Method for separating and purifying glycine

Abstract

The invention provides a glycine separation and purification method, which can be widely applied to the technical field of preparation of diketopiperazine by glycine condensation, and solves the problem of low raw material utilization rate caused by incomplete reaction of glycine raw materials, enrichment in mother liquor and difficulty in purification in the existing process of preparing diketopiperazine from glycine. The glycine separation and purification method comprises the following steps: firstly, carrying out heating concentration pretreatment on a mother solution of diketopiperazine to remove moisture in the mother solution, then adding an inorganic copper compound, heating and stirring, concentrating and cooling, and filtering to obtain a copper diglycinate complex; and dissolving the copper diglycinate complex in the solution, adding acid, controlling the pH value, and filtering to obtain glycine. The whole process is easy to operate, the glycine recovery rate is high, the purity can reach 99.5% to the maximum, the yield can reach 98.1% to the maximum, the amplification effect is not obvious during amplification, and the method has good industrial application value.

Description

Technical Field

[0001] The invention belongs to the technical field of fine organic synthesis and relates to a method for separating and purifying glycine. Background Art

[0002] Diketopiperazine is a very important chemical raw material, which is obtained by condensation of glycine. Due to its special six-membered heterocyclic structure, it can be used as a multifunctional compound with a wide range of uses. The main uses are as follows, for example, in the pharmaceutical industry: Diketopiperazine can be used as a drug intermediate and plays an important role in pharmaceutical chemistry. It is used to synthesize a variety of drug molecules, including antiviral drugs and anticancer drugs. Diketopiperazine can be used as a biochemical reagent. By hydrolyzing with alkali, acid or hot water, glycylglycine can be generated. In the food industry, glycine anhydride can be used as a food additive to increase the nutritional value of food or improve the sensory properties of food.

[0003] US Patent US0024180 provides a method for preparing 2,5-diketopiperazine by cyclization of glycine, wherein the glycine organic solvent is heated at a temperature between about 50-200°C, especially between about 80°C and about 150°C, wherein the solvent is preferably a solvent that can form a low-boiling azeotrope with water, such as acetonitrile, allyl alcohol, benzene, benzyl alcohol, n-butanol, but the synthesis efficiency is low and high temperature is required. Patent CN109317194 discloses a method for synthesizing cyclodipeptides in one step by preparing a highly active titanium salt catalyst to catalyze the dimerization of N-alkyl substituted amino acids, in which the catalyst for synthesizing cyclodipeptides in one step is prepared by a metal titanium compound and an organic superacid through a double decomposition reaction.

[0004] In the existing reports, the synthesis of diketopiperazine using glycine as a raw material, without the addition of an additional catalyst, has the main problem of low conversion rate of glycine raw material, resulting in glycine enrichment in the solvent, which is difficult to purify, resulting in low raw material utilization rate and uneconomical. The conventional purification method is to remove the high boiling point solvent by distillation to achieve the purpose of purifying glycine, but the distillation temperature is very high and cannot achieve the effect of rapid purification. Summary of the invention

[0005] The present invention provides a separation and purification method of glycine, which can quickly purify glycine enriched in a diketopiperazine mother liquor. The method is a separation and purification method with simple process, safety, low cost, high purification efficiency and suitable for industrial purification of glycine.

[0006] To achieve the above-mentioned purpose, the technical solution of the present invention is as follows: A method for separating and purifying glycine, the method comprising the following steps: Step (1): firstly heat and concentrate the mother liquor of diketopiperazine to remove the water in the mother liquor, then add the inorganic copper compound, heat and stir, concentrate and cool, filter, and obtain the diglycine copper complex. The reaction formula is as follows: ; Step (2): dissolving the diglycine copper complex in step (1) in a solution, adding acid, controlling the pH value, filtering, and obtaining glycine. The reaction formula is as follows: ; Where X is Cl, NO3 - 、SO4 - 、CH3COO - 、C2O4 - Any of In the steps, the mother liquor is the mother liquor obtained after heating glycine in ethylene glycol to obtain a diketopiperazine product, and the mother liquor is enriched with 30-40% of glycine that has not participated in the reaction.

[0007] In the steps, the copper compound in step (1) is any one of copper chloride, copper nitrate, copper acetate, copper carbonate, copper hydroxide, copper sulfate, and basic copper carbonate.

[0008] In the steps, the molar ratio of the inorganic copper compound in step (1) to the glycine ion in the diketopiperazine filtrate is 0.3-0.7:1.

[0009] In the steps, the temperature in step (1) is 25-120°C.

[0010] In the steps described above, the reaction time in step (1) is 2-8 h.

[0011] In the steps, the pH value of the diglycine copper complex solution obtained in step (1) is 6.0-9.0.

[0012] In the steps, in step (2), the pH value is controlled to be 3.0-5.0.

[0013] In the steps, the solution is any one of methanol, ethanol, acetone, toluene, ethyl acetate and water.

[0014] In the steps, the acid is any one or more of hydrochloric acid, sulfuric acid, nitric acid, acetic acid and oxalic acid.

[0015] The beneficial effects of the present invention are as follows: 1. First, an inorganic copper compound is added, and a strongly coordinated diglycine copper complex is formed by copper ions and glycine ions, which is crystallized and precipitated, thereby achieving the purpose of extracting glycine ions from the diketopiperazine mother liquor. The process of extracting glycine by distilling a high boiling point solvent is avoided.

[0016] 2. Then, by adding acid, the copper ions in the diglycine copper complex can be removed, and hydrogen ions are formed to form glycine with the dissociated glycine ions. After simple post-treatment operations, high-purity and high-yield glycine can be recovered, which solves the problems of difficulty in purifying glycine, low yield and purity in the diketopiperazine mother liquor.

[0017] 3. Through the glycine separation and purification method provided by the present invention, the purity of the glycine finally recovered reaches more than 90%, and the yield can reach more than 90% at the highest. In the scale-up experiment, the scale-up effect is not obvious, and the final glycine yield is more than 90%, and the purity is more than 90%, which significantly improves the purification efficiency. In addition, the process of the present invention is simple, no special equipment is required, and efficient purification of glycine can be achieved by concentration and filtration, which is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 The glycine recovered in Example 1 of the present invention 1 H NMR spectrum.

[0019] Figure 2 The glycine recovered in Example 1 of the present invention 13 C NMR spectrum.

[0020] Figure 3 The HPLC spectrum of glycine recovered in Example 1 of the present invention. DETAILED DESCRIPTION

[0021] The present invention is further described below with reference to embodiments, but the scope of protection claimed by the present invention is not limited to the scope described in the embodiments.

[0022] Instruments and reagents: Nuclear magnetic resonance (NMR) spectra were measured using a Bruker AVANCE III 400 MHz Plus NMR spectrometer with D2O as solvent. 2YZ-4A rotary vane vacuum oil pump (Gongyi Yuhua Instrument Co., Ltd.), EYELA SB-1100 rotary evaporator, SHZ-E circulating water vacuum pump (Shanghai Rongya Biochemical Instrument Factory), DZE-6120 vacuum drying oven (Shanghai Hengtian Scientific Instrument Manufacturing Co., Ltd.), EB2005A electronic balance, DFX-5L / 30 low temperature constant temperature reaction bath (Wuxi Baichuan Instrument Factory), all reagents used were analytical grade.

[0023] The source of the diketopiperazine mother liquor is Professor Aneta Pokorna<Investigation ofPermeation of Theophylline through Skin Using Selected Piperazine-2,5-Diones> It was reported in an article that glycine was heated in ethylene glycol to obtain diketopiperazine, and in the diketopiperazine mother liquor, 38% of glycine that did not participate in the reaction was also enriched. In the following examples, the diketopiperazine mother liquor obtained by the same method was used, and it was assumed that 38% of glycine was enriched therein, with a theoretical mass of 2.85 g.

[0024] Example 1 (1) The diketopiperazine mother liquor (pH = 4.0, glycine content 38%) was first subjected to a heating liquid concentration pretreatment to remove the water in the mother liquor. Then, 2.4 g of copper carbonate (0.5 equivalent) was added and heated and stirred at 80 °C for 4 h to obtain a dark blue solution. After concentration, cooling and filtration, 3.91 g of diglycine copper complex was obtained with a yield of 98.5%.

[0025] (2) Dissolve the diglycine copper complex in 20 mL of methanol (pH = 7.9), add hydrochloric acid, control the pH value to 5.0, and filter to obtain the precipitate, which is the final product, glycine. 2.795 g of solid was obtained with a yield of 98.1% and a purity of 99.5%.

[0026] Example 2 (1) The diketopiperazine mother liquor (pH = 4.2, glycine content 38%) was first subjected to a heating liquid concentration pretreatment to remove the water in the mother liquor. Then 1.85 g of copper hydroxide (0.5 equivalent) was added and heated and stirred at 80 °C for 4 h to obtain a dark blue solution. The solution was concentrated, cooled and filtered to obtain 3.88 g of diglycine copper complex with a yield of 97.7%.

[0027] (2) Dissolve the diglycine copper complex in 20 mL of methanol (pH = 8.2), add hydrochloric acid, control the pH value to 5.0, and filter to obtain the precipitate, which is the final product glycine. 2.78 g of solid was obtained with a yield of 97.9% and a purity of 99.2%.

[0028] Example 3 (1) The diketopiperazine mother liquor (pH = 4.2, glycine content 38%) was first subjected to a heating liquid concentration pretreatment to remove the water in the mother liquor. Then 4.20 g of basic copper carbonate (0.5 equivalent) was added and heated and stirred at 80 °C for 4 h to obtain a dark blue solution. The solution was concentrated, cooled and filtered to obtain 3.87 g of diglycine copper complex with a yield of 97.4%.

[0029] (2) Dissolve the diglycine copper complex in 20 mL of methanol (pH = 8.8), add hydrochloric acid, control the pH value to 5.0, filter and obtain the precipitate, which is the final product glycine. 2.79 g of solid is obtained, with a yield of 97.9% and a purity of 98.7%.

[0030] Example 4 (1) The diketopiperazine mother liquor (pH = 4.2, glycine content 38%) was first subjected to a heating liquid concentration pretreatment to remove the water in the mother liquor. Then 3.03 g of copper sulfate (0.5 equivalent) was added and heated and stirred at 80 °C for 4 h to obtain a dark blue solution. The solution was concentrated, cooled and filtered to obtain 3.83 g of diglycine copper complex with a yield of 96.5%.

[0031] (2) Dissolve the diglycine copper complex in 20 mL of methanol (pH = 7.8), add hydrochloric acid, control the pH value to 5.0, and filter to obtain the precipitate, which is the final product glycine. 2.78 g of solid was obtained with a yield of 97.5% and a purity of 98.8%.

[0032] Example 5 (1) The diketopiperazine mother liquor (pH = 4.2, glycine content 38%) was first subjected to a heating liquid concentration pretreatment to remove the water in the mother liquor. Then 3.03 g of copper sulfate (0.5 equivalent) was added and heated and stirred at 80 °C for 4 h to obtain a dark blue solution. The solution was concentrated, cooled and filtered to obtain 3.83 g of diglycine copper complex with a yield of 96.5%.

[0033] (2) Dissolve the diglycