CN104371001A - Process for synthesizing high-purity glycyk-L-glutamine in mixed solvent - Google Patents
Process for synthesizing high-purity glycyk-L-glutamine in mixed solvent Download PDFInfo
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Abstract
The invention discloses a process for synthesizing high-purity glycyk-L-glutamine in a mixed solvent and belongs to the field of medicinal chemistry. The process includes that N-chloracetyl-L-glutamine is taken as a raw material for ammonolysis reaction, wherein the ammonolysis reaction is characterized in that reaction activity of ammonolysis of N-chloracetyl-L-glutamine is improved by utilizing the mixed solvent of a aprotic polar solvent and ammonia water; stronger ammonia water and (NH4)2CO3 are adopted for ammonolysis reaction under a closed condition, concentration of active ammonia is increased effectively, N-chloracetyl-L-glutamic acid byproduct generated by hydrolysis of N-chloracetyl-L-glutamine is reduced, and selectivity of ammonolysis is improved; reaction liquid is concentrated, a system mixing water, methanol and ester is adopted for crystallization to obtain an N-chloracetyl-L-glutamine crude product with purity of 98.5%, and glycyk-L-glutamine of 99.8% in purity can be obtained by refining the crude product for one time through the mixed solvent of water, methanol and ester. By the process, yield is increased, and operation is simplified. The process is suitable for industrialized production.
Description
Technical field
The invention belongs to medicinal chemistry art, relate to the preparation technology of glycyl-L-glutamine, relate to more specifically and a kind ofly in enclosed system, adopt N-chloracetyl-L-glutaminate under aprotic polar solvent and ammoniacal liquor mixed solvent condition and volatile salt carries out the method that ammonolysis reaction prepares Ganguertai.
Background technology
L-glutaminate (L-Gln) is reasonable amino acid the abundantest in human body, is that a kind of condition must amino acid for critical and dietetic patient.Although L-glutaminate physiological function and pharmacological action are subject to most attention, but due to its solubleness is low in aqueous add transfusion time patient Water l oad, generate the larger Pyrrolidonecarboxylic acid of toxic side effect at high-temperature sterilization with when storing, limit its widespread use clinically.Glycyl-L-glutamine (abbreviation Ganguertai) is a kind of dipeptide amino acid of synthetic, can be hydrolyzed into the synthesis of total free aminoacids for tissue protein in vivo, also can directly be utilized by the histoorgan such as liver, kidney by pepx.Glycyl-L-glutamine is soluble in water, stable in properties in solution thermal sterilising and long-time storage process.Therefore, compare with like product, glycyl-L-glutamine has clear superiority, wide market.
At present, the preparation method of glycyl-L-glutamine mainly contains following several:
1. with chloroacetyl chloride and glutamine-γ-methyl esters for raw material, generate chloracetyl L-glutamic acid-γ-methyl esters, and then ammonia solution obtains glycylglutamine (JP63051399,1988).The method GLN-γ-methyl esters cost is higher, and during intermediate ammonia solution, side reaction is more, and ammonia solution is not thorough, and the aftertreatment cycle is long.
2. with protection after carbobenzoxyglycine be raw material; under dicyclohexylcarbodiimide (DCC) effect; obtained hydroxyl fourth diimine (HOSU) active ester; then react with glutamine and generate dipeptides; finally in methanol/water mixed solvent, obtain glycyl-L-glutamine (CN 1532204,2004) by Pd-C catalytic hydrogenation.This reaction process is more complicated, and DCC is difficult to removing, and product is difficult to purify, and will use the higher raw material of some prices in reaction process, and as DCC, palladium charcoal, tetrahydrofuran (THF) etc. make product cost increase, and pressure hydration requires harsher to production unit.
3. glycine and and L-glutaminate be main raw material, first with Tetra hydro Phthalic anhydride, glycine is protected, generates corresponding acyl chlorides reacting to sulfur oxychloride; with recycle hydrazine hydrate hydrazinolysis after L-glutaminate condensation and obtain product (chemical reagent; 2011,33,177).Although it is passable that the method obtains product purity, take in intermediate condensate process to carve and detect pH, be unfavorable for production control; And a large amount of acid solutions of process are unfriendly to environment.
