CN112480208B - Industrial preparation method of glycyl-L-glutamine - Google Patents
Industrial preparation method of glycyl-L-glutamine Download PDFInfo
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- PNMUAGGSDZXTHX-BYPYZUCNSA-N Gly-Gln Chemical compound NCC(=O)N[C@H](C(O)=O)CCC(N)=O PNMUAGGSDZXTHX-BYPYZUCNSA-N 0.000 title claims abstract description 68
- 108010010147 glycylglutamine Proteins 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 86
- 239000012043 crude product Substances 0.000 claims abstract description 34
- 239000007864 aqueous solution Substances 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 28
- 238000001914 filtration Methods 0.000 claims abstract description 23
- LCHLONXFHVEQSU-BYPYZUCNSA-N (2s)-5-amino-2-[(2-chloroacetyl)amino]-5-oxopentanoic acid Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)CCl LCHLONXFHVEQSU-BYPYZUCNSA-N 0.000 claims abstract description 22
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims abstract description 21
- 239000000047 product Substances 0.000 claims abstract description 20
- 229930182816 L-glutamine Natural products 0.000 claims abstract description 19
- 238000002425 crystallisation Methods 0.000 claims abstract description 18
- 239000011347 resin Substances 0.000 claims abstract description 18
- 229920005989 resin Polymers 0.000 claims abstract description 18
- 230000008025 crystallization Effects 0.000 claims abstract description 17
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000000909 electrodialysis Methods 0.000 claims abstract description 15
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000005915 ammonolysis reaction Methods 0.000 claims abstract description 14
- 238000001035 drying Methods 0.000 claims abstract description 9
- 238000009776 industrial production Methods 0.000 claims abstract description 9
- 238000005917 acylation reaction Methods 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 72
- 238000003756 stirring Methods 0.000 claims description 56
- 239000008213 purified water Substances 0.000 claims description 46
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 238000005406 washing Methods 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 238000010438 heat treatment Methods 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 19
- 239000013505 freshwater Substances 0.000 claims description 18
- 239000000706 filtrate Substances 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000012528 membrane Substances 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 239000003014 ion exchange membrane Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 238000001471 micro-filtration Methods 0.000 claims description 6
- 238000007670 refining Methods 0.000 claims description 6
- 238000005516 engineering process Methods 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 238000004321 preservation Methods 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 3
- YIPWKFBLGUQCJW-UHFFFAOYSA-N CC1=CC=CC=C1.ClCC(=O)Cl Chemical compound CC1=CC=CC=C1.ClCC(=O)Cl YIPWKFBLGUQCJW-UHFFFAOYSA-N 0.000 claims 1
- 108010016626 Dipeptides Proteins 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 7
- 239000002699 waste material Substances 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 238000011112 process operation Methods 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 239000012065 filter cake Substances 0.000 description 6
- 238000005191 phase separation Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- QWNVNPSFHISUID-UHFFFAOYSA-N 2-chloro-4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C(Cl)=C1 QWNVNPSFHISUID-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- CJUMAFVKTCBCJK-UHFFFAOYSA-M N-benzyloxycarbonylglycinate Chemical compound [O-]C(=O)CNC(=O)OCC1=CC=CC=C1 CJUMAFVKTCBCJK-UHFFFAOYSA-M 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 2
- -1 compound amino acid Chemical class 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 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
- WQINSVOOIJDOLJ-UHFFFAOYSA-N 2-(1,3-dioxoisoindol-2-yl)acetic acid Chemical compound C1=CC=C2C(=O)N(CC(=O)O)C(=O)C2=C1 WQINSVOOIJDOLJ-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 238000006698 hydrazinolysis reaction Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002608 ionic liquid Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- BJQWBACJIAKDTJ-UHFFFAOYSA-N tetrabutylphosphanium Chemical compound CCCC[P+](CCCC)(CCCC)CCCC BJQWBACJIAKDTJ-UHFFFAOYSA-N 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a glycyl-L-glutamine industrial preparation method, which belongs to the technical field of organic synthesis, and comprises the steps of firstly carrying out acylation reaction on chloroacetyl chloride and L-glutamine under low temperature and alkaline conditions, carrying out phase splitting to obtain an N-chloroacetyl-L-glutamine aqueous solution, then treating the aqueous solution by electrodialysis, introducing ammonia gas into the aqueous solution obtained by treatment to carry out ammonolysis under pressure, and carrying out concentration, crystallization, filtration and drying to obtain a glycyl-L-glutamine crude product; finally dissolving the crude glycyl-L-glutamine in water, purifying by WA-30 resin, and crystallizing to obtain the high-purity glycyl-L-glutamine. The invention improves the yield and quality of the product, simplifies the process steps, realizes the preparation of the dipeptide crude product by a one-pot method, generates less industrial three wastes, has simple and convenient process operation, is suitable for large-scale industrial production, and can meet the requirement of injection-grade raw materials on the quality of the prepared glycyl-L-glutamine product.
Description
Technical Field
The invention relates to an industrial preparation method of glycyl-L-glutamine, belonging to the technical field of organic synthesis.
Background
Glycyl-L-glutamine (Glycyl-L-glutamine) belongs to artificially synthesized dipeptide amino acid, and is one of main components of compound amino acid (15) dipeptide (2) injection. glycyl-L-glutamine is mainly used to provide glutamine to promote protein synthesis. Compared with L-glutamine, the water solubility and the heat stability of the glutamine are better. glycyl-L-glutamine is used as a carrier for transporting nitrogen sources in vivo, can remove metabolic wastes such as ammonia and the like, provides nitrogen sources for the synthesis of proteins and DNA, and plays a very important role in the stability of proteins in cells. With the rapid development of medical technology, the application of polypeptide amino acids in clinic is increasing.
At present, glycyl-L-glutamine is prepared mainly by the following methods:
1. n-benzyloxycarbonyl glycine and L-glutamine are taken as starting materials, the N-benzyloxycarbonyl glycine and N-Hydroxysuccinimide (HOSU) are firstly prepared into active ester under the action of N, N-Dicyclohexylcarbodiimide (DCC), then the active ester and the L-glutamine are condensed to produce a dipeptide intermediate with a protecting group, and finally the dipeptide intermediate is subjected to palladium catalytic hydrogenation and deprotection to prepare a product (EP1050317B1, 1994). The raw materials and the catalyst used in the method are expensive, the material cost is high, the used DCC is difficult to remove, the high-purity product is difficult to prepare, and the requirement of palladium-carbon hydrogenation reaction equipment is strict.
2. Phthalic anhydride and glycine are prepared into phthaloyl glycine in a molten state, then the phthalic anhydride and the glycine are condensed by adopting an active ester or mixed anhydride method, and then hydrazinolysis is carried out to obtain a final product (CN 200410066112, 2004). The method has the problems of complicated process route and high production cost, and triethylamine, hydrazine hydrate and various organic compounds are difficult to treat, thus being not beneficial to environmental protection.
3. WO2012014809 (A1) discloses a novel synthesis method of dipeptide amino acids, which comprises the synthesis of Gly-Gln, mixing L-glutamine and tetrabutyl phosphine oxide solution, heating under reduced pressure to evaporate water, performing dehydration condensation to prepare L-glutamine ionic liquid (L-Gln-TBP), and adding glycine methyl ester hydrochloride into L-Gln-TBP to form Gly-Gln. The method has simple process, avoids using various organic reagents, but is immature, has low yield and cannot realize industrial production.
4. Chloroacetyl chloride is used as a starting material and reacts with L-glutamine for acylation reaction to prepare a crude product of the N-chloroacetyl-L-glutamine, the intermediate is refined, and ammonia water and ammonium carbonate are used as ammonolysis agents to react to prepare the product (EP 0678501, 1997). In the first step of preparing the chloroacetyl-L-glutamine, the crystalline solid particles are fine, so that the crystalline system is viscous, water is difficult to filter, and the drying is easy to melt; and in the second step, ammonolysis reaction is carried out in ammonia water, the ammonia activity is low, the reaction time is long, the generation of hydrolysis impurity glycyl-L-glutamic acid is difficult to control, a large amount of ammonium salt is introduced, and the recovery energy consumption is high. Although the raw materials are cheap and easy to obtain, the method has the advantages of low total yield of the process, more industrial three wastes, complicated production procedures and longer production period.
Disclosure of Invention
The invention aims to provide an industrial preparation method of glycyl-L-glutamine, which has the advantages of cheap and easily obtained raw materials, simple process operation, single type of used organic solvent, easy recovery and reutilization, environmental protection, high purity of obtained products, capability of meeting the requirements of injection-grade raw materials and suitability for industrial production.
In order to achieve the purpose, the invention adopts the technical scheme that:
an industrialized preparation method of glycyl-L-glutamine comprises the steps of firstly carrying out acylation reaction on chloroacetyl chloride and L-glutamine under low temperature and alkaline conditions, carrying out phase splitting to obtain an N-chloroacetyl-L-glutamine aqueous solution, then treating the N-chloroacetyl-L-glutamine aqueous solution by adopting an electrodialysis membrane separation technology, introducing ammonia gas into the treated N-chloroacetyl-L-glutamine aqueous solution to carry out ammonolysis under pressure, and concentrating, crystallizing, filtering and drying to obtain a glycyl-L-glutamine crude product; finally dissolving the crude glycyl-L-glutamine in water, purifying by WA-30 resin, and crystallizing to obtain high-purity glycyl-L-glutamine, wherein the specific reaction formula is as follows:
the technical scheme of the invention is further improved in that the method comprises the following steps:
(1) Preparation of a glycyl-L-glutamine crude product: adding L-glutamine into a mixed solvent of purified water and toluene, simultaneously dropwise adding a toluene solution of chloroacetyl chloride and alkaline water under low-temperature stirring, controlling the pH of a reaction mixture in the dropwise adding process, continuously stirring for acylation reaction after dropwise adding is finished, standing for 0.5h after the reaction is finished, carrying out phase separation, adjusting the pH of an obtained water phase with acid, carrying out electrodialysis treatment, and controlling the conductivity of fresh water to be lower than 10ms/cm as an end point to obtain an N-chloroacetyl-L-glutamine aqueous solution; adding an organic solvent into the aqueous solution of N-chloroacetyl-L-glutamine, introducing ammonia gas, carrying out ammonolysis reaction under pressure for 2-3 h at a certain temperature, concentrating under reduced pressure until no moisture is evaporated after the reaction is finished, adding purified water into the remainder, heating to 55 ℃, stirring completely, slowly adding the organic solvent in a flowing manner, continuing to keep warm and stir for 0.5h after the adding in the flowing manner is finished, cooling to 20-25 ℃ for crystallization, keeping warm and stirring for 3-4 h, centrifuging, filtering and washing after the crystallization reaction is finished to obtain a wet product, and carrying out vacuum drying on the obtained wet product to obtain a crude product of glycyl-L-glutamine;
(2) Refining a glycyl-L-glutamine crude product: dissolving the glycyl-L-glutamine crude product obtained in the step (1) in purified water, adding WA-30 resin after dissolving, stirring for 2-3 h at room temperature, filtering and recovering the resin, concentrating the obtained filtrate under reduced pressure to be dry, adding purified water to the remainder for dissolving, performing microfiltration after completely dissolving, adding purified water to wash a container and a pipeline after filtering, combining the washing solution with the filtrate after microfiltration of washing water, stirring and heating to 40-45 ℃, adding an organic solvent in a flowing manner, performing heat preservation stirring for 20min after the end of the flowing addition, cooling to 20-25 ℃, performing heat preservation stirring for crystallization reaction for 1h, centrifuging, filtering and washing after the completion of the crystallization reaction to obtain a wet product, and performing vacuum drying on the wet product to obtain the glycyl-L-glutamine with high purity.
The technical scheme of the invention is further improved as follows: the molar ratio of L-glutamine to chloroacetyl chloride in the step (1) is 1.05-1.
The technical scheme of the invention is further improved as follows: the alkaline water in the step (1) is NaOH aqueous solution, the temperature is controlled to be 8-12 ℃ when the toluene solution of chloracetyl chloride and the alkaline water are dripped, and the pH of the reaction mixture in the dripping process is controlled to be 10.0-11.0; the temperature of the acylation reaction is 0-5 ℃, and the time is 0.5-1 h.
The technical scheme of the invention is further improved as follows: the acid used for adjusting the pH value in the step (1) is hydrochloric acid or sulfuric acid, and the concentration of the acid solution is 0.5-3 mol/L; the electrodialysis treatment uses a homogeneous phase ion exchange membrane, and the pH value of the fresh water is controlled to be 7.5-8.0.
The technical scheme of the invention is further improved as follows: the organic solvent added into the N-chloroacetyl-L-glutamine aqueous solution in the step (1) is one of dimethyl sulfoxide, N-dimethylformamide, N-dimethyl-2-imidazolidinone and N-methylpyrrolidone, and the dosage of the organic solvent is 1/20 of the weight of the N-chloroacetyl-L-glutamine aqueous solution.
