CN1740188A - Prepn process of glycylglutamine - Google Patents
Prepn process of glycylglutamine Download PDFInfo
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- CN1740188A CN1740188A CN 200510010897 CN200510010897A CN1740188A CN 1740188 A CN1740188 A CN 1740188A CN 200510010897 CN200510010897 CN 200510010897 CN 200510010897 A CN200510010897 A CN 200510010897A CN 1740188 A CN1740188 A CN 1740188A
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- methyl ester
- ester hydrochloride
- glutamine
- glycylglutamine
- glutaminate
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Abstract
The preparation process of glycylglutamine includes preparing L-glutamine-gamma-methyl ester hydrochloride with L-glutamic acid, the subsequent preparing chloroacetyl glutamine-gamma-methyl ester hydrochloride with L-glutamine-gamma-methyl ester hydrochloride, and final aminolyzing chloroacetyl glutamine-gamma-methyl ester hydrochloride and purifying to obtain glycylglutamine. The preparation process utilizes chemical material chloroacetyl chloride directly, and has simple reaction, short period, high product yield and low production cost. The purified product has molting point higher than 204 deg.c, and content of 99-100 %.
Description
Technical field
The present invention relates to a kind of preparation method of glycylglutamine.
Background technology
Glutamine is a kind of important amino acid of fast breeding cell purine biosynthesis, pyrimidine and Nucleotide etc., complete and immunodeficiency syndromes diseases such as (immunological competence as AIDS are low) has good therapeutic action to serious katabolism disease (as burning/locate wound/major operation etc.) and intestinal function, also is the condition indispensable amino acid of human body under specific katabolism situation.Although existing oral glutamine preparation because its glutamy content is few or patient's absorption difference of gastrointestinal function obstacle, can not satisfy the needs of patient's body to glutamine.Therefore, need vein glutamine preparation clinically.Yet, because the water-soluble difference of glutamine and when the aqueous solution, thermal sterilising and standing storage chemically unstable, in heat-processed, easily be degraded to ammonia and Pyrrolidonecarboxylic acid, limited its application as the intravenous nutrition preparation, because glutamine is unstable in liquid, so the aminoacids solution of present clinical application does not generally contain glutamine.Thereby, the glutamine preparation of vein medicinal standard never for a long time.Professor Peter has proposed the notion of two peptides, promptly passes through two peptides of synthetic glycylglutamine or the two peptides of the alanyl-glutamine donor as glutamine.Contain stable, water-soluble strong glutamine in the two peptides of this synthetic, have necessary whole biochemistry and physiological property when using as parenteral nutrition matrix glutamine.L-L-glutamic acid is a kind of condition indispensable amino acid, and body's immunity and trauma repair etc. is had vital role.But, can improve stability by the form that it is changed into two peptides because it to instabilities such as soda acid, high temperature, causes its clinical application limited.Two peptides that contain glutamine as glycylglutamine, can overcome above-mentioned shortcoming, and two peptides reduce the clinical infection except that making to injured and the infected, use also can for bone marrow transplant patient and multiple traumatic patient.The production firm of present domestic this product of nothing can only rely on import, and price is very expensive.
Traditional enzyme catalysis connects the peptide method, because synthetic cost costliness can't realize industrialization production in Industrial processes.More external up-to-date synthetic methods though simplified synthesis step, use the price of raw material higher, and product cost is higher.Aspect purifying technique, traditional purifying technique is to adopt silicagel column and ion exchange method to make with extra care purifying, and the purifying products cost is also higher.Patent documentation " a kind of preparation method of glycylglutamine " (invention of Sichuan Sangao Biochemical Co., Ltd 2004), this invention provides a kind of preparation method of glycylglutamine.Described method is: earlier carbobenzoxyglycine (N-Z-Gly) and N-maloyl imines (HOSu) are dissolved in the organic solvent, the solution that adds dicyclohexylcarbodiimide (DCC) again, make the sweet ester solution of Acibenzolar N-carbobenzoxy-(Cbz) and under alkaline condition, react, obtain the carbobenzoxy-(Cbz) glycylglutamine with glutamine; Make solvent with the mixed solution of water and alcohol again, under palladium catalyst catalysis, the carbobenzoxy-(Cbz) glycylglutamine of gained is promptly got the glycylglutamine product through hydrogenolysis, recrystallization, needing to be characterized in synthetic two raw material midbody one benzyloxy carbonyl acyl L-glutamic acid and benzyloxy carbonyl acyl glycine, reactions steps is more, technical requirements height, cost height are not suitable for suitability for industrialized production.
Summary of the invention
The purpose of this invention is to provide a kind of L-of employing L-glutamic acid-R-methyl ester hydrochloride and chloroacetyl chloride and react again the preparation method that ammonia is separated the generation glycylglutamine, reduced reactions steps, reduced production cost.
The present invention improves by the optimization to the glycylglutamine production technique, need not synthesize two raw material midbody, one benzyloxy carbonyl acyl L-glutamic acid and benzyloxy carbonyl acyl glycine, and it is synthetic directly to use the industrial chemicals chloroacetyl chloride to participate in.Concrete grammar is: make L-glutaminate-γ-methyl ester hydrochloride by L-L-glutamic acid, make chloracetyl glutamine γ-methyl ester hydrochloride by L-glutaminate-γ-methyl ester hydrochloride again, chloracetyl glutamine γ-methyl ester hydrochloride ammonia is separated purifying and is got glycylglutamine.Wherein:
1, the method for producing L-glutaminate-γ-methyl ester hydrochloride is:
1) gets raw material L-L-glutamic acid, methyl alcohol, sulfur oxychloride;
2) L-L-glutamic acid and methyl alcohol are put in the three-necked bottle stir, external salt ice bath, when interior temperature drop during to-10 ℃, dripping thionyl chloride, interior temperature maintains below 5 ℃, after dropwising, continues stirring reaction 30～35 minutes;
3) after upward the step reaction finishes, pour in the beaker, add anhydrous diethyl ether, L-glutaminate-γ-methyl ester hydrochloride is separated out, place moments later and filter, wash twice, put into 40～45 ℃ of bakings of baking oven 3～3.5 hours with anhydrous diethyl ether, built-in Vanadium Pentoxide in FLAKES vacuum-drying, vacuum-drying spend the night L-glutaminate-γ-methyl ester hydrochloride.
2, the step of producing chloracetyl glutamine γ-methyl ester hydrochloride is:
1) gets L-glutaminate-γ-methyl ester hydrochloride and be dissolved in the distilled water, under the salt solution ice bath, drip potassium hydroxide aqueous solution, drip, temperature is 0～5 ℃ in the control, drips chloroacetyl chloride, drip the mixed aqueous solution of potassium hydroxide and salt of wormwood and water simultaneously, control pH=8～9, temperature keeps below 10 ℃, continues reaction 30～35 minutes, filter, precipitate washes twice with water, and merging filtrate gets chloracetyl glutamine γ-methyl ester hydrochloride after the filter residue vacuum-drying.
3, the method for producing the L-glycylglutamine is:
1) chloracetyl glutamine γ-methyl ester hydrochloride is put into the bulb bottle, add strong aqua and be stirred to molten entirely;
2) room temperature is placed a week, after ammonia is separated fully, is evaporated to driedly, adds ethyl acetate and separates out, and crystallization is filtered, and washes once with ethyl acetate, and anhydrous diethyl ether is washed once, 50 ℃ of oven dry of baking oven, the L-glycylglutamine.
It is synthetic that the preparation method of glycylglutamine of the present invention directly uses the industrial chemicals chloroacetyl chloride to participate in.When preparing two peptides, changed classics and connect peptide technology, reaction is simple, and not only the rise time of amido bond shortens greatly, and the yield of product can significantly improve, and has reduced production cost.The chloracetyl L-L-glutamic acid-γ-methyl ester hydrochloride yield that generates is 81.6%, and it is 33.72% that ammonia is separated yield, forms the ammonification of glycyl paddy ammonia.The present invention reforms purifying, adopts the method for recrystallization to replace the method that traditional silicagel column and ion exchange method are made with extra care purifying, has landed production cost greatly low, and behind the purifying, the product fusing point reaches greater than 204 ℃, and content reaches 99%～100%.The present invention can improve liquid phase polypeptide synthetic classical way, has reduced reactions steps, because raw materials for production are selected routine, at a low price chemistry and biochemical raw material for use, has reduced production cost again, and the production cost of two peptides per ton can be reduced to about 1,200,000 yuan.
Embodiment
Embodiment 1:
1, produce L-glutaminate-γ-methyl ester hydrochloride:
1) get L-L-glutamic acid 100 grams, 500 milliliters of methyl alcohol, 100 milliliters of sulfur oxychlorides, carry out according to the following steps:
2) L-L-glutamic acid and methyl alcohol are put in the constant voltage agitator stirs in 800 milliliters the three-necked bottle, external salt ice bath, when interior temperature drop during to-10 ℃, dripping thionyl chloride, temperature maintenance after dropwising, continue stirring reaction about 30 minutes below 5 ℃;
3) after reaction finishes, pour in 1000 ml beakers, add 1000 milliliters of anhydrous diethyl ethers, L-glutaminate-γ-methyl ester hydrochloride is separated out, place moments later and filter, wash twice, put into 40 ℃ of bakings of baking oven about 3 hours with anhydrous diethyl ether, built-in Vanadium Pentoxide in FLAKES vacuum-drying, vacuum-drying spend the night L-glutaminate-γ-methyl ester hydrochloride (158～162 ℃ of fusing points).