4. mixed anhydride Master grows up at the initial stage fifties.Reaction is carried out in two steps, is first acylamino acid is generated mixed acid anhydride with chloromethyl ester reaction under the existence of low temperature and tertiary amine, and then generated mixed acid anhydride is obtained by reacting peptide with moiety again.Its advantage is that method is simple, and speed of response is fast, and the abstraction and purification of product is more convenient, but there is the shortcoming of easy racemization, is therefore necessary to the selection of reaction conditions and control.
5. take chloroacetyl chloride as starting raw material, with L-glutaminate amidation, product ammonia solution in ammoniacal liquor obtains glycyl-L-glutamine (US 5780677,1988).Although this method step is short, simple to operate, but ammonia solution in ammoniacal liquor, the concentration of active ammonia is low, reaction is slow, the γ amido linkage of L-glutaminate may be hydrolyzed simultaneously and introduce glycyl-L-glutamic acid, because glycyl-L-glutamic acid and glycyl-L-glutamine are the very similar dipeptides of structure, finally makes product be difficult to purifying.Obtained crude product glycyl-L-glutamine purity is low, is unfavorable for the production of bulk drug.
Summary of the invention
The object of the invention is for overcoming above-mentioned the deficiencies in the prior art, a kind of preparation technology of mixed solvent synthesis of high purity Ganguertai is provided, adopts high-content N-chloracetyl-L-glutaminate under aprotic polar solvent and ammoniacal liquor mixed solvent condition and (NH4)
2cO
3ammoniation agent carries out ammonolysis reaction in confined conditions.Reaction terminates rear recovery ammoniacal liquor, decomposes (NH4)
2cO
3, concentrated by reaction solution, obtain highly purified glycyl-L-glutamine crude product with the mixed solvent crystallization of water, methyl alcohol and ester, crude product refines the Ganguertai that just can obtain purity more than 99.8% through the mixed solvent primary of water, methyl alcohol and ester.
Its ammonolysis reaction, due under utilizing aprotic polar solvent and ammoniacal liquor mixed solvent condition, improves the reactive behavior of N-chloracetyl-L-glutaminate ammonia solution; Adopt strong aqua and (NH
4)
2cO
3carry out the concentration that ammonolysis reaction effectively improves active ammonia in confined conditions, greatly reduce the glycyl-L-glutamic acid by product of glycyl-L-glutamine hydrolysis and generation, improve the selectivity of ammonia solution.After reaction terminates, reclaim excessive ammonia under normal temperature, decomposing excessive (NH is steamed in pressurization
4)
2cO
3the mixed solvent concentrating reaction solution, adopt methyl alcohol and ester carries out the crystallization of crude product glycyl-L-glutamine, utilize methyl alcohol and ester to the different solubility of different impurities, the bag reducing product crystallization is mixed, and effectively improves glycyl-L-glutamine crude product purity to more than 98.5%.Crude product suspends in water, and rising temperature for dissolving, charcoal absorption decolouring, add the mixed solvent of methyl alcohol and ester after heat filtering, cooling crystallization, suction filtration, drying under reduced pressure obtains the glycyl-L-glutamine of purity 99.8%.
For achieving the above object, the present invention adopts following technical proposals:
With N-chloracetyl-L-glutaminate for Ganguertai prepared by raw material, comprise and the mixed solvent of aprotic polar solvent and ammoniacal liquor is put in closed reactor, under stirring, drop into (NH successively
4)
2cO
3with N-chloracetyl-L-glutaminate, airtight heating makes its complete reaction, and after reaction terminates, reclaim under reduced pressure excess of ammonia water under normal temperature, at 60 DEG C, under-0.08 ~-0.10MPa, the (NH of decomposing excessive is steamed in decompression
4)
2cO
3.Reaction solution is concentrated the mixed solvent crystallization of rear use methyl alcohol and ester, filter, dry crude product glycyl-L-glutamine, crude product is suspended in water, rising temperature for dissolving, charcoal absorption decolouring, add the mixed solvent of methyl alcohol and ester, cooling crystallization after heat filtering, suction filtration, drying under reduced pressure obtains the glycyl-L-glutamine of purity 99.8%;
Described ammonolysis reaction carries out in confined conditions, and sealing system reaction pressure is: 0.01-0.5MPa.
In described ammonolysis reaction, solvent is the mixed solvent of aprotic polar solvent and ammoniacal liquor, wherein aprotic polar solvent, refer to dimethyl sulfoxide (DMSO) (DMSO), dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE (DMAC), N-Methyl pyrrolidone (NMP), preferred dimethyl formamide (DMF).Aprotic polar solvent and ammoniacal liquor volume ratio=1:3-20, preferred 1:5 in mixed solvent.。
In described ammonolysis reaction, ammonia solution reagent is strong aqua and (NH
4)
2cO
3compound system, the mass concentration of strong aqua is 25% ~ 34%, preferably 28% ammoniacal liquor.N-chloracetyl-L-glutaminate and ammoniacal liquor and (NH
4)
2cO
3mol ratio be 1:13 ~ 22:4 ~ 10, preferred 1:16.5:5.5.
In described ammonolysis reaction, temperature of reaction is 20 DEG C ~ 60 DEG C, preferably 25 ~ 40 DEG C.Ammonolysis reaction time 4h ~ 12h.
Recrystallisation solvent is the mixed solvent of methyl alcohol and ester, and ester refers to ethyl acetate, butylacetate, methyl acetate, tert.-butyl acetate, ethyl acetate, tert.-butyl acetate.Methyl alcohol and ester ratio=1 ~ 5:1 in mixed solvent, preferred 3:1.
Described treating process comprises the steps:
(1) dissolve: glycyl-L-glutamine crude product is suspended in water, is warming up to 50 DEG C and makes it dissolve.Water add volume and glycyl-L-glutamine mass ratio=3 ~ 6:1, preferred 4:1;
(2) adsorption bleaching: add gac and carry out adsorption bleaching, then filter, the mass ratio of gac and glycyl-L-glutamine is 2%;
(3) crystallization: the mixed solvent dripping methyl alcohol and ester at temperature 30 DEG C ~ 40 DEG C in filtrate, crystal is cooled to 0 DEG C ~ 5 DEG C and continues crystallization 3h after separating out, ester refers to ethyl acetate, butylacetate, methyl acetate, tert.-butyl acetate, ethyl acetate, tert.-butyl acetate.Methyl alcohol and ester ratio=1:1 ~ 5 in mixed solvent, preferably: 1:3.The volume of the mixed solvent of methyl alcohol and ester and volume ratio=1 of water ~ 2.5:1, preferred 1.5:1.
(4) filtration drying: carry out 65 DEG C of vacuum-dryings after filtration, obtain highly purified glycyl-L-glutamine.
The glycyl-L-glutamine prepared by above-mentioned steps uses high performance liquid chromatography to detect purity more than 99.8%.
The invention has the beneficial effects as follows:
1. ammonolysis reaction of the present invention carries out in aprotic polar solvent, improves the reactive behavior of N-chloracetyl-L-glutaminate, improves speed of reaction, decreases impurity and produces.
2. the present invention uses strong aqua and (NH
4)
2cO
3react in confined conditions, decrease the loss of ammonia, improve reaction efficiency, substantially increase the concentration of active ammonia, effectively inhibit the hydrolysis of γ amido linkage, the amount of impurity glycyl-L-glutamic acid is reduced.
3. use water-methanol-ester system crystallization and refine, utilizing methyl alcohol and ester to the different solubility of different impurities, the bag decreasing product crystallization is mixed, and improves product purity.
4. temperature of reaction reduces, and decreases the impurity L-Glutimic acid and the amount of ring (glycyl-L-glutamine) introduced due to high temperature.
Embodiment
Below in conjunction with embodiment, the present invention is further described.
Example 1:
Be that the mixed solvent of the ammoniacal liquor 40ml of 25% is put in closed reactor by dimethyl sulfoxide (DMSO) (DMSO) 18ml and massfraction, under stirring, drop into 43g (NH successively
4)
2cO
3with 10g N-chloracetyl-L-glutaminate, be airtightly heated to 50 DEG C and make its complete reaction, complete through HPLC detection reaction after 4.5h, reclaim under reduced pressure excess of ammonia water under normal temperature, at 60 DEG C, under-0.08 ~-0.10MPa, the (NH of decomposing excessive is steamed in decompression
4)
2cO
3, reaction solution is concentrated into 27g, drips the mixed solvent of 20ml methyl alcohol and 20ml butylacetate at 50 DEG C, crystal is cooled to 0 ~ 3 DEG C of crystallization 3h after separating out, and filter, drying under reduced pressure obtains crude product glycyl-L-glutamine 7.78g, purity 98.85%.
Example 2:
Be that the mixed solvent of the ammoniacal liquor 50ml of 28% is put in closed reactor by dimethyl formamide (DMF) 10ml and massfraction, under stirring, drop into 23.5g (NH successively
4)
2cO
3with 10g N-chloracetyl-L-glutaminate, be airtightly heated to 25 DEG C and make its complete reaction, complete through HPLC detection reaction after 8h, reclaim under reduced pressure excess of ammonia water under normal temperature, at 60 DEG C, under-0.08 ~-0.10MPa, the (NH of decomposing excessive is steamed in decompression
4)
2cO
3, reaction solution is concentrated into 27g, drips the mixed solvent of 30ml methyl alcohol and 10ml ethyl acetate at 50 DEG C, crystal is cooled to 0 ~ 3 DEG C of crystallization 3h after separating out, and filter, drying under reduced pressure obtains crude product glycyl-L-glutamine 7.81g, purity 98.92%.
Example 3:
Be that the mixed solvent of the ammoniacal liquor 66ml of 28% is put in closed reactor by N-Methyl pyrrolidone (NMP) 7ml and massfraction, under stirring, drop into 17.5g (NH successively
4)
2cO
3with 10g N-chloracetyl-L-glutaminate, be airtightly heated to 40 DEG C and make its complete reaction, complete through HPLC detection reaction after 6h, reclaim under reduced pressure excess of ammonia water under normal temperature, at 60 DEG C, under-0.08 ~-0.10MPa, the (NH of decomposing excessive is steamed in decompression
4)
2cO
3, reaction solution is concentrated into 27g, drips the mixed solvent of 27ml methyl alcohol and 13ml methyl acetate at 50 DEG C, crystal is cooled to 0 ~ 3 DEG C of crystallization 3h after separating out, and filter, drying under reduced pressure obtains crude product glycyl-L-glutamine 7.80g, purity 98.87%.
Example 4:
Be that the mixed solvent of the ammoniacal liquor 33ml of 34% is put in closed reactor by N,N-DIMETHYLACETAMIDE (DMAC) 6ml and massfraction, under stirring, drop into 23.5g (NH successively
4)
2cO
3with 10g N-chloracetyl-L-glutaminate, be airtightly heated to 60 DEG C and make its complete reaction, complete through HPLC detection reaction after 4h, reclaim under reduced pressure excess of ammonia water under normal temperature, at 60 DEG C, under-0.08 ~-0.10MPa, the (NH of decomposing excessive is steamed in decompression
4)
2cO
3, reaction solution is concentrated into 27g, drips the mixed solvent of 32ml methyl alcohol and 8ml tert.-butyl acetate at 50 DEG C, crystal is cooled to 0 ~ 3 DEG C of crystallization 3h after separating out, and filter, drying under reduced pressure obtains crude product glycyl-L-glutamine 7.81g, purity 98.88%.
Example 5:
Be that the mixed solvent of the ammoniacal liquor 50ml of 34% is put in closed reactor by dimethyl formamide (DMF) 2.5ml and massfraction, under stirring, drop into 43g (NH successively
4)
2cO
3with 10g N-chloracetyl-L-glutaminate, be airtightly heated to 20 DEG C and make its complete reaction, complete through HPLC detection reaction after 10h, reclaim under reduced pressure excess of ammonia water under normal temperature, at 60 DEG C, under-0.08 ~-0.10MPa, the (NH of decomposing excessive is steamed in decompression
4)
2cO
3, reaction solution is concentrated into 27g, drips the mixed solvent of 33.3ml methyl alcohol and 6.7ml tert.-butyl acetate at 50 DEG C, crystal is cooled to 0 ~ 3 DEG C of crystallization 3h after separating out, and filter, drying under reduced pressure obtains crude product glycyl-L-glutamine 7.80g, purity 98.87%.
