CN116284213A - Improved process for synthesizing glycylglycine - Google Patents
Improved process for synthesizing glycylglycine Download PDFInfo
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- CN116284213A CN116284213A CN202310017364.XA CN202310017364A CN116284213A CN 116284213 A CN116284213 A CN 116284213A CN 202310017364 A CN202310017364 A CN 202310017364A CN 116284213 A CN116284213 A CN 116284213A
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- 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
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Abstract
The invention discloses an improved process method for synthesizing glycylglycine, which comprises the following steps of S1: dissolving glycine, dripping chloroacetyl chloride, and reacting for 18-24 hours until the glycine serving as a raw material disappears; s2: adding dichloromethane for extraction, then adjusting the pH to 1, taking an extract, adding anhydrous sodium sulfate, stirring and drying for 3 hours, and concentrating filtrate; s3: adding concentrated ammonia water and chloroacetylglycine into a reactor in sequence, and reacting for 12-16 hours at room temperature; s4: heating and concentrating the reaction liquid to one fifth of the volume, cooling to room temperature, adding absolute ethyl alcohol, standing for crystallization to obtain a large amount of white solid, filtering, washing a filter cake with 95% ethyl alcohol, refining the obtained solid once with ethyl alcohol-water, and drying to obtain the white solid. The invention adopts cheap and easily available glycine, chloracetyl chloride, ammonia water and other conventional industrialized products, realizes the preparation of the glycylglycine with low cost, high efficiency and high yield, and breaks the bottleneck of the current production situation.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to an improved process for synthesizing glycylglycine.
Background
The diglycolamine (L-Glycylglycine), also called diglycolamine, glycylglycine, is a white leaf-like crystal with a melting point of 260-262 ℃ (decomposition). The solubility in water at 25 ℃ is 13.4g/100mL, and the water-soluble polyurethane emulsion is easy to dissolve in hot water, difficult to dissolve in alcohol and insoluble in ether. The N-glycylglycine is a biochemical reagent, and can be used as a stabilizer for blood preservation and protein medicine cytochrome C water injection in biological research and medicine, and can be used for measuring substrates of N-glycylglycine dipeptidase and synthesizing polypeptides. And the diglycolamine is taken as a short peptide, and the interaction of the diglycolamine and transition metal has critical effects in a plurality of fields such as bioengineering, pharmaceutical chemistry and the like.
The known synthesis method is generally obtained by condensing glycine to obtain piperazine dione and then refining the piperazine dione by hydrolysis. For example, CN101759767a and CN103204905A report that ethylene glycol, glycine and a large amount of high boiling point solvents such as ethylene glycol or glycerol or ethylenediamine are mixed and stirred, the temperature is raised to 170-180 ℃ for reaction, after the reaction is completed, the reaction is cooled to room temperature, the intermediate 2, 5-piperazinedione crude product is obtained by centrifugation, hydrochloric acid is added into the intermediate for hydrolysis, the solid is obtained by cooling and centrifugation, lithium hydroxide solution is added for regulating the pH value to 5.5-6, activated carbon is added for decolorization, alcohol is added for filtration to obtain a glycylglycine crude product, water-alcohol is used for repeated recrystallization for three to four times, the impurities are filtered and washed to be qualified, and the glycylglycine is obtained by sterilization and drying. The method has extremely high equipment requirements, high consumption of ultrahigh temperature and high consumption of high boiling point solvents, high consumption of high average yield (30-33%), long production period, complicated refining procedures, large pollution of three wastes and the like, severely restricts the productivity of the product and limits the market popularization capability of the product. Dunn; butler; deakers et al Journal of Biological Chemistry; vol 99; (1932); the synthesis of glycylglycine from chloroacetylglycine is reported on p.218, but the process is not described in detail herein. Li Ruiping of university of three gorges et al in Yb 3＋ Synthesis and characterization of glycylglycine complexes, [ J ]]Rare earths, 2021, 22 (3), 28-30 report that chloroacetylglycine is obtained by reacting glycine with chloroacetylchloride, followed by ammonolysis to obtain glycylglycine. Since chloroacetyl chloride is rapidly decomposed in an excessive strong alkaline system, but is directly extracted by a strong acid, a large amount of chloroacetic acid obtained by decomposing the excessive chloroacetyl chloride is extracted together with chloroacetylglycine, and then concentrated into viscous oil, frozen and solidified into white solid, and the obtained intermediate isContains a large amount of chloroacetic acid by-product, can directly participate in the next reaction, and can cause great difficulty for the purification of the subsequent reaction. The ammonolysis reaction of chloroacetylglycine in the second step, besides the product glycylglycine, also contains a large amount of ammonium chloride generated by ammonolysis of glycylglycine and chloroacetic acid, because glycylglycine and glycine have similar properties and are difficult to remove under recrystallization conditions, resulting in difficulty in purification. The process descriptions described in the article are therefore difficult to meet the demands of industrial production.
In order to overcome the defects that the domestic general high-temperature cyclization and hydrolysis production of the glycylglycine and the chloroacetyl chloride method are unfavorable for the purification of the final product, the invention adopts the process route of glycine chloroacetylation and ammonolysis, and optimizes the process route on the basis so as to meet the condition of industrial production. The preparation of the glycylglycine is realized with low cost, high efficiency and high yield by adopting cheap and easily available glycine, chloroacetyl chloride, ammonia water and other conventional industrialized products and taking water as a reaction medium under the condition of room temperature, and the bottleneck of the current production state shortage is broken.
Disclosure of Invention
The invention aims to provide an improved process for synthesizing glycylglycine, which solves the technical problems of the prior art that glycylglycine is produced by high-temperature cyclization and hydrolysis and the chloroacetyl chloride method is unfavorable for purifying the final product.
In order to achieve the above purpose, the present invention provides the following technical solutions:
the invention adopts the process route of glycine chloracetyl and ammonolysis, and optimizes on the basis, so that the process meets the condition of industrial production. The preparation of the glycylglycine is realized with low cost, high efficiency and high yield by adopting cheap and easily available glycine, chloroacetyl chloride, ammonia water and other conventional industrialized products and taking water as a reaction medium under the condition of room temperature, and the bottleneck of the current production state shortage is broken.
The process route is illustrated as follows:
the process comprises the steps of reacting glycine with chloroacetyl chloride to obtain chloroacetylglycine, and ammonolyzing the chloroacetylglycine with concentrated ammonia water to obtain the glycylglycine.
The invention provides an improved process method for synthesizing glycylglycine, which specifically comprises the following steps:
s1: dissolving glycine, adding sodium carbonate to regulate the pH value to 7-8, dripping chloroacetyl chloride at room temperature, and reacting for 18-24 hours until the glycine serving as a raw material disappears;
s2: adding dichloromethane to extract excessive chloroacetyl chloride, adding concentrated hydrochloric acid to adjust the pH to 1-2, adding anhydrous sodium sulfate, stirring and drying for 3 hours, filtering, concentrating the filtrate to dryness to obtain oily matter, adding a reagent into the oily matter to recrystallize to obtain white chloroacetyl glycine solid;
s3: sequentially adding concentrated ammonia water and chloroacetylglycine into a reactor, and reacting for 12-16 hours at room temperature until the raw materials disappear;
s4: heating and concentrating the reaction solution to one fifth of the volume, measuring the pH value of the solution to be neutral at the moment, cooling to room temperature, adding absolute ethyl alcohol, standing for crystallization to obtain a large amount of white solid, filtering, washing a filter cake with 95% ethanol, refining the obtained solid once with ethanol-water, and drying to obtain the white solid.
Further, in the step S1, the solvent selected for dissolution is any one or a mixture of any several of water, a water-toluene system, a water-dichloromethane system and a water-tetrahydrofuran system.
Further, the mass volume ratio of glycine to solvent is 1:1 to 100, preferably 1:20 to 80 percent.
Further, the molar ratio of glycine, chloroacetyl chloride and sodium carbonate is 1:1 to 3:1 to 2, preferably 1: 1-2: 1 to 1.5.
Further, in the step S2, the dichloromethane is added three times for extraction.
Further, in the step S2, the added reagent for recrystallization is diethyl ether, isopropyl ether, ethyl acetate, tetrahydrofuran, ethyl acetate-petroleum ether or methyl tert-butyl ether, preferably isopropyl ether, so as to rapidly remove chloroacetic acid by-product, and the obtained solid is a large-particle crystal form product.
Further, in the step S3, the mass-volume ratio of chloroacetylglycine to concentrated ammonia water is 1:1 to 30, preferably 1:5 to 20.
Further, the reaction temperature during the experiment is 0 to 50 ℃, preferably 0 to 30 ℃.
Based on the technical scheme, the embodiment of the invention at least has the following technical effects:
the improved process for synthesizing the glycylglycine adopts a process route of glycine chloracetyl and ammonolysis, and optimizes the process on the basis of the process route to ensure that the process meets the condition of industrial production. The preparation of the glycylglycine is realized with low cost, high efficiency and high yield by adopting cheap and easily available glycine, chloroacetyl chloride, ammonia water and other conventional industrialized products and taking water as a reaction medium under the condition of room temperature, and the bottleneck of the current production state shortage is broken.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. In addition, the technical solutions of the embodiments may be combined with each other, but it is necessary to base that the technical solutions can be realized by those skilled in the art, and when the technical solutions are contradictory or cannot be realized, the technical solutions should be considered that the combination does not exist and is not within the scope of protection claimed by the present invention.
The aim of the invention is realized by the following technical scheme:
example 1:
the first step: preparation of chloroacetylglycine
15 g glycine was dissolved in 100mL water, 32g of sodium carbonate was added, 20mL of chloroacetyl chloride was added dropwise at room temperature, the pH was maintained at 7.5 after the addition, the reaction was carried out at room temperature for 20 hours, and TLC monitored the disappearance of glycine starting material. After the reaction, adding dichloromethane to extract excessive chloroacetyl chloride, then adjusting the pH to 1, adding dichloromethane three times, extracting each time by using 100mL, combining the extracts, adding anhydrous sodium sulfate, stirring and drying for 3 hours, filtering, concentrating the filtrate to dryness to obtain oily matter, and recrystallizing the oily matter by isopropyl ether to obtain 26.2g of white chloroacetyl glycine solid with the yield of 86.11 percent.
And a second step of: preparation of Bispyrimidine
Concentrated ammonia water (1.73 mol,25 percent, 117.5 g) and 26g of chloroacetylglycine are sequentially added into a 500 mL three-neck flask to react for 14 hours at room temperature, TLC monitors disappearance of raw materials, after the reaction is finished, the reaction solution is heated and concentrated to one fifth of the volume, the pH value of the measured solution is neutral, absolute ethyl alcohol is added after cooling to the room temperature, standing and crystallizing are carried out, a large amount of white solid is obtained, the white solid is filtered, a filter cake is washed by 95 percent of ethanol, the obtained solid is refined once by ethanol-water, and the white solid 19 g is obtained after drying, and the yield is 85 percent.
Example 2:
the first step: preparation of chloroacetylglycine
15 g glycine was dissolved in 100mL water, 21g sodium carbonate was added, 30mL chloroacetyl chloride was added dropwise at room temperature, the pH was maintained at 8 after the addition, the reaction was carried out at room temperature for 24 hours, and TLC monitored the disappearance of glycine starting material. After the reaction, adding dichloromethane to extract excessive chloroacetyl chloride, then adjusting the pH to 1, adding dichloromethane three times, extracting each time by using 100mL, combining the extracts, adding anhydrous sodium sulfate, stirring and drying for 3 hours, filtering, concentrating the filtrate to dryness to obtain oily matter, and recrystallizing the oily matter by isopropyl ether to obtain white chloroacetyl glycine solid with the yield of 90.02%.
And a second step of: preparation of Bispyrimidine
Concentrated ammonia water (1.73 mol,25 percent, 117.5 g) and 30g of chloroacetylglycine are sequentially added into a 500 mL three-neck flask to react for 14 hours at room temperature, TLC monitors disappearance of raw materials, after the reaction is finished, the reaction solution is heated and concentrated to one fifth of the volume, the pH value of the measured solution is neutral, absolute ethyl alcohol is added after cooling to the room temperature, standing and crystallizing are carried out, a large amount of white solid is obtained, the white solid is filtered, a filter cake is washed by 95 percent of ethanol, and the obtained solid is refined once by ethanol-water, dried to obtain white solid, and the yield is 89 percent.
Example 3:
the first step: preparation of chloroacetylglycine
15 g glycine was dissolved in 100mL water, 21g sodium carbonate was added, 16mL chloroacetyl chloride was added dropwise at room temperature, the pH was maintained at 7 after the addition, the reaction was carried out at room temperature for 18 hours, and TLC monitored the disappearance of glycine starting material. After the reaction, adding dichloromethane to extract excessive chloroacetyl chloride, then adjusting the pH to 1, adding dichloromethane three times, extracting each time by using 100mL, combining the extracts, adding anhydrous sodium sulfate, stirring and drying for 3 hours, filtering, concentrating the filtrate to dryness to obtain oily matter, and recrystallizing the oily matter by isopropyl ether to obtain white chloroacetyl glycine solid with the yield of 84.72 percent.
And a second step of: preparation of Bispyrimidine
Concentrated ammonia water (1.73 mol,25 percent, 117.5 g) and 24g of chloroacetylglycine are sequentially added into a 500 mL three-neck flask to react for 14 hours at room temperature, TLC monitors disappearance of raw materials, after the reaction is finished, the reaction solution is heated and concentrated to one fifth of the volume, the pH value of the measured solution is neutral, absolute ethyl alcohol is added after cooling to the room temperature, standing and crystallizing are carried out, a large amount of white solid is obtained, the white solid is filtered, a filter cake is washed by 95 percent of ethanol, and the obtained solid is refined once by ethanol-water, dried to obtain white solid with the yield of 84 percent.
The first step of temperature is to screen different reaction temperatures from low temperature to room temperature, and the difference of reaction results is not great; the sodium hydroxide, sodium carbonate and sodium bicarbonate are screened by the alkali, and the sodium hydroxide is found to be too strong in alkalinity, so that the chloroacetyl chloride is seriously hydrolyzed, the acyl chloride is seriously consumed, the sodium bicarbonate reaction is very slow in progress, the sodium carbonate acyl chloride is slowly decomposed, and the reaction can be carried out thoroughly, so that the sodium carbonate is selected as the alkali; the reaction medium is selected from pure water phase, water-toluene, water-methylene dichloride, water-tetrahydrofuran and other systems, and the reaction is not very different, and can be well completed in the pure water phase, so pure water is selected as the reaction medium. The intermediate product obtained by extraction is a mixture of chloroacetylglycine and chloroacetic acid, various solvents such as diethyl ether, isopropyl ether, ethyl acetate, tetrahydrofuran, ethyl acetate-petroleum ether, methyl tertiary butyl ether and the like are tried to be recrystallized, the best solvent is found to be isopropyl ether, chloroacetic acid byproducts can be removed rapidly, the obtained solid is a large-particle crystal form product, and the solid is identified as a high-purity intermediate by TLC.
In the second step of reaction, the systems of concentrated ammonia water, concentrated ammonia water-ammonium bicarbonate, ammonia-ethanol, ammonia-methanol, concentrated ammonia water-ethanol, concentrated ammonia water-methanol and the like are researched, and only the reaction of the concentrated ammonia water and the concentrated ammonia water-ammonium bicarbonate system can be smoothly carried out, the reaction of an organic phase or a mixed system is not carried out, and meanwhile, the reaction rate of the concentrated ammonia water-ammonium bicarbonate system is faster than that of the concentrated ammonia water, and the concentrated ammonia water system is directly adopted in consideration of the convenience of ammonium salt removal in the later stage; when the temperature is increased again, the solubility of ammonia in water is reduced, ammonia is escaped from water, the content of ammonia is reduced, the reaction is unfavorable, and the reaction can be well carried out at room temperature through comprehensive comparison. Considering the energy consumption comprehensively, the reaction temperature of room temperature is adopted. The amount of ammonia was examined and was from 20 equivalents to 10 equivalents, 5 equivalents, incomplete reaction, and 10 equivalents and 20 equivalents were reacted sufficiently, so that 10 equivalents were used.
The improved process for synthesizing the glycylglycine adopts a process route of glycine chloracetyl and ammonolysis, and optimizes the process on the basis of the process route to ensure that the process meets the condition of industrial production. The preparation of the glycylglycine is realized with low cost, high efficiency and high yield by adopting cheap and easily available glycine, chloroacetyl chloride, ammonia water and other conventional industrialized products and taking water as a reaction medium under the condition of room temperature, and the bottleneck of the current production state shortage is broken.
The foregoing has shown and described the basic principles and main features of the present invention and the advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that the above embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the spirit and scope of the invention, which is defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (8)
1. An improved process for synthesizing diglycolide is characterized by comprising the following steps:
s1: dissolving glycine, adding sodium carbonate to regulate the pH value to 7-8, dripping chloroacetyl chloride at room temperature, and reacting for 18-24 hours until the glycine serving as a raw material disappears;
s2: adding dichloromethane to extract excessive chloroacetyl chloride, adding concentrated hydrochloric acid to adjust the pH to 1-2, adding anhydrous sodium sulfate, stirring and drying for 3 hours, filtering, concentrating the filtrate to dryness to obtain oily matter, adding a reagent into the oily matter to recrystallize to obtain white chloroacetyl glycine solid;
s3: sequentially adding concentrated ammonia water and chloroacetylglycine into a reactor, and reacting for 12-16 hours at room temperature until the raw materials disappear;
s4: heating and concentrating the reaction solution to one fifth of the volume, measuring the pH value of the solution to be neutral at the moment, cooling to room temperature, adding absolute ethyl alcohol, standing for crystallization to obtain a large amount of white solid, filtering, washing a filter cake with 95% ethanol, refining the obtained solid once with ethanol-water, and drying to obtain the white solid.
2. The improved process for synthesizing the glycylglycine as set forth in claim 1, wherein: in the step S1, the solvent selected during dissolution is any one or a mixture of any several of water, a water-toluene system, a water-methylene dichloride system and a water-tetrahydrofuran system.
3. The improved process for synthesizing the glycylglycine as set forth in claim 2, wherein: the mass volume ratio of glycine to solvent is 1:1 to 100, preferably 1:20 to 80 percent.
4. The improved process for synthesizing the glycylglycine as set forth in claim 1, wherein: in the step S1, the molar ratio of glycine to chloroacetyl chloride to sodium carbonate is 1:1 to 3:1 to 2, preferably 1: 1-2: 1 to 1.5.
5. The improved process for synthesizing the glycylglycine as set forth in claim 1, wherein: in the step S2, dichloromethane is added into the mixture for extraction in three times.
6. The improved process for synthesizing the glycylglycine as set forth in claim 1, wherein: in the step S2, the reagent added in the recrystallization is diethyl ether, isopropyl ether, ethyl acetate, tetrahydrofuran, ethyl acetate-petroleum ether or methyl tertiary butyl ether, preferably isopropyl ether, chloroacetic acid byproducts are rapidly removed, and the obtained solid is a large-particle crystal form product.
7. The improved process for synthesizing the glycylglycine as set forth in claim 1, wherein: in the step S3, the mass volume ratio of the chloroacetylglycine to the concentrated ammonia water is 1:1 to 30, preferably 1:5 to 20.
8. The improved process for synthesizing the glycylglycine as set forth in claim 1, wherein: the reaction temperature during the experiment is 0 to 50 ℃, preferably 0 to 30 ℃.
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