical functions: can promote gastrointestinal mucosa hyperplasia, keep the integrity of enteron aisle; The phagolysis of scavenger cell, lymphocytic increment and the proteinic synthetic all necessary competent glutamine that relies on.Can synthesize the glutamine that satisfies self needs generally speaking in the human body.But be subjected at health under the stress situations such as big wound, severe infections, body is in the superelevation metabolism state, body glutamine storehouse is seriously consumed, other histoorgans such as small intestine, lymphocyte etc. all increase the picked-up to glutamine in the blood simultaneously, make in the blood plasma and the interior glutamine concentration decline of cell.Explanation increases greatly in the requirement of trauma stress state lower body to glutamine, the synthesis capability that has surpassed body, simultaneously, wound often causes the inhibition of body's immunity, glutamine is the important energy source material of immunocytes such as scavenger cell, lymphocyte, these cells are with the very high-speed glutamine that utilizes, under hypermetabolism condition like this, gastrointestinal function is suppressed, may cause that intestinal mucosal injury, permeability increase, cause bacterium, toxin displacement, further increase the weight of the situation of body hypermetabolism.And the glutamine metabolic important matrix that is intestinal cells, competent glutamine is one of small intestine essential condition of keeping eubolism, 26S Proteasome Structure and Function.Therefore be subjected under the stress situations such as big wound, severe infections at health, the external glutamine that replenishes in large quantities is very necessary.
But glutamine solubleness is low and unstable, can produce deleterious Pyrrolidonecarboxylic acid and ammonia after the heating, has therefore limited the intestines of glutamine and has used outward.And L-alanyl-L-glutamine solubleness height (solubleness under the normal temperature in water is up to 68 grams per liters) not only, be 200 times of free glutamine under the similarity condition, and stable in properties, heat sterilization under different pH value conditions (120 ℃, 0.5 hour) can not produce deleterious Pyrrolidonecarboxylic acid and ammonia yet.The most important thing is that the L-alanyl-L-glutamine can fast and effeciently be decomposed into L-Ala and glutamine by body, satisfy the body needs, and without any side effects.After the L-alanyl-L-glutamine enters body, be decomposed into the amino acid of its composition by pepx: L-Ala and glutamine, L-alanyl-L-glutamine through trace (the 1%-2% weight ratio of intake) is arranged is discharged from urine, has avoided the damage that may cause because of the accumulation of L-alanyl-L-glutamine.Thereby the application of L-alanyl-L-glutamine in parenteral nutrition come into one's own just day by day, and widespread use clinically.
The preparation method of L-alanyl-L-glutamine mainly contains three kinds at present,
1. in the presence of dicyclohexylcarbodiimide, generate active ester with Bian oxygen carbonyl L-Ala, be condensed into dipeptides with glutamine then, make through catalytic hydrogenation deprotection base again.Dicyclohexylcarbodiimide impurity is difficult to remove in this method, and product is difficult to purify.
2. utilize the reaction of phosgene and alanyl to generate and mix acid anhydride, react in water with glutamine then.Last acidifying is sloughed protection and can be obtained the L-alanyl-L-glutamine.This kind method is simple, but phosgene is hypertoxic gas, and is very harmful to human body.
3. utilize amino acid and three basic phosphorus reactions of the protection of N end to form active ester, the mineral acid acidifying is used in active ester of gained and glutamine reaction then, sloughs N end protecting group and promptly gets the L-alanyl-L-glutamine.The amino acid price of the raw material N end protection that this method is used is higher, causes whole technology cost higher.
Chinese patent 200510102315. discloses a kind of preparation method of L-alanyl-L-glutamine.This method is included in condensing agent and exists down, in inert solvent D-2-halopropanoic acid and glutamine is carried out condensation reaction, acidifying, obtains D-2-halo propionyl glutamine; The D-2-halo propionyl glutamine that obtains is carried out ammonolysis reaction with ammoniacal liquor get the L-alanyl-L-glutamine.
Chinese patent 200510054083.3 discloses N (2)-L-alanyl-L-glutamine dipeptides synthetic method: the amino acid of N segment protect and triphenylphosphinc oxide, triphosgene are reacted in organic solvent, form active ester.Active ester and glutamine react in inorganic base aqueous solution.Be acidified to pH≤3.0 with mineral acid, slough N segment protect group then and obtain N (2)-L-alanyl-L-glutamine dipeptides.