Example 6:
Be that the mixed solvent of the ammoniacal liquor 40ml of 25% is put in closed reactor by dimethyl sulfoxide (DMSO) (DMSO) 10ml and massfraction, under stirring, drop into 17.5g (NH successively
4)
2cO
3with 10g N-chloracetyl-L-glutaminate, be airtightly heated to 30 DEG C and make its complete reaction, complete through HPLC detection reaction after 7.5h, reclaim under reduced pressure excess of ammonia water under normal temperature, at 60 DEG C, under-0.08 ~-0.10MPa, the (NH of decomposing excessive is steamed in decompression
4)
2cO
3, reaction solution is concentrated into 27g, drips the mixed solvent of 20ml methyl alcohol and 20ml ethyl acetate at 50 DEG C, crystal is cooled to 0 ~ 3 DEG C of crystallization 3h after separating out, and filter, drying under reduced pressure obtains crude product glycyl-L-glutamine 7.79g, purity 98.91%.
Example 7:
10g glycyl-L-glutamine crude product is added in 250mL there-necked flask, adds 30mL purified water, stir, being warming up to 50 DEG C makes it dissolve completely, adds 0.2g gac, stirs 30 ~ 40min, filter, filtrate is kept 30 DEG C, drip the mixed solvent of 50mL methyl alcohol and 25ml ethyl acetate wherein, after crystallize out, be cooled to 0 ~ 5 DEG C, continue crystallization 3h, filtration, 65 DEG C of vacuum-dryings, obtain sterling 8.87g, purity 99.85%.
Example 8:
10g glycyl-L-glutamine crude product is added in 250mL there-necked flask, adds 60mL purified water, stir, being warming up to 50 DEG C makes it dissolve completely, adds 0.2g gac, stirs 30 ~ 40min, filter, filtrate is kept 40 DEG C, drip the mixed solvent of 45mL methyl alcohol and 15ml ethyl acetate wherein, after crystallize out, be cooled to 0 ~ 5 DEG C, continue crystallization 3h, filtration, 65 DEG C of vacuum-dryings, obtain sterling 8.84g, purity 99.88%.
Example 9:
10g glycyl-L-glutamine crude product is added in 250mL there-necked flask, adds 40mL purified water, stir, being warming up to 50 DEG C makes it dissolve completely, adds 0.2g gac, stirs 30 ~ 40min, filter, filtrate is kept 40 DEG C, drip the mixed solvent of 45mL methyl alcohol and 15ml tert.-butyl acetate wherein, after crystallize out, be cooled to 0 ~ 5 DEG C, continue crystallization 3h, filtration, 65 DEG C of vacuum-dryings, obtain sterling 8.86g, purity 99.87%.
The specific embodiment of the present invention is described although above-mentioned in conjunction with the embodiments; but not limiting the scope of the invention; one of ordinary skill in the art should be understood that; on the basis of technical scheme of the present invention, those skilled in the art do not need to pay various amendment or distortion that creative work can make still within protection scope of the present invention.
Claims (8)
1. the technique of synthesis of high purity Ganguertai in mixed solvent, its feature comprises following steps: adopt high-content N-chloracetyl-L-glutaminate under aprotic polar solvent and ammoniacal liquor mixed solvent condition and (NH4)
2cO
3carry out ammonolysis reaction, in closed reactor, add the mixed solvent of aprotic polar solvent and ammoniacal liquor, volatile salt and high-content N-chloracetyl-L-glutaminate successively, heat up and react; After reaction terminates, reclaim under reduced pressure excess of ammonia water under normal temperature, (the NH of decomposing excessive is steamed in the decompression that heats up
4)
2cO
3, reaction solution is concentrated the mixed solvent crystallization of rear use methyl alcohol and ester, filters, the glycyl-L-glutamine crude product that dry purity is high; Suspended in water by crude product, rising temperature for dissolving, charcoal absorption decolouring, add the mixed solvent of methyl alcohol and ester after heat filtering, crystallization, suction filtration, vacuum-drying obtains highly purified glycyl-L-glutamine.
