CN103936824A - Green preparation method of phthalylglycyl-L-glutamine - Google Patents
Green preparation method of phthalylglycyl-L-glutamine Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 108010010147 glycylglutamine Proteins 0.000 claims abstract description 28
- 239000003513 alkali Substances 0.000 claims abstract description 20
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims description 32
- -1 phthalyl glycyl-L-glutamine Chemical compound 0.000 claims description 29
- 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
- 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 description 14
- 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
- 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
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 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 3
- 238000010790 dilution Methods 0.000 claims description 2
- 239000012895 dilution Substances 0.000 claims description 2
- 230000004044 response Effects 0.000 claims description 2
- 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 6
- 238000001914 filtration Methods 0.000 abstract description 6
- 239000003960 organic solvent Substances 0.000 abstract description 4
- 239000002699 waste material Substances 0.000 abstract description 4
- 239000007788 liquid Substances 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 1
- 229930182816 L-glutamine Natural products 0.000 abstract 1
- 229910052801 chlorine Inorganic materials 0.000 abstract 1
- 239000000460 chlorine Substances 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- 238000003912 environmental pollution Methods 0.000 abstract 1
- 238000009776 industrial production 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 Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 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
- 238000004519 manufacturing process Methods 0.000 description 4
- 231100000614 poison Toxicity 0.000 description 4
- 230000007096 poisonous effect Effects 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
- 239000003814 drug Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
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- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 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
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical class ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 206010021460 Immunodeficiency syndromes Diseases 0.000 description 1
- UEPMMHVOZBNPTE-CVYQJGLWSA-N N[C@@]1([C@H](CC(N)=O)C1)C(O)=O Chemical compound N[C@@]1([C@H](CC(N)=O)C1)C(O)=O UEPMMHVOZBNPTE-CVYQJGLWSA-N 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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- 239000012670 alkaline solution Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
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- 229910052799 carbon Inorganic materials 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 231100001261 hazardous Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 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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- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003871 intestinal function Effects 0.000 description 1
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- 238000003032 molecular docking Methods 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 235000016236 parenteral nutrition Nutrition 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000011003 system suitability test Methods 0.000 description 1
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- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a green preparation method of phthalylglycyl-L-glutamine, which comprises the following steps: reacting raw materials phthalylglycyl chlorine and L-glutamine in an inorganic alkali water solution, acidifying twice, crystallizing, filtering and drying to obtain the product. The preparation method has the advantages of accessible raw materials, high product yield and high product purity, is simple to operate, avoids using toxic and harmful organic solvents, effectively lowers the emissions of waste water, waste liquid and waste gas in industrial production, and reduces the environmental pollution. The high-purity phthalylglycyl-L-glutamine prepared by the method provides a reliable raw material for further synthesizing ultrahigh-purity glycyl glutamine, thereby effectively lowering the clinical side effect of the glycyl glutamine preparation.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of phthalyl glycyl-L-glutamine environment-friendly preparation method thereof.
Background technology
Glycylglutamine is called again 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, can effectively strengthen patient's cellular immune function, reduces the infected risk of patient.Therefore, be widely used in because treatment intestinal function is complete, severe infections, burn, immunodeficiency syndromes 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, by L-Ala and glutamine, form glutamine dipeptide, using the preparation that is prepared into as the donor of glutamine, by intravenous mode, meet patient's demand.This pair of peptide decomposes the amino acid that discharges and is stored in separately the corresponding site of health and need to carries out metabolism with body as nutritive substance.
The preparation method of multiple glycylglutamine is disclosed at present, both at home and abroad.
Zhang Zhe etc. have proposed a kind of toluene solution and sodium hydroxide solution that simultaneously drips phthalyl glycyl chloride in the inorganic base aqueous solution of L-glutaminate, and docking makes phthalyl glycyl-L-glutamine; Then in hydrazine hydrate, react, acidifying obtains product.The method is used mixed solvent and is belonged to inhomogeneous reaction, can hinder to a certain extent collision mutually between reaction raw materials, thereby reduce yield.Toluene belongs to poisonous strong carcinogen in addition, and environment and human body are all had to larger toxic action; Two droppings in simultaneous reactions process also improved equipment investment (chemical reagent, 2011,33 (2), 177-178).
Chinese patent CN1680428A uses phthalyl glycine and L-glutaminate as raw material, under the existence of Acibenzolar isopropyl chlorocarbonate, reacts, and finally utilizes underpressure distillation to separate product, makes phthalyl glycyl glutamy, yield 58%.The method isopropyl chlorocarbonate used belongs to highly toxic substance, and environment and operator are had to very big harm, so to equipment and personnel, requires very high in suitability for industrialized production.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 to provide a kind of phthalyl glycyl-L-glutamine preparation method of environmental protection, adopt that this preparation method is simple to operate and cost is low, be easy to suitability for industrialized production, synthetic phthalyl glycyl-L-glutamine impurity is few, purity is high, can be applied in well field of medicaments, 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 ℃, forming the aqueous solution; Described mineral alkali is selected from a kind of in sheet alkali, soda ash or their any mixture;
B. in the aqueous solution of step a, drip fast phthalyl glycyl chloride, rate of addition is controlled between 2.5～3 Grams Per Seconds, and controls temperature of reaction between 8～12 ℃, and it is reacted as follows:
C. after question response finishes, in the solution of step b, add concentrated acid solution, regulate between pH to 3～4, separate out for the first time white crystal;
D. in the solution of step c, add dilute acid soln, regulate between pH to 1.5～2, further separate out white crystal;
The white crystal of e. step c and d being separated out filters, and dries, and obtains finished product.