Summary of the invention
The present invention is in order to overcome the deficiency that exists in the prior art, and provides a kind of technology simple, the preparation method of the N that cost is low (2)-L-alanyl-L-glutamine,
In order to reach above purpose, the present invention takes following scheme:
The preparation method of a kind of N (2)-L-alanyl-L-glutamine, its preparation method is as follows
(1). mineral alkali is added drop-wise in the solution of the toluene that contains L-glutaminate and water, the final pH value reaches 8-11; Drip D-α-chlorpromazine chloride, toluene mixing solutions, control reacting solution pH value at 9.5-10.5 with mineral alkali; Temperature of reaction remains on 0 ℃-5 ℃; Dropwising the back keeps temperature to continue to stir 1 hour, stop then stirring and cooling, the static toluene layer of telling, under the room temperature sodium-chlor is added in the rest solution, dripping hydrochloric acid continues stirring and was cooled to 0 ℃ of-10 ℃ of discharging, filtration, dry N (the 2)-D-α-chlorine propionyl-L-glutaminate that gets in 10 minutes to pH value of solution=1;
(2). N (2)-D-α-chlorine propionyl-L-glutaminate is dropped into the aminating reaction jar, add ammoniacal liquor, pressure reaches 0.3Mpa gradually, after 8 hours, when tensimeter shows pressure recovery just often, then reacts and finishes; Temperature is reduced to room temperature, through concentrating under reduced pressure concentrated solution is moved to crystallizer, drips methyl alcohol, after dropwising, continues to stir 1 hour, is cooled to 10 ℃, places filtration, the dry crude product that gets 2 hours.
(3). with crude product input dissolving bleacher, add purified water, stirring and dissolving under the room temperature, add gac, continue to stir 30 minutes, filter, filtrate suction crystallizer, 30 ℃ add ethanol, stir, and place 2 hours, continue to drip ethanol in 30 ℃, dropwised in about 1 hour, and continued to stir 2 hours, filtration, dry finished product N (the 2)-L-alanyl-L-glutamine that gets.
Mineral alkali is sodium hydroxide or potassium hydroxide solution in the described step (1).
The volume ratio of toluene and water is 1: 1 in the described step (1); The weight ratio of chlorpromazine chloride and toluene is 1: 1.07.
The concentration of ammoniacal liquor is 30% in the described step (2).
Technology of the present invention is simple, thus since lower without N segment protect cost, compare with phosgenation, and toxicity of the present invention is less, helps people's healthy and environment protection, is more suitable for large-scale industrial production.
Embodiment
Below by specific embodiment the present invention is further described.
Embodiment
One. preparation N (2)-D-α-chlorine propionyl-L-glutaminate
Pour in the reaction flask behind the toluene with the water of 31ml and 31ml and mix, open and stir, add the 10g L-glutaminate, be cooled to 5 ℃.Slowly the sodium hydroxide of Dropwise 5 N makes the pH value of solution reach 10, and L-glutaminate all dissolves.Meanwhile in 2 hours, drip the dry toluene that 10.6ml contains 8.5g D-α-chlorpromazine chloride, with 5N sodium hydroxide in above-mentioned solution, regulate pH value with sodium hydroxide, maintenance pH value of solution value is 10, the sodium hydroxide that adds for twice is 29.5ml altogether, and temperature remains on 5 ℃; After dropwising, continue to stir 1 hour under the condition that the maintenance temperature is 5 ℃.Stop then stirring, cool off; Static layering is told toluene layer, under the room temperature 12.6g sodium-chlor is joined in the mixing solutions that does not have toluene, open stirring and make it dissolving, dripping hydrochloric acid regulator solution pH value to 2.5, and stir half an hour, dripping hydrochloric acid makes pH value of solution value to 1.0 again, continues stirring reaction 10 minutes; Stop to stir, be cooled to temperature to 5 ℃, places discharging in 1 hour, through overanxious, dry must N (2)-D-α-chlorine propionyl-L-glutaminate.