The technical scheme of the invention is further improved as follows: the ammonolysis reaction pressure in the step (1) is 0.6-0.8 Mpa, and the reaction temperature is 38-42 ℃.
The technical scheme of the invention is further improved as follows: in the step (1), purified water with the mass 1.5-2.0 times of that of the remainder is added into the remainder, the crystallization organic solvent is methanol, and the volume ratio of the purified water to the methanol is 1.
The technical scheme of the invention is further improved as follows: the amount of purified water for dissolving the glycyl-L-glutamine crude product in the step (2) is 10 times of the mass of the glycyl-L-glutamine crude product; the dosage of the WA-30 resin is 3.0 to 4.0 times of the mass of the glycyl-L-glutamine crude product.
The technical scheme of the invention is further improved as follows: the total consumption of the purified water and the purified water washing liquid of the dissolving remainder in the step (2) is 3 times of the mass of the crude glycyl-L-glutamine product; the crystallization organic solvent is methanol, and the ratio of the amount of the methanol to the total volume of the purified water is 2.
Due to the adoption of the technical scheme, the invention has the following technical effects:
the preparation method adopts an electrodialysis membrane separation technology, improves the yield and quality of the product by combining with WA-30 resin purification, simplifies the process steps, realizes the preparation of the dipeptide crude product by a one-pot method, generates less industrial three wastes, has simple and convenient process operation, is suitable for large-scale industrial production, and can prepare the glycyl-L-glutamine product with high quality and meet the requirements of injection-grade raw materials.
The main raw materials used in the invention, such as chloracetyl chloride, L-glutamine and the like, have low price and are easy to be obtained commercially.
The method adopts an electrodialysis membrane separation technology to prepare the N-chloroacetyl-L-glutamine aqueous solution with higher purity, avoids the problems that the solid N-chloroacetyl-L-glutamine prepared by a crystallization method is difficult to filter, dry and easy to melt and the like, reduces material loss caused by intermediate preparation by simplified treatment operation, and has higher total yield, lower production cost and environmental friendliness.
According to the invention, ammonia gas is introduced to carry out pressurized ammonolysis, so that the reaction efficiency is improved, and compared with an ammonia ammonolysis method, the generation of a large amount of ammonium salt and waste liquid is reduced; an aprotic polar solvent is introduced, the ammonolysis reaction activity is improved, the generation of a hydrolyzed impurity glycyl-L-glutamic acid can be effectively controlled, the subsequent purification difficulty is reduced, and the crude product quality is improved.
Detailed Description
The invention is further illustrated in detail below with reference to specific examples:
an industrial preparation method of glycyl-L-glutamine comprises the following steps:
(1) Preparation of glycyl-L-glutamine crude product
Adding L-glutamine into a mixed solvent of purified water and toluene, simultaneously dropwise adding a toluene solution of chloroacetyl chloride and alkaline water under low-temperature stirring, wherein the molar ratio of the L-glutamine to the chloroacetyl chloride is 1.05-1.50, the alkaline water is a NaOH aqueous solution, the pH of the reaction mixture is controlled to be 10.0-11.0 in the dropwise adding process, the temperature is 8-12 ℃, and after the dropwise adding is finished, cooling to 0-5 ℃ and continuously stirring for acylation reaction for 0.5-1 h. And after the reaction is finished and the solution is kept stand for 0.5h, phase separation is carried out, the pH of the obtained water phase is adjusted to 7.5-8.0 by using 0.5-3 mol/L hydrochloric acid or sulfuric acid, and then electrodialysis treatment is carried out, wherein the membrane used in the electrodialysis treatment is a homogeneous phase ion exchange membrane, the pH of fresh water is controlled to be 7.5-8.0, and the conductivity of the fresh water is controlled to be lower than 10ms/cm to be used as an end point, so that the N-chloroacetyl-L-glutamine aqueous solution is obtained.
Adding one of dimethyl sulfoxide, N-dimethylformamide, N-dimethyl-2-imidazolidinone and N-methylpyrrolidone into the N-chloroacetyl-L-glutamine aqueous solution obtained by electrodialysis treatment, introducing ammonia gas, and carrying out pressure ammonolysis reaction for 2-3 h at 38-42 ℃, wherein the pressure of the ammonolysis reaction is 0.6-0.8 Mpa. Concentrating under reduced pressure (the water bath temperature is 60-65 ℃, the vacuum degree is less than or equal to-0.09 Mpa) after the reaction is finished until no moisture is evaporated, adding purified water with the mass of 1.5-2.0 times of that of the remainder into the remainder, heating to 55 ℃, stirring completely, slowly adding methanol in a flowing manner, wherein the volume ratio of the methanol to the purified water is 2.
(2) Refining of glycyl-L-glutamine crude product
Dissolving the glycyl-L-glutamine crude product obtained in the step (1) in purified water with the mass 10 times of that of the glycyl-L-glutamine crude product, adding WA-30 resin with the mass 3.0-4.0 times of that of the glycyl-L-glutamine crude product after the dissolution is clear, stirring at room temperature for 2-3 h, filtering and recovering the resin, concentrating the obtained filtrate under reduced pressure (the water bath temperature is 60-65 ℃, the vacuum degree is less than or equal to-0.09 Mpa) until the filtrate is dry, adding the purified water into the remainder for dissolution, carrying out microfiltration after the complete dissolution is clear, adding purified water washing liquid for washing a container and a pipeline, combining the purified water and the purified water washing liquid with the mass 3 times of that of the glycyl-L-glutamine crude product after the microfiltration, stirring and heating to 40-45 ℃, adding methanol in a flowing mode, wherein the ratio of the methanol amount to the total volume of the purified water is 2.
Example 1
(1) Preparation of glycyl-L-glutamine crude product
Adding 7.5kg of purified water and 1.9kg of toluene into a reaction kettle, adding 3.0kg of L-glutamine under stirring, cooling to 10 ℃, dropwise adding a prepared sodium hydroxide solution (5 mol/L, about 1.3L) under stirring, keeping the temperature at 8-12 ℃, dropwise adding a mixed solution of 2.48kg of chloroacetyl chloride and 1.6kg of toluene, and dropwise adding a sodium hydroxide solution (5 mol/L) at the same time, and controlling the pH of a reaction mixture to be 10.0-11.0. After the dropwise addition, the temperature is reduced to 0-5 ℃, the stirring is continued for 0.5h, the standing is carried out for 0.5h, the phase separation is carried out, the toluene is recovered, the pH of the water phase is adjusted to 7.5-8.0 by 0.5mol/L hydrochloric acid, the water phase is added into a fresh water chamber of an electrodialysis device, equal volume water is added into a concentrated water chamber, 100 pairs of homogeneous phase ion exchange membranes are used, the voltage is controlled not to exceed 100V, the pH of the fresh water is controlled to 7.5-8.0, and the conductivity of the fresh water is controlled to be lower than 10ms/cm to be used as an end point, so that the N-chloroacetyl-L-glutamine aqueous solution in the fresh water chamber is obtained.
Adding the N-chloroacetyl-L-glutamine aqueous solution (23.5 kg) prepared in the previous step into a high-pressure reaction kettle, adding 1.18kgN and N-dimethylformamide, introducing ammonia gas to the pressure of 0.6-0.8 Mpa, slowly heating to 38-42 ℃, keeping the temperature and pressure and stirring for 2h, concentrating under reduced pressure (vacuum is less than or equal to-0.09 Mpa), heating in a water bath at the temperature of 60-65 ℃, concentrating until no moisture is evaporated, adding 6L of purified water, heating to 55 ℃, stirring until the purified water is completely dissolved, slowly adding 12L of methanol, continuously stirring for 0.5h, cooling to 20-25 ℃, precipitating a large amount of crystals, keeping the temperature and stirring for 3h, centrifugally filtering, washing a filter cake twice with a small amount of methanol, and drying in vacuum at the temperature of 60-65 ℃ to obtain the glycyl-L-glutamine crude product of 3.1kg, wherein the molar yield is 74%, and the purity is 98.8%.
(2) Refining of glycyl-L-glutamine crude product
Dissolving 3.0kg of crude glycyl-L-glutamyl in 30L of purified water, adding 10.0kg of WA-30 resin, stirring for 2h at room temperature, filtering and recovering the resin, concentrating the filtrate under reduced pressure (vacuum is less than or equal to-0.09 Mpa), concentrating at the water bath temperature of 60-65 ℃, adding 8L of purified water until the filtrate is nearly anhydrous, completely dissolving, filtering through a 0.22 mu m microporous filter membrane, washing the tank wall and a pipeline filter membrane with 1L of purified water, merging the filtrate and the washing solution, adding the filtrate into a crystallization tank, stirring and heating to 40-45 ℃, slowly adding 18L of methanol, stirring for 20min at a constant temperature, cooling to 20-25 ℃, stirring for 1h at the constant temperature, centrifugally filtering, washing the filter cake twice with a small amount of methanol, and drying at the temperature of 60-65 ℃ in vacuum until the water content is 7.0-10.0%, thus obtaining 2.59kg of refined glycyl-L-glutamine with the molar yield of 86.3%.
Example 2
(1) Preparation of glycyl-L-glutamine crude product
Adding 6.25kg of purified water and 1.6kg of toluene into a reaction kettle, adding 2.5kg of L-glutamine under stirring, cooling to 9 ℃, dropwise adding a prepared sodium hydroxide solution (5 mol/L, about 1.1L) under stirring, keeping the temperature at 8-12 ℃, dropwise adding a mixed solution of 2.89kg of chloroacetyl chloride and 1.9kg of toluene, and dropwise adding a sodium hydroxide solution (5 mol/L) at the same time, and controlling the pH of a reaction mixture to be 10.0-11.0. After the dropwise addition, the temperature is reduced to 0-5 ℃, the stirring is continued for 0.5h, the standing is carried out for 0.5h, the phase separation is carried out, the toluene is recovered, the pH of the water phase is adjusted to 7.5-8.0 by 0.5mol/L sulfuric acid, the water phase is added into a fresh water chamber of an electrodialysis device, equal volume water is added into a concentrated water chamber, 100 pairs of homogeneous phase ion exchange membranes are used, the voltage is controlled not to exceed 100V, the pH of the fresh water is controlled to 7.5-8.0, and the conductivity of the fresh water is controlled to be lower than 10ms/cm to be used as an end point, so that the N-chloroacetyl-L-glutamine aqueous solution in the fresh water chamber is obtained.
Adding the N-chloroacetyl-L-glutamine aqueous solution (19.2 kg) prepared in the previous step and 0.96kg of dimethyl sulfoxide into a high-pressure reaction kettle, introducing ammonia gas until the pressure is 0.6-0.8 Mpa, slowly heating to 38-42 ℃, keeping the temperature and pressure and stirring for 2h, reducing the pressure (the vacuum is less than or equal to-0.09 Mpa), concentrating, heating the water bath to 60-65 ℃, concentrating until no water is evaporated, adding 5L of purified water, heating to 55 ℃, stirring until the water is completely dissolved, slowly adding 10L of methanol, continuously stirring for 0.5h, cooling to 20-25 ℃, precipitating a large number of crystals, keeping the temperature and stirring for 3h, carrying out centrifugal filtration, washing a filter cake twice with a small amount of methanol, and carrying out vacuum drying at the temperature of 60-65 ℃ to obtain 2.46kg of glycyl-L-glutamine crude product, wherein the molar yield is 70.8%, and the purity is 98.9%.
(2) Refining of glycyl-L-glutamine crude product
Dissolving 2.4kg of crude glycyl-L-glutamyl in 24L of purified water, adding 9.6kg of WA-30 resin, stirring for 3h at room temperature, filtering and recovering the resin, concentrating the filtrate under reduced pressure (vacuum is less than or equal to-0.09 Mpa), heating the filtrate and the washing liquid together, adding into a crystallization tank, stirring and heating to 40-45 ℃, slowly adding 14.4L of methanol, stirring for 20min at the temperature of 20-25 ℃, stirring for 1h at the temperature of 20-25 ℃, centrifugally filtering, washing the filter cake twice with a small amount of methanol, and drying at the temperature of 60-65 ℃ in vacuum until the water content is 7.0-10.0%, thus obtaining 1.98kg of refined glycyl-L-glutamine with the molar yield of 82.5%.
Example 3
(1) Preparation of glycyl-L-glutamine crude product
Adding 7.5kg of purified water and 1.9kg of toluene into a reaction kettle, adding 3.0kg of L-glutamine under the stirring condition, cooling to 10 ℃, dropwise adding a prepared sodium hydroxide solution (5 mol/L, about 1.3L) under the stirring condition, keeping the temperature at 8-12 ℃, dropwise adding a mixed solution of 2.9kg of chloroacetyl chloride and 1.87kg of toluene, and dropwise adding a sodium hydroxide solution (5 mol/L) at the same time, wherein the pH of the reaction mixture is controlled to be = 10.0-11.0. After the dropwise addition, the temperature is reduced to 0-5 ℃, the stirring is continued for 1h, the standing is carried out for 0.5h, the phase separation is carried out, the toluene is recovered, the pH of the water phase is adjusted to 7.5-8.0 by 3mol/L hydrochloric acid, the water phase is added into a fresh water chamber of an electrodialysis device, equal volume water is added into a concentrated water chamber, 100 pairs of homogeneous phase ion exchange membranes are used, the voltage is controlled not to exceed 100V, the pH of the fresh water is controlled to 7.5-8.0, and the conductivity of the fresh water is controlled to be lower than 10ms/cm to be used as an end point, so that the N-chloroacetyl-L-glutamine aqueous solution in the fresh water chamber is obtained.
Adding the N-chloroacetyl-L-glutamine aqueous solution (21.8 kg) prepared in the previous step into a high-pressure reaction kettle, adding 1.1kg of N-methylpyrrolidone, introducing ammonia gas to the pressure of 0.6-0.8 Mpa, slowly heating to 38-42 ℃, keeping the temperature and pressure and stirring for 3h, concentrating under reduced pressure (vacuum is less than or equal to-0.09 Mpa), heating the water bath to 60-65 ℃, concentrating until no moisture is evaporated, adding 6L of purified water, heating to 55 ℃, stirring until the purified water is completely dissolved, slowly adding 12L of methanol, continuously stirring for 0.5h, cooling to 20-25 ℃, precipitating a large amount of crystals, keeping the temperature and stirring for 3h, centrifugally filtering, washing a filter cake twice with a small amount of methanol, and drying under vacuum at the temperature of 60-65 ℃ to obtain the glycyl-L-glutamine crude product of 3.2kg, wherein the molar yield is 76.7%, and the purity is 98.6%.
(2) Refining of glycyl-L-glutamine crude product
Dissolving 3.0kg of crude glycyl-L-glutamyl in 30L of purified water, adding 10.5kg of WA-30 resin, stirring for 2.5h at room temperature, filtering and recovering the resin, concentrating the filtrate under reduced pressure (vacuum is less than or equal to-0.09 Mpa), heating the water bath to 60-65 ℃, concentrating to be nearly anhydrous, adding 8L of purified water, completely dissolving, filtering through a 0.22 mu m microporous filter membrane, washing the tank wall and a pipeline filter membrane with 1L of purified water, merging the filtrate and the washing solution, adding the filtrate into a crystallization tank, stirring and heating to 40-45 ℃, slowly adding 18L of methanol, stirring for 20min at a constant temperature, cooling to 20-25 ℃, stirring for 1h at the constant temperature, centrifuging and filtering, washing the filter cake twice with a small amount of methanol, drying at 60-65 ℃ under vacuum to 7.0-10.0% of water, obtaining 2.51kg of refined glycyl-L-glutamine with the molar yield of 83.7%.
In the Chinese pharmacopoeia 2020 edition, the glycyl-L-glutamine standard is as follows: calculated as anhydrate, contains C 7 H 13 N 3 O 4 Not less than 99.0%; the area of other unknown impurities must not be larger than 1.0% of the area of the main peak of the control solution. The content and the purity of the finished product prepared by the method meet the requirements of Chinese pharmacopoeia standards, and the specific quality conditions of the product of the embodiment are shown in the following table:
Claims (6)
1. an industrial preparation method of glycyl-L-glutamine is characterized in that: firstly, chloracetyl chloride and L-glutamine are subjected to acylation reaction under low temperature and alkaline conditions, an N-chloracetyl-L-glutamine aqueous solution is obtained after phase splitting, then the N-chloracetyl-L-glutamine aqueous solution is treated by adopting an electrodialysis membrane separation technology, ammonia gas is introduced into the treated N-chloracetyl-L-glutamine aqueous solution for ammonolysis under pressure, and a glycyl-L-glutamine crude product is obtained through concentration, crystallization, filtration and drying; finally dissolving the crude glycyl-L-glutamine in water, purifying by WA-30 resin, and crystallizing to obtain high-purity glycyl-L-glutamine;
the method specifically comprises the following steps:
(1) Preparation of a glycyl-L-glutamine crude product: adding L-glutamine into a mixed solvent of purified water and toluene, simultaneously dropwise adding a chloroacetyl chloride toluene solution and a NaOH aqueous solution under stirring at the temperature of 8-12 ℃, controlling the pH of a reaction mixture to be 10.0-11.0 in the dropwise adding process, cooling to 0-5 ℃ after the dropwise adding is finished, continuously stirring for carrying out acylation reaction for 0.5-1 h, standing for 0.5h after the reaction is finished, carrying out phase splitting, adjusting the pH of the obtained water phase with acid, carrying out electrodialysis treatment, and controlling the conductivity of fresh water to be lower than 10ms/cm as an end point to obtain an N-chloroacetyl-L-glutamine aqueous solution; adding an organic solvent into the N-chloroacetyl-L-glutamine aqueous solution, wherein the organic solvent is one of dimethyl sulfoxide, N-dimethylformamide, N-dimethyl-2-imidazolidinone and N-methylpyrrolidone, and the dosage of the organic solvent is 1/20 of the weight of the N-chloroacetyl-L-glutamine aqueous solution; introducing ammonia gas to carry out pressurized ammonolysis reaction for 2-3 h at a certain temperature, wherein the pressure of the ammonolysis reaction is 0.6-0.8 Mpa, the reaction temperature is 38-42 ℃, after the reaction is finished, concentrating under reduced pressure until no moisture is evaporated, adding purified water into the residue, heating to 55 ℃, stirring completely, slowly adding an organic solvent in a flowing manner, continuing to keep warm and stir for 0.5h after the flowing is finished, cooling to 20-25 ℃ for crystallization, keeping warm and stirring for 3-4 h, centrifuging, filtering and washing after the crystallization reaction is finished to obtain a wet product, and carrying out vacuum drying on the obtained wet product to obtain a glycyl-L-glutamine crude product;
(2) Refining a glycyl-L-glutamine crude product: dissolving the glycyl-L-glutamine crude product obtained in the step (1) in purified water, adding WA-30 resin after dissolving, stirring for 2-3 h at room temperature, filtering and recovering the resin, concentrating the obtained filtrate under reduced pressure to be dry, adding purified water to the remainder for dissolving, performing microfiltration after completely dissolving, adding purified water to wash a container and a pipeline after filtering, combining the washing solution with the filtrate after microfiltration of washing water, stirring and heating to 40-45 ℃, adding an organic solvent in a flowing manner, performing heat preservation stirring for 20min after the end of the flowing addition, cooling to 20-25 ℃, performing heat preservation stirring for crystallization reaction for 1h, centrifuging, filtering and washing after the completion of the crystallization reaction to obtain a wet product, and performing vacuum drying on the wet product to obtain the glycyl-L-glutamine with high purity.
2. The industrial production method of glycyl-L-glutamine according to claim 1, characterized in that: the molar ratio of L-glutamine to chloroacetyl chloride in the step (1) is 1.05-1.
3. The industrial production method of glycyl-L-glutamine according to claim 1, characterized in that: the acid used for adjusting the pH value in the step (1) is hydrochloric acid or sulfuric acid, and the concentration of the acid solution is 0.5-3 mol/L; the electrodialysis treatment uses a homogeneous phase ion exchange membrane, and the pH value of the fresh water is controlled to be 7.5-8.0.
4. The industrial production method of glycyl-L-glutamine according to claim 1, characterized in that: in the step (1), purified water with the mass 1.5-2.0 times of that of the remainder is added into the remainder, the crystallization organic solvent is methanol, and the volume ratio of the purified water to the methanol is 1.
5. The industrial production method of glycyl-L-glutamine according to claim 1, characterized in that: the amount of the purified water for dissolving the crude glycyl-L-glutamine in the step (2) is 10 times of the mass of the crude glycyl-L-glutamine; the dosage of the WA-30 resin is 3.0 to 4.0 times of the mass of the glycyl-L-glutamine crude product.
6. The industrial production method of glycyl-L-glutamine according to claim 1, characterized in that: the total consumption of the purified water and the purified water washing liquid of the dissolving remainder in the step (2) is 3 times of the mass of the crude glycyl-L-glutamine product; the crystallization organic solvent is methanol, and the ratio of the amount of the methanol to the total volume of the purified water is 2.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5780677A (en) * | 1994-04-18 | 1998-07-14 | Kyowa Hakko Kogyo Co., Ltd. | Process for producing glutamine derivative |
| 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 |
| 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 |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5780677A (en) * | 1994-04-18 | 1998-07-14 | Kyowa Hakko Kogyo Co., Ltd. | Process for producing glutamine derivative |
| 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 |
| 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 |
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