CN103936824B - The environment-friendly preparation method thereof of phthalyl glycyl-L-glutamine - Google Patents
The environment-friendly preparation method thereof of phthalyl glycyl-L-glutamine Download PDFInfo
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- 108010010147 glycylglutamine Proteins 0.000 title claims abstract description 32
- -1 phthalyl glycyl-L-glutamine Chemical compound 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- RHZBRCQIKQUQHQ-UHFFFAOYSA-N 2-(1,3-dioxoisoindol-2-yl)acetyl chloride Chemical compound C1=CC=C2C(=O)N(CC(=O)Cl)C(=O)C2=C1 RHZBRCQIKQUQHQ-UHFFFAOYSA-N 0.000 claims abstract description 14
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims abstract description 10
- 239000007864 aqueous solution Substances 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 31
- 239000000243 solution Substances 0.000 claims description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 22
- 239000003513 alkali Substances 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 11
- 235000017550 sodium carbonate Nutrition 0.000 claims description 11
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 11
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 8
- 239000011707 mineral Substances 0.000 claims description 8
- 235000010755 mineral Nutrition 0.000 claims description 8
- 239000013078 crystal Substances 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 239000001117 sulphuric acid Substances 0.000 claims description 5
- 235000011149 sulphuric acid Nutrition 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 2
- 238000010790 dilution Methods 0.000 claims description 2
- 239000012895 dilution Substances 0.000 claims description 2
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- 238000000034 method Methods 0.000 abstract description 13
- 239000002994 raw material Substances 0.000 abstract description 10
- PNMUAGGSDZXTHX-BYPYZUCNSA-N Gly-Gln Chemical compound NCC(=O)N[C@H](C(O)=O)CCC(N)=O PNMUAGGSDZXTHX-BYPYZUCNSA-N 0.000 abstract description 7
- 238000001914 filtration Methods 0.000 abstract description 6
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- 239000007788 liquid Substances 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 231100001261 hazardous Toxicity 0.000 abstract description 2
- 150000007529 inorganic bases Chemical class 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 238000002425 crystallisation Methods 0.000 abstract 1
- 230000008025 crystallization Effects 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- 239000002912 waste gas Substances 0.000 abstract 1
- 239000002351 wastewater Substances 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 22
- 239000000047 product Substances 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 230000008569 process Effects 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 4
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 4
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 108010044940 alanylglutamine Proteins 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 3
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- DLZVKKBSFAECMQ-RXMQYKEDSA-N CCC(N[C@H](CCC(N)=O)C(O)=O)=O Chemical compound CCC(N[C@H](CCC(N)=O)C(O)=O)=O DLZVKKBSFAECMQ-RXMQYKEDSA-N 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical class ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- CGIHPACLZJDCBQ-UHFFFAOYSA-N acibenzolar Chemical compound SC(=O)C1=CC=CC2=C1SN=N2 CGIHPACLZJDCBQ-UHFFFAOYSA-N 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 208000012826 adjustment disease Diseases 0.000 description 1
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- 150000001413 amino acids Chemical class 0.000 description 1
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- VHHHONWQHHHLTI-UHFFFAOYSA-N hexachloroethane Chemical compound ClC(Cl)(Cl)C(Cl)(Cl)Cl VHHHONWQHHHLTI-UHFFFAOYSA-N 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
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- 239000008057 potassium phosphate buffer Substances 0.000 description 1
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Abstract
The invention discloses a kind of environment-friendly preparation method thereof of phthalyl glycyl-L-glutamine, this preparation method, reacts, through twice acidifying for raw material with phthalyl glycyl chloride and L-glutaminate in inorganic base aqueous solution, crystallization, filtering drying obtains product.This preparation method's raw material is easy to get, simple to operate, product yield high purity is high, and avoids the poisonous and hazardous organic solvent of use, effectively reduces the discharge of waste water, waste liquid, waste gas in suitability for industrialized production, reduces the pollution to environment.The high-purity o phenyl-diformyl glycyl-L-glutamine that the inventive method obtains is that the glycylglutamine synthesizing ultra-high purity further provides a kind of raw material reliably, thus effectively reduces the side effect clinically of glycylglutamine preparation.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of phthalyl glycyl-L-glutamine environment-friendly preparation method thereof.
Background technology
Glycylglutamine is also called N-glycyl-L-glutamine (formula 1), molecular formula C
7h
13n
3o
4, molecular weight 202.1.
Glycylglutamine is a kind of important composition composition of parenteral nutrition medicine, effectively can strengthen the cellular immune function of patient, reduces the infected risk of patient.Therefore, be widely used in because treatment intestinal function is incomplete, severe infections, burn, immune deficiency syndrome etc.Glycylglutamine can be decomposed into glutamine and L-Ala in human body, therefore professor peter proposes the concept of a kind of pair of peptide, namely glutamine dipeptide is formed by L-Ala and glutamine, using the preparation be prepared into as the donor of glutamine, meet disease Man's Demands by intravenous mode.This pair of peptide decompose the amino acid that discharges as nutritive substance be stored in separately health corresponding site and with body need carry out metabolism.
At present, the preparation method of multiple glycylglutamine has been disclosed both at home and abroad.
Zhang Zhe etc. are at " chemical reagent " 33 volume 2 phase 177-178 pages in 2011, namely the autograph delivered on February 15th, 2011 is propose a kind of in the inorganic base aqueous solution of L-glutaminate, drip phthalyl glycyl chloride toluene solution and sodium hydroxide solution in " synthesis of glycyl-L-glutamine " simultaneously, the obtained phthalyl glycyl-L-glutamine of docking; Then react in hydrazine hydrate, acidifying obtains product.The method is used mixed solvent and is belonged to inhomogeneous reaction, can hinder between reaction raw materials to a certain extent and mutually collide, thus reduces yield.Toluene belongs to poisonous strong carcinogen in addition, all has larger toxic action to environment and human body; Two dropping in simultaneous reactions process also improves equipment investment.
Chinese patent CN1680428A phthalyl glycine and L-glutaminate, as raw material, react under the existence of Acibenzolar isopropyl chlorocarbonate, finally utilize underpressure distillation to separate product, obtained phthalyl glycyl glutamy, yield 58%.The method isopropyl chlorocarbonate used belongs to highly toxic substance, has high risks to environment and operator, therefore in suitability for industrialized production to equipment and personnel requirement very high.And underpressure distillation needs lot of energy, discharges poisonous and hazardous waste gas and waste liquid.
So, still need a kind of less investment, simple to operate, low-carbon environment-friendly, environment amenable environment-friendly preparation method thereof.
Summary of the invention
The object of the invention is the phthalyl glycyl-L-glutamine preparation method providing a kind of environmental protection, adopt that this preparation method is simple to operate and cost is low, be easy to suitability for industrialized production, the phthalyl glycyl-L-glutamine impurity of synthesis is few, purity is high, field of medicaments can be applied in well, for pharmacy provides high-purity raw.
The concrete preparation method of phthalyl glycyl-L-glutamine of the present invention comprises the steps:
A. in water, add mineral alkali and L-glutaminate and be cooled between-5 ~-12 DEG C, forming the aqueous solution; Described mineral alkali is selected from the one in sheet alkali, soda ash, or their any mixture;
B. fast drop phthalyl glycyl chloride in the aqueous solution of step a, rate of addition controls between 2.5 ~ 3 Grams Per Seconds, and controls temperature of reaction between 8 ~ 12 DEG C, makes it react as follows:
C. after question response terminates, add concentrated acid solution in the solution of step b, regulate between pH to 3 ~ 4, first time separates out white crystal;
D. in the solution of step c, add dilute acid soln, regulate between pH to 1.5 ~ 2, separate out white crystal further;
E. the white crystal that step c and d separates out is filtered, dry, obtain finished product.
Scheme as a further improvement on the present invention, described mineral alkali is the mixture of sheet alkali and soda ash and its consumption is 8 ~ 9:20 according to the ratio of mass ratio, adopt the mineral alkali of this ratio, the yield of its phthaloyl-L-alanyl-L-glutamine obtained is all more than 98%, and purity is not less than 99%.
Further, in described step a be cooled to less than-5 ~-12 DEG C be preferably cooling most between-7 ~-8 DEG C.
Temperature of reaction in described step b preferably controls between 9 ~ 10 DEG C.
Concentrated acid in described step c is preferably the concentrated hydrochloric acid of 12mol/L or the sulphuric acid soln of 6mol/L.
Diluted acid in described steps d is preferably the dilute hydrochloric acid of 0.2mol/L or the dilution heat of sulfuric acid of 0.1mol/L.
The present invention with phthalyl glycyl chloride for raw material, react with L-glutaminate in without any the aqueous solution of organic solvent and produce phthalyl glycyl-L-glutamine, through acidifying, filter, dry and obtain high purity phthaloyl-L-alanyl-L-glutamine.Its beneficial effect shows:
One, be that raw material replaces the hazardous and noxious substances such as triphenylphosphine, hexachloroethane, triphenylphosphinc oxide, triphosgene with the phthalyl glycyl chloride being simple and easy to produce, the possibility these materials being introduced product is eliminated from raw material, pollution-free, also reduce the input of equipment and personal security aspect in suitability for industrialized production to a great extent simultaneously.
Two, use the mineral alkali of more low cost, as sheet alkali, soda ash or its mixed base replace original potassium hydroxide, thus avoid the use of the organic solvents such as toluene, preparation process can be carried out completely in aqueous phase.Avoid processing organic solvent in preparation process and discharge poisonous and hazardous waste gas, waste liquid and waste residue, the low and environmental protection of cost.
Three, water provides best guarantee as the high yield high purity that the single solvent reacted is product in the present invention.The present invention adopts two step liberation methods, and the first step is by concentrated acid, and quick adjustment reaction solution pH, tentatively separates out; Second step is by diluted acid, turns down reaction solution pH further, promotes that phthalyl glycyl-L-glutamy chloramines crystal is separated out completely.The method that two steps are separated out, not only need not drop into the equipment of high cost and numerous manpower, and only just need can obtain the highly purified product of high yield with simple filter operation.
Four, do not use the two of phthalyl glycyl chloride and alkaline solution in preparation process to drip, only the single dropping of just phthalyl glycyl chloride, this improvement can simplified apparatus greatly in suitability for industrialized production, reduces and drops into.
In view of Dipeptiven purity is on the impact of its activity, the phthalyl glycyl-L-glutamine that the inventive method obtains is that the Dipeptiven synthesizing ultra-high purity further provides a kind of raw material reliably.
The present invention fundamentally solves and produces at present both at home and abroad in Dipeptiven process, uses poisonous and harmful, high cost raw material and solvent, the difficult problem that complicated operation, product yield are low, avoids and that cause a series of clinical adverse more due to impurity.
Embodiment
HPLC measures the purity of phthalyl glycine-L-glutaminate.
Measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD)
Chromatographic condition and system suitability test: measure with nh 2 column C18, with potassium phosphate buffer (with phosphorus acid for adjusting pH to 3.8)-acetonitrile (40:60) for moving phase; Determined wavelength is 220nm, flow velocity 0.6ml/min, and phthalyl glycine-L-glutaminate resolution should be not less than 2.0
Embodiment 1:
Get 16g sheet alkali and 40g soda ash joins in 500mL water, and add 50gL-glutamine, stirring and dissolving, gained reaction soln is cooled to-7 DEG C, form solution.With the speed fast drop phthalyl glycyl chloride of 2.5g/s, control reaction soln temperature in the process between 9 ~ 10 DEG C.After dripping, stirring reaction 60 minutes.And in backward solution, slowly add the hydrochloric acid soln of 12mol/L, regulate pH to 4, stir 9 minutes, separate out a large amount of white solid.Continue the hydrochloric acid soln dripping 0.2mol/L in reaction solution, regulate pH to 1.5, product is separated out completely, stirs 5 minutes.Solid filtering is dried and obtains product phthalyl glycyl-L-glutamine 111.9g, yield 98.2%, measure according to high performance liquid chromatography (HPLC), its phthalyl glycyl-L-glutamine purity 99.1%.
Embodiment 2:
Get 16g sheet alkali and 40g soda ash joins in 500mL water, and add 50gL-glutamine, stirring and dissolving, gained reaction soln is cooled to-8 DEG C, form solution.With the quick phthalyl glycyl chloride of the speed of 2.8g/s, control reaction soln temperature in the process between 9 ~ 10 DEG C.After dripping, stirring reaction 60 minutes.And in backward solution, slowly add the hydrochloric acid soln of 12mol/L, regulate pH to 3, stir 9 minutes, separate out a large amount of white solid.Continue the hydrochloric acid soln dripping 0.2mol/L in reaction solution, regulate pH to 1.5, product is separated out completely, stirs 5 minutes.Solid filtering is dried and obtains product phthalyl glycyl-L-glutamine 112.3g, yield 98.5%, HPLC purity 99.2%.
Embodiment 3:
Get 18g sheet alkali and 40g soda ash joins in 500mL water, and add 50gL-glutamine, stirring and dissolving, gained reaction soln is cooled to-7 DEG C.With the quick phthalyl glycyl chloride of the speed of 2.8g/s, control reaction soln temperature in the process between 9 ~ 10 DEG C.After dripping, stirring reaction 60 minutes.And in backward solution, slowly add the sulphuric acid soln of 6N, regulate pH to 3, stir 9 minutes, separate out a large amount of white solid.Continue the hydrochloric acid soln dripping 0.2mol/L in reaction solution, regulate pH to 2, product is separated out completely, stirs 5 minutes.Solid filtering is dried and obtains product phthalyl glycyl-L-glutamine 111.9g, yield 98.2%, HPLC purity 99.3%.
Embodiment 4:
Get 18g sheet alkali and 40g soda ash joins in 500mL water, and add 50gL-glutamine, stirring and dissolving, gained reaction soln is cooled to-8 DEG C.With the quick phthalyl glycyl chloride of the speed of 2.6g/s, control reaction soln temperature in the process at 9 ~ 10 DEG C.After dripping, stirring reaction 60 minutes.And in backward solution, slowly add the hydrochloric acid soln of 12N, regulate pH to 4, stir 9 minutes, separate out a large amount of white solid.Continue the hydrochloric acid soln dripping 0.2mol/L in reaction solution, regulate pH to 1.5, product is separated out completely, stirs 5 minutes.Solid filtering is dried and obtains product phthalyl glycyl-L-glutamine 113.2g, yield 99.3%, HPLC purity 99.5%.
Embodiment 5:
Get 16g sheet alkali and 40g soda ash joins in 500mL water, and add 50gL-glutamine, stirring and dissolving, gained reaction soln is cooled to-8 DEG C.With the quick phthalyl glycyl chloride of the speed of 2.5g/s, control reaction soln temperature in the process at 9 ~ 10 DEG C.After dripping, stirring reaction 60 minutes.And in backward solution, slowly add the sulphuric acid soln of 6mol/L, regulate pH to 4, stir 9 minutes, separate out a large amount of white solid.Continue the sulphuric acid soln dripping 0.1mol/L in reaction solution, regulate pH to 2, product is separated out completely, stirs 5 minutes.Solid filtering is dried and obtains product phthalyl glycyl-L-glutamine 113.0g, yield 99.1%, HPLC purity 99.4%.
Comparative example 1:
41g phthalyl glycine and 20.4g triethylamine are dissolved in the N of 350mL, in dinethylformamide, be cooled to-5 DEG C, then 24.6g isopropyl chlorocarbonate is added, the sodium hydrogen carbonate solution 250mL containing 29.2gL-glutamine of precooling is added after 25 minutes, withdraw cryosel bath after stirring reaction 2h, room temperature places 12h.Underpressure distillation, solids is water-soluble, and filter, filtrate uses 6N hcl acidifying, separates out phthalyl glycyl-L-glutamine, filters, and dries, solid 40.0g, yield 60.0%, HPLC purity 83.2%.
Comparative example 2:
In the mixed solution of 100mL water and 50mL toluene, add 8g sodium hydroxide and 30gL-glutamine, stirring and dissolving is also lowered the temperature.Drip the toluene solution of phthalyl glycyl chloride, drip the sodium hydroxide solution of 20%, control pH is 7 ~ 8 simultaneously.Treat that acyl chlorides drips the water-bath of recession deicing, natural temperature reaction 2h.After reaction terminates, separatory, water intaking layer, adds concentrated hydrochloric acid and regulates pH to 2 ~ 3, crystallize out, filter, dry and obtain solid 49.8g, yield 74.3%, HPLC purity 97.2%.
Table 1: the preparation method of various embodiments of the present invention and the contrast table of prior art
Visible, preparation method of the present invention compares with the prior art of comparative example 2 with comparative example 1, and its yield exceeds at least 14%, and its purity obtaining phthalyl glycyl-L-glutamine at least exceeds 2%.