Two. preparation N (2)-L-alanyl-L-glutamine
10g N (2)-D-α-chlorine propionyl-L-glutaminate is inserted the ammoniacal liquor that the aminating reaction bottle adds 100g30%, heat to 65 ℃ of stirring reactions, along with carrying out corresponsively, pressure progressively reaches 0.3MPa, and after 8 hours, reaction finishes, pressure recovery is normal, and temperature is reduced to room temperature, the reactant concentrating under reduced pressure; In concentrated solution, drip 71.5ml methyl alcohol under the room temperature, dropwise, continue to stir 1 hour, cool, placed 2 hours, filtration, dry N (the 2)-L-alanyl-L-glutamine crude product that gets to 10 ℃; 10gN (2)-L-alanyl-L-glutamine crude product is dissolved in the 17.5ml pure water, adds the 0.2g gac, stirred 30 minutes under the room temperature.Consider the deactivation charcoal,, stir and placed 2 hours in 30 ℃ of dropping 95% ethanol, 30 ℃ of maintenance temperature, continuation drips 95% ethanol, dropwises in 1 hour, and continuation was stirred 2 hours, and twice dropping ethanol is total to 61ml.Filtration, dry N (the 2)-L-alanyl-L-glutamine highly finished product that get.
Claims (4)
1. the preparation method of a N (2)-L-alanyl-L-glutamine is characterized in that the step of its preparation method is:
(1). mineral alkali is added drop-wise in the solution of the toluene that contains L-glutaminate and water, makes the pH value of solution value reach 8-11; Drip D-α-chlorpromazine chloride, toluene mixing solutions, control reacting solution pH value at 9.5-10.5 with mineral alkali; Temperature of reaction remains on 0 ℃-5 ℃; Dropwising the back keeps this temperature to continue to stir 1 hour, stop then stirring, cool off, leave standstill and tell toluene layer, open and stir, under the room temperature sodium-chlor is added in the rest solution, dripping hydrochloric acid to pH value of solution value is 1, continue stirring reaction 10 minutes, and stopped to stir, be cooled to 0 ℃ of-10 ℃ of discharging, filtration, dry N (the 2)-D-α-chlorine propionyl-L-glutaminate that gets;
(2). N (2)-D-α-chlorine propionyl-L-glutaminate is dropped into the aminating reaction jar, add ammoniacal liquor, pressure reaches 0.3Mpa gradually, after 8 hours, when tensimeter shows pressure recovery just often, then reacts and finishes; Temperature is reduced to room temperature, through concentrating under reduced pressure concentrated solution is moved to crystallizer, drips methyl alcohol, after dropwising, continues to stir 1 hour, is cooled to 10 ℃, places filtration, the dry crude product that gets 2 hours;
(3). with crude product input dissolving bleacher, add purified water, stirring and dissolving under the room temperature, add gac, continue to stir 30 minutes, filter, filtrate suction crystallizer, 30 ℃ add ethanol, stir, and place 2 hours, continue to drip ethanol in 30 ℃, dropwised in about 1 hour, and continued to stir 2 hours, filtration, dry finished product N (the 2)-L-alanyl-L-glutamine that gets.
2. the preparation method of N according to claim 1 (2)-L-alanyl-L-glutamine is characterized in that L-glutaminate is 1 in the volume ratio that contains toluene solution in the step (1): 6-12; The volume ratio of toluene and water is 1: 1-1.5; The weight ratio of chlorpromazine chloride and toluene is 1: 1-2.
3. the preparation method of N according to claim 1 (2)-L-alanyl-L-glutamine is characterized in that mineral alkali is sodium hydroxide or the potassium hydroxide solution of 5N in the step (1).
4. the preparation method of N according to claim 1 (2)-L-alanyl-L-glutamine is characterized in that the concentration of ammoniacal liquor in the step (2) is 30%.