2, produce chloracetyl glutamine γ-methyl ester hydrochloride:
Getting L-glutaminate-γ-methyl ester hydrochloride 60 grams is dissolved in 150 ml distilled waters, under the salt solution ice bath, drip 30～45 milliliters of potassium hydroxide aqueous solutions (potassium hydroxide 15 grams+50 ml waters), drip, temperature is 0～5 ℃ in the control, drip 36 milliliters of chloroacetyl chlorides, drip 180～200 milliliters of the aqueous solution (potassium hydroxide 36 gram+salt of wormwood 80 gram+200 ml waters) of potassium hydroxide and salt of wormwood and water simultaneously, reaction about 30 minutes is continued below 10 ℃ in control pH=8～9, temperature, filter, precipitate washes twice with water, and merging filtrate gets chloracetyl glutamine γ-methyl ester hydrochloride after the filter residue vacuum-drying.
3, produce the L-glycylglutamine:
Produce according to the following steps:
1) chloracetyl glutamine γ-methyl ester hydrochloride 25 grams is put into 1000 milliliters of bulb bottles, add 500 milliliters of strong aquas and be stirred to molten entirely;
2) room temperature is placed a week, after ammonia is separated fully, is evaporated to driedly, adds 360 milliliters of re-crystallizing in ethyl acetate, and precipitate filters, and washes once with ethyl acetate, and anhydrous diethyl ether is washed once, and about 50 ℃ oven dry of baking oven must the L-glycylglutamine.
Embodiment 2:
1, produce L-glutaminate-γ-methyl ester hydrochloride:
1) get L-L-glutamic acid 200 grams, 1000 milliliters of methyl alcohol, 200 milliliters of sulfur oxychlorides, carry out according to the following steps:
2) L-L-glutamic acid and methyl alcohol are put in the constant voltage agitator stirs in 1500 milliliters the three-necked bottle, external salt ice bath, when interior temperature drop during to-10 ℃, dripping thionyl chloride, temperature maintenance after dropwising, continue stirring reaction about 30 minutes below 5 ℃;
3) after reaction finishes, pour in 3000 ml beakers, add 2000 milliliters of anhydrous diethyl ethers, L-glutaminate-γ-methyl ester hydrochloride is separated out, place moments later and filter, wash twice, put into 45 ℃ of bakings of baking oven about 3 hours with anhydrous diethyl ether, built-in Vanadium Pentoxide in FLAKES vacuum-drying, vacuum-drying spend the night L-glutaminate-γ-methyl ester hydrochloride (158～162 ℃ of fusing points.
2, produce chloracetyl glutamine γ-methyl ester hydrochloride:
Getting L-glutaminate-γ-methyl ester hydrochloride 60 grams is dissolved in 150 ml distilled waters, under the salt solution ice bath, drip 30～45 milliliters of potassium hydroxide aqueous solutions (potassium hydroxide 15 grams+50 ml waters), drip, temperature is 0～5 ℃ in the control, drip 36 milliliters of chloroacetyl chlorides, drip 180～200 milliliters of the aqueous solution (potassium hydroxide 36 gram+salt of wormwood 80 gram+200 ml waters) of potassium hydroxide and salt of wormwood and water simultaneously, reaction about 30 minutes is continued below 10 ℃ in control pH=8～9, temperature, filter, precipitate washes twice with water, and merging filtrate gets chloracetyl glutamine γ-methyl ester hydrochloride after the filter residue vacuum-drying.
3, produce the L-glycylglutamine:
Produce according to the following steps:
1) chloracetyl glutamine γ-methyl ester hydrochloride 25 grams is put into 1000 milliliters of bulb bottles, add 600 milliliters of strong aquas and be stirred to molten entirely;
2) room temperature is placed a week, after ammonia is separated fully, is evaporated to driedly, adds 360 milliliters of re-crystallizing in ethyl acetate, and precipitate filters, and washes once with ethyl acetate, and anhydrous diethyl ether is washed once, and about 50 ℃ oven dry of baking oven must the L-glycylglutamine.
Claims (4)
1. the preparation method of a glycylglutamine, it is characterized in that making L-glutaminate-γ-methyl ester hydrochloride by L-L-glutamic acid, make chloracetyl glutamine γ-methyl ester hydrochloride by L-glutaminate-γ-methyl ester hydrochloride again, chloracetyl glutamine γ-methyl ester hydrochloride ammonia is separated purifying and is got glycylglutamine.
2. the preparation method of glycylglutamine according to claim 1 is characterized in that the method for producing L-glutaminate-γ-methyl ester hydrochloride is:
1) get L-L-glutamic acid, methyl alcohol, sulfur oxychloride, carry out according to the following steps:
2) L-L-glutamic acid and methyl alcohol are put in the three-necked bottle stir, external salt ice bath, when interior temperature drop during to-10 ℃, dripping thionyl chloride, interior temperature maintains below 5 ℃, after dropwising, continues stirring reaction 30～35 minutes;
3) after upward the step reaction finishes, pour in the beaker, add anhydrous diethyl ether, L-glutaminate-γ-methyl ester hydrochloride is separated out, place moments later and filter, wash twice, put into baking oven 40～4 5 ℃ baking 3～3.5 hours with anhydrous diethyl ether, built-in Vanadium Pentoxide in FLAKES vacuum-drying, vacuum-drying spend the night L-glutaminate-γ-methyl ester hydrochloride.
3. the preparation method of glycylglutamine according to claim 1 is characterized in that the step of producing chloracetyl glutamine γ-methyl ester hydrochloride is:
1) gets L-glutaminate-γ-methyl ester hydrochloride and be dissolved in the distilled water, under the salt solution ice bath, drip potassium hydroxide aqueous solution, drip, temperature is 0～5 ℃ in the control, drips chloroacetyl chloride, drip the mixed aqueous solution of potassium hydroxide and salt of wormwood and water simultaneously, control pH=8～9, temperature keeps below 10 ℃, continues reaction 30～35 minutes, filter, precipitate washes twice with water, and merging filtrate gets chloracetyl glutamine γ-methyl ester hydrochloride after the filter residue vacuum-drying.
4. the preparation method of glycylglutamine according to claim 1 is characterized in that the method for producing the L-glycylglutamine is: produce according to the following steps with chloracetyl glutamine γ-methyl ester hydrochloride, strong aqua, anhydrous diethyl ether:
1) chloracetyl glutamine γ-methyl ester hydrochloride is put into the bulb bottle, add strong aqua and be stirred to molten entirely;
2) room temperature is placed a week, after ammonia is separated fully, is evaporated to driedly, adds ethyl acetate and separates out, and crystallization is filtered, and washes once with ethyl acetate, and anhydrous diethyl ether is washed once, 50 ℃ of oven dry of baking oven, the L-glycylglutamine.
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| CN 200510010897 CN1740188A (en) | 2005-07-02 | 2005-07-02 | Prepn process of glycylglutamine |
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| CN 200510010897 CN1740188A (en) | 2005-07-02 | 2005-07-02 | Prepn process of glycylglutamine |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964424A (en) * | 2012-11-14 | 2013-03-13 | 湖北一半天制药有限公司 | Industrialized glycyl-L-glutamine synthetizing method suitable |
| CN103694313A (en) * | 2013-12-24 | 2014-04-02 | 济南诚汇双达化工有限公司 | Glycyl-L-glutamine preparation method |
| CN104529807A (en) * | 2014-12-13 | 2015-04-22 | 济南诚汇双达化工有限公司 | Preparation method of N-chloracetyl-L-glutamine |
| CN106083635A (en) * | 2016-06-30 | 2016-11-09 | 山东诚汇双达药业有限公司 | A kind of preparation method of N (chloracetyl) L glutamic acid methyl ester |
-
2005
- 2005-07-02 CN CN 200510010897 patent/CN1740188A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964424A (en) * | 2012-11-14 | 2013-03-13 | 湖北一半天制药有限公司 | Industrialized glycyl-L-glutamine synthetizing method suitable |
| CN103694313A (en) * | 2013-12-24 | 2014-04-02 | 济南诚汇双达化工有限公司 | Glycyl-L-glutamine preparation method |
| CN103694313B (en) * | 2013-12-24 | 2015-10-07 | 济南诚汇双达化工有限公司 | A kind of preparation method of glycyl-L-glutamine |
| CN104529807A (en) * | 2014-12-13 | 2015-04-22 | 济南诚汇双达化工有限公司 | Preparation method of N-chloracetyl-L-glutamine |
| CN104529807B (en) * | 2014-12-13 | 2017-01-18 | 济南诚汇双达化工有限公司 | Preparation method of N-chloracetyl-L-glutamine |
| CN106083635A (en) * | 2016-06-30 | 2016-11-09 | 山东诚汇双达药业有限公司 | A kind of preparation method of N (chloracetyl) L glutamic acid methyl ester |
| CN106083635B (en) * | 2016-06-30 | 2018-11-06 | 山东诚汇双达药业有限公司 | A kind of N-（Chloracetyl）The preparation method of Pidolidone methyl esters |
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