Claims (6)
1. an environment-friendly preparation method thereof for phthalyl glycyl-L-glutamine, is characterized in that this preparation method comprises the steps:
A. in water, add mineral alkali and L-glutaminate and be cooled between-5 ~-12 DEG C, forming the aqueous solution; Described mineral alkali is selected from the one in sheet alkali, soda ash, or their any mixture;
B. fast drop phthalyl glycyl chloride in the aqueous solution of step a, rate of addition controls between 2.5 ~ 3 Grams Per Seconds, and controls temperature of reaction between 8 ~ 12 DEG C, makes it react as follows:
C. after question response terminates, add concentrated acid solution in the solution of step b, regulate between pH to 3 ~ 4, first time separates out white crystal;
D. in the solution of step c, add dilute acid soln, regulate between pH to 1.5 ~ 2, separate out white crystal further;
E. the white crystal that step c and d separates out is filtered, dry, obtain finished product.
2. the environment-friendly preparation method thereof of a kind of phthalyl glycyl-L-glutamine according to claim 1, is characterized in that: described mineral alkali is the mixture of sheet alkali and soda ash, and the consumption of described alkali and soda ash is 8 ~ 9:20 according to the ratio of mass ratio.
3. the environment-friendly preparation method thereof of a kind of phthalyl glycyl-L-glutamine according to claim 1, is characterized in that: the greenhouse cooling in described step a is extremely between-7 ~-8 DEG C.
4. the environment-friendly preparation method thereof of a kind of phthalyl glycyl-L-glutamine according to claim 1 or 2 or 3, is characterized in that: the temperature of reaction in described step b controls between 9 ~ 10 DEG C.
5. the environment-friendly preparation method thereof of a kind of phthalyl glycyl-L-glutamine according to claim 1 or 2 or 3, is characterized in that: the concentrated acid in described step c is concentrated hydrochloric acid or the 6mol/L sulphuric acid soln of 12mol/L.
6. the environment-friendly preparation method thereof of a kind of phthalyl glycyl-L-glutamine according to claim 1 or 2 or 3, is characterized in that: the diluted acid in described steps d is the dilute hydrochloric acid of 0.2mol/L or the dilution heat of sulfuric acid of 0.1mol/L.
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| CN104650178A (en) * | 2015-02-05 | 2015-05-27 | 南京理工大学 | Technical preparation method of glycyl glutamine |
| CN107857795A (en) * | 2017-11-16 | 2018-03-30 | 山东齐都药业有限公司 | The preparation method of glycylglutamine impurity |
| CN113929734B (en) * | 2021-09-22 | 2023-09-05 | 湖北泓肽生物科技有限公司 | Synthesis method of dipeptide-2 |
| CN114957384B (en) * | 2022-04-14 | 2023-11-14 | 湖北泓肽生物科技有限公司 | Synthesis method of dipeptide-4 |
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| US4082751A (en) * | 1976-02-13 | 1978-04-04 | Bristol-Myers Company | Therapeutic agents |
| SE9003844L (en) * | 1990-12-03 | 1992-06-04 | Kabi Pharmacia Ab | NAERINGSTILLSATS |
| JP3440129B2 (en) * | 1994-04-18 | 2003-08-25 | 協和醗酵工業株式会社 | Method for producing glutamine derivative |
| CN100343275C (en) * | 2003-03-19 | 2007-10-17 | 四川三高生化股份有限公司 | Process for preparing glycyl gtutamine |
| CN1298737C (en) * | 2004-12-08 | 2007-02-07 | 南京大学 | Synthesis method of dipeptide containing L-glutamine |
| CN1680428A (en) * | 2005-02-01 | 2005-10-12 | 上海依福瑞实业有限公司 | Preparation of alanyl glutamine dipeptide compound |
| CN101343313B (en) * | 2008-09-03 | 2011-11-16 | 南京农业大学 | Glucose dipeptide compounds, preparation method and application thereof |
| CN101747261B (en) * | 2008-12-16 | 2012-02-22 | 浙江东亚药业有限公司 | Method for preparing 4-[4-(1-piperidinyl) pyridine-2-O]-cis-2-butene-1-ol |
| CN102040651A (en) * | 2009-10-14 | 2011-05-04 | 北京和诚先锋医药技术有限公司 | Preparation method of phthaloyl-L-alanyl-L-glutamine |
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