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| CNA2007101511080A CN101463075A (en) | 2007-12-19 | 2007-12-19 | Preparation of N(2)-L-alanyl-L-glutamine |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102093250A (en) * | 2010-12-02 | 2011-06-15 | 海南本创医药科技有限公司 | Glutamine dipeptide compound and novel method thereof |
| CN102491918A (en) * | 2011-11-28 | 2012-06-13 | 海南灵康制药有限公司 | Alanyl glutamine compound and preparation method thereof |
| CN103012550A (en) * | 2011-09-26 | 2013-04-03 | 重庆莱美药业股份有限公司 | Preparation method of N (2)-L-alanyl-L-glutamine |
| CN103012191A (en) * | 2011-09-26 | 2013-04-03 | 重庆莱美药业股份有限公司 | Method for preparing D-2-substituted propionyl-L-glutamine |
| CN103360462A (en) * | 2013-07-09 | 2013-10-23 | 山东齐都药业有限公司 | Refining method of alanyl-glutamine crude drug |
| CN103588860A (en) * | 2013-11-14 | 2014-02-19 | 天津大学 | Preparation method of N-(2)-L-alanyl-L-glutamine sphaerocrystal |
| CN103626838A (en) * | 2013-11-26 | 2014-03-12 | 精晶药业股份有限公司 | Removal method of endotoxin in N-(2)-L-alanyl-L-glutamine active pharmaceutical ingredient |
| CN103623777A (en) * | 2013-11-26 | 2014-03-12 | 精晶药业股份有限公司 | Active adsorbent and application thereof in N(2)-L-alanyl-L-glutamine production process |
| CN103910780A (en) * | 2014-04-09 | 2014-07-09 | 上海皓骏医药科技有限公司 | Preparation method of L-alanine-L-glutamine compound |
| CN104561202A (en) * | 2015-02-06 | 2015-04-29 | 江苏诚信药业有限公司 | Preparation method and technological system for enzymatically synthesizing N(2)-L-alanyl-L-glutamine |
| CN110845351A (en) * | 2019-10-08 | 2020-02-28 | 安徽生源化工有限公司 | Production process of chloropropylglutamine |
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2007
- 2007-12-19 CN CNA2007101511080A patent/CN101463075A/en active Pending
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102093250B (en) * | 2010-12-02 | 2013-03-20 | 海南本创医药科技有限公司 | Refining method of alanyl-glutamine compound |
| CN102093250A (en) * | 2010-12-02 | 2011-06-15 | 海南本创医药科技有限公司 | Glutamine dipeptide compound and novel method thereof |
| CN103012191B (en) * | 2011-09-26 | 2015-04-22 | 重庆莱美药业股份有限公司 | Method for preparing D-2-substituted propionyl-L-glutamine |
| CN103012550B (en) * | 2011-09-26 | 2014-12-10 | 重庆莱美药业股份有限公司 | Preparation method of N (2)-L-alanyl-L-glutamine |
| CN103012191A (en) * | 2011-09-26 | 2013-04-03 | 重庆莱美药业股份有限公司 | Method for preparing D-2-substituted propionyl-L-glutamine |
| CN103012550A (en) * | 2011-09-26 | 2013-04-03 | 重庆莱美药业股份有限公司 | Preparation method of N (2)-L-alanyl-L-glutamine |
| CN102491918B (en) * | 2011-11-28 | 2013-07-10 | 海南灵康制药有限公司 | Alanyl glutamine compound and preparation method thereof |
| US9024064B2 (en) | 2011-11-28 | 2015-05-05 | Hainan Lingkang Pharmaceutical Co., Ltd. | Alanyl glutamine compound and preparation method thereof |
| CN102491918A (en) * | 2011-11-28 | 2012-06-13 | 海南灵康制药有限公司 | Alanyl glutamine compound and preparation method thereof |
| CN103360462B (en) * | 2013-07-09 | 2015-06-24 | 山东齐都药业有限公司 | Refining method of alanyl-glutamine crude drug |
| CN103360462A (en) * | 2013-07-09 | 2013-10-23 | 山东齐都药业有限公司 | Refining method of alanyl-glutamine crude drug |
| CN103588860A (en) * | 2013-11-14 | 2014-02-19 | 天津大学 | Preparation method of N-(2)-L-alanyl-L-glutamine sphaerocrystal |
| CN103588860B (en) * | 2013-11-14 | 2016-02-10 | 天津大学 | The preparation method of glutamine dipeptide sphaerocrystal |
| CN103623777A (en) * | 2013-11-26 | 2014-03-12 | 精晶药业股份有限公司 | Active adsorbent and application thereof in N(2)-L-alanyl-L-glutamine production process |
| CN103626838A (en) * | 2013-11-26 | 2014-03-12 | 精晶药业股份有限公司 | Removal method of endotoxin in N-(2)-L-alanyl-L-glutamine active pharmaceutical ingredient |
| CN103623777B (en) * | 2013-11-26 | 2016-01-06 | 精晶药业股份有限公司 | A kind of hypersober and the application in glutamine dipeptide is produced thereof |
| CN103910780A (en) * | 2014-04-09 | 2014-07-09 | 上海皓骏医药科技有限公司 | Preparation method of L-alanine-L-glutamine compound |
| CN104561202A (en) * | 2015-02-06 | 2015-04-29 | 江苏诚信药业有限公司 | Preparation method and technological system for enzymatically synthesizing N(2)-L-alanyl-L-glutamine |
| CN110845351A (en) * | 2019-10-08 | 2020-02-28 | 安徽生源化工有限公司 | Production process of chloropropylglutamine |
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