Scheme as a further improvement on the present invention, described mineral alkali is that mixture and its consumption of sheet alkali and soda ash is 8～9:20 according to the ratio of mass ratio, adopt the mineral alkali of this ratio, the yield of phthalyl-Ala-Gln that it obtains is all more than 98%, and purity is not less than 99%.
Further, being cooled to-5～-12 ℃ and being preferably below between cooling most-7～-8 ℃ in described step a.
Temperature of reaction in described step b is preferably controlled between 9～10 ℃.
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 be take phthalyl glycyl chloride as raw material, in the aqueous solution without any organic solvent, react with L-glutaminate and produce phthalyl glycyl-L-glutamine, through acidifying, filter, dry and obtain high-purity o phenyl-diformyl-Ala-Gln.Its beneficial effect shows:
One, with the phthalyl glycyl chloride that is simple and easy to produce, be that raw material replaces the hazardous and noxious substances such as triphenylphosphine, hexachloroethane, triphenylphosphinc oxide, triphosgene, from raw material, got rid of the possibility of these materials being introduced to product, pollution-free, simultaneously also reduced to a great extent the input of equipment and personal security aspect in suitability for industrialized production.
Two, use mineral alkali more cheaply, as sheet alkali, soda ash or its mixed base replace original potassium hydroxide, thereby avoided the use of the organic solvents such as toluene, preparation process can be carried out completely in water.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 as reaction single solvent in the present invention for the high yield high purity of product provides best assurance.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, further turns down reaction solution pH, promotes phthalyl glycyl-L-glutamy chloramines crystal to separate out completely.The method that two steps are separated out, not only need not drop into expensive equipment and numerous manpower, and only need just can obtain the highly purified product of high yield with simple filter operation.
Four, in preparation process, do not use the two of phthalyl glycyl chloride and alkaline solution and drip, the only just single dropping of phthalyl glycyl chloride, this improvement simplified apparatus greatly in suitability for industrialized production, reduces and drops into.
In view of the impact of Dipeptiven purity on its activity, the phthalyl glycyl-L-glutamine that the inventive method obtains provides a kind of reliable raw material for further synthesizing the Dipeptiven of ultra-high purity.
The present invention has fundamentally solved at present and has produced both at home and abroad in Dipeptiven process, uses poisonous and harmful, expensive raw material and solvent, and complicated operation, the difficult problem that product yield is low, avoided a series of clinical adverse that cause because impurity is more.
Embodiment
HPLC measures the purity of phthalyl glycine-L-glutaminate.
According to high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2010), measure
Chromatographic condition and system suitability test: with nh 2 column C18, measure, potassium phosphate buffer (with phosphorus acid for adjusting pH to the 3.8)-acetonitrile (40:60) of take is moving phase; Detection 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 50g L-glutaminate, stirring and dissolving, is cooled to-7 ℃ by gained reaction soln, forms solution.Speed with 2.5g/s drips phthalyl glycyl chloride fast, controls reaction soln temperature in this process between 9～10 ℃.After dripping, stirring reaction 60 minutes.And in backward solution, slowly add the hydrochloric acid soln of 12mol/L, and regulate pH to 4, stir 9 minutes, separate out a large amount of white solids.Continuation, to the hydrochloric acid soln that drips 0.2mol/L in reaction solution, regulates pH to 1.5, and product is separated out completely, stirs 5 minutes.Solid filtering is dried and obtained product phthalyl glycyl-L-glutamine 111.9g, and yield 98.2%, measures its phthalyl glycyl-L-glutamine purity 99.1% according to high performance liquid chromatography (HPLC).