2. the technique of synthesis of high purity Ganguertai in a kind of mixed solvent as claimed in claim 1, is characterized in that, in described ammonolysis reaction, in aprotic polarity and ammoniacal liquor mixed solvent, and N-chloracetyl-L-glutaminate and strong aqua and (NH4)
2cO
3drop in closed reactor and react, wherein aprotic polar solvent, refer to dimethyl sulfoxide (DMSO) (DMSO), dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE (DMAC), N-Methyl pyrrolidone (NMP), preferred dimethyl formamide (DMF).
3. the technique of synthesis of high purity Ganguertai in a kind of mixed solvent as claimed in claim 1, is characterized in that, in described ammonolysis reaction, and aprotic polar solvent and ammoniacal liquor volume ratio=1:3-20, preferred 1:5 in mixed solvent.
4. the technique of synthesis of high purity Ganguertai in a kind of mixed solvent as claimed in claim 1, is characterized in that, in described ammonolysis reaction, ammonia solution reagent is strong aqua and (NH
4)
2cO
3compound system, the mass concentration of strong aqua is 25%-34%, preferably 28% ammoniacal liquor.
5. the technique of synthesis of high purity Ganguertai in a kind of mixed solvent as claimed in claim 1, is characterized in that, in described ammonolysis reaction, and N-chloracetyl-L-glutaminate and ammoniacal liquor and (NH
4)
2cO
3mol ratio be 1:13-22:4-10, preferred 1:16.5:5.5.
6. the technique of synthesis of high purity Ganguertai in a kind of mixed solvent as claimed in claim 1, it is characterized in that, in described ammonolysis reaction, sealing system reaction pressure is: 0.01-0.5MPa, and temperature of reaction is 20 DEG C-60 DEG C, preferred 25-40 DEG C; Ammonolysis reaction time 4h-12h.
7. the technique of synthesis of high purity Ganguertai in a kind of mixed solvent as claimed in claim 1, it is characterized in that, recrystallisation solvent is the mixed solvent of methyl alcohol and ester, and ester refers to ethyl acetate, butylacetate, methyl acetate, tert.-butyl acetate, ethyl acetate, tert.-butyl acetate; Methyl alcohol and ester ratio=1-5:1, preferred 3:1 in mixed solvent.
8. as the technique of synthesis of high purity Ganguertai in claim 1 mixed solvent, it is characterized in that in described water, methyl alcohol and ester recrystallization process, water add volume and glycyl-L-glutamine mass ratio=3-6:1, preferred 4:1, the volume of water in milliliter, glycyl-L-glutamine quality in gram; Ester refers to ethyl acetate, butylacetate, methyl acetate, tert.-butyl acetate, ethyl acetate, tert.-butyl acetate; The volume of the mixed solvent of methyl alcohol and ester and the volume ratio=1-2.5:1 of water, preferred 1.5:1; The temperature of cooling crystallization is 0-5 DEG C.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1532204A (en) * | 2003-03-19 | 2004-09-29 | 四川三高生化股份有限公司 | Process for preparing glycyl gtutamine |
| CN101429230A (en) * | 2008-12-05 | 2009-05-13 | 北京博时安泰科技发展有限公司 | Refining method for Ganguertai |
| CN102993271A (en) * | 2012-12-13 | 2013-03-27 | 山东齐都药业有限公司 | Preparation method of glycyl-L-glutamine |
| 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 |
-
2014
- 2014-12-01 CN CN201410706801.XA patent/CN104371001B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1532204A (en) * | 2003-03-19 | 2004-09-29 | 四川三高生化股份有限公司 | Process for preparing glycyl gtutamine |
| CN101429230A (en) * | 2008-12-05 | 2009-05-13 | 北京博时安泰科技发展有限公司 | Refining method for Ganguertai |
| CN102993271A (en) * | 2012-12-13 | 2013-03-27 | 山东齐都药业有限公司 | Preparation method of glycyl-L-glutamine |
| 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 |
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