Embodiment 2:
Get 16g sheet alkali and 40g soda ash joins in 500mL water, and add 50g L-glutaminate, stirring and dissolving, is cooled to-8 ℃ by gained reaction soln, forms solution.With the quick phthalyl glycyl chloride of speed of 2.8g/s, in this process, control reaction soln temperature between 9～10 ℃.After dripping, stirring reaction 60 minutes.And in backward solution, slowly add the hydrochloric acid soln of 12mol/L, and regulate pH to 3, stir 9 minutes, separate out a large amount of white solids.Continuation, to the hydrochloric acid soln that drips 0.2mol/L in reaction solution, regulates pH to 1.5, and product is separated out completely, stirs 5 minutes.Solid filtering is dried and obtained 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 50g L-glutaminate, stirring and dissolving, is cooled to-7 ℃ by gained reaction soln.With the quick phthalyl glycyl chloride of speed of 2.8g/s, in this process, control reaction soln temperature between 9～10 ℃.After dripping, stirring reaction 60 minutes.And in backward solution, slowly add the sulphuric acid soln of 6N, and regulate pH to 3, stir 9 minutes, separate out a large amount of white solids.Continuation, to the hydrochloric acid soln that drips 0.2mol/L in reaction solution, regulates pH to 2, and product is separated out completely, stirs 5 minutes.Solid filtering is dried and obtained 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 50g L-glutaminate, stirring and dissolving, is cooled to-8 ℃ by gained reaction soln.With the quick phthalyl glycyl chloride of speed of 2.6g/s, in this process, control reaction soln temperature at 9～10 ℃.After dripping, stirring reaction 60 minutes.And in backward solution, slowly add the hydrochloric acid soln of 12N, and regulate pH to 4, stir 9 minutes, separate out a large amount of white solids.Continuation, to the hydrochloric acid soln that drips 0.2mol/L in reaction solution, regulates pH to 1.5, and product is separated out completely, stirs 5 minutes.Solid filtering is dried and obtained 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 50g L-glutaminate, stirring and dissolving, is cooled to-8 ℃ by gained reaction soln.With the quick phthalyl glycyl chloride of speed of 2.5g/s, in this process, control reaction soln temperature at 9～10 ℃.After dripping, stirring reaction 60 minutes.And in backward solution, slowly add the sulphuric acid soln of 6mol/L, and regulate pH to 4, stir 9 minutes, separate out a large amount of white solids.Continuation, to the sulphuric acid soln that drips 0.1mol/L in reaction solution, regulates pH to 2, and product is separated out completely, stirs 5 minutes.Solid filtering is dried and obtained 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 to the N of 350mL, in dinethylformamide, be cooled to-5 ℃, then add 24.6g isopropyl chlorocarbonate, the sodium hydrogen carbonate solution 250mL that contains 29.2g L-glutaminate that adds precooling after 25 minutes, after stirring reaction 2h, withdraw cryosel and bathe, room temperature is placed 12h.Underpressure distillation, solids is water-soluble, filters, filtrate use 6N hcl acidifying, separates out phthalyl glycyl-L-glutamine, filter, oven dry, 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 30g L-glutaminate, stirring and dissolving cooling.The toluene solution that drips phthalyl glycyl chloride drips 20% sodium hydroxide solution simultaneously, controls pH 7～8.Treat that acyl chlorides drips the water-bath of recession deicing, natural temperature reaction 2h.After reaction finishes, separatory, water intaking layer, adds concentrated hydrochloric acid to regulate pH to 2～3, and crystallize out, filters, and dries and obtains 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 1 with comparative example 2, and its yield exceeds at least 14%, and its purity that obtains 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 ℃, forming the aqueous solution; Described mineral alkali is selected from a kind of in sheet alkali, soda ash or their any mixture;
B. in the aqueous solution of step a, drip fast phthalyl glycyl chloride, rate of addition is controlled between 2.5～3 Grams Per Seconds, and controls temperature of reaction between 8～12 ℃, and it is reacted as follows:
C. after question response finishes, in the solution of step b, add concentrated acid solution, regulate between pH to 3～4, separate out for the first time white crystal;
D. in the solution of step c, add dilute acid soln, regulate between pH to 1.5～2, further separate out white crystal;
The white crystal of e. step c and d being separated out filters, and dries, and obtains 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 ℃.
4. according to the environment-friendly preparation method thereof of a kind of phthalyl glycyl-L-glutamine described in claim 1 or 2 or 3, it is characterized in that: the temperature of reaction in described step b is controlled between 9～10 ℃.
5. according to the environment-friendly preparation method thereof of a kind of phthalyl glycyl-L-glutamine described in claim 1 or 2 or 3, it is characterized in that: the concentrated hydrochloric acid that the concentrated acid in described step c is 12mol/L or 6mol/L sulphuric acid soln.
6. according to the environment-friendly preparation method thereof of a kind of phthalyl glycyl-L-glutamine described in claim 1 or 2 or 3, it is characterized in that: the dilute hydrochloric acid that the diluted acid in described steps d is 0.2mol/L or the dilution heat of sulfuric acid of 0.1mol/L.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| CN113929734A (en) * | 2021-09-22 | 2022-01-14 | 湖北泓肽生物科技有限公司 | Method for synthesizing dipeptide-2 |
| CN114957384A (en) * | 2022-04-14 | 2022-08-30 | 湖北泓肽生物科技有限公司 | Synthesis method of dipeptide-4 |
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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 |
| CN113929734A (en) * | 2021-09-22 | 2022-01-14 | 湖北泓肽生物科技有限公司 | Method for synthesizing dipeptide-2 |
| 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 |
| CN114957384A (en) * | 2022-04-14 | 2022-08-30 | 湖北泓肽生物科技有限公司 | Synthesis method of dipeptide-4 |
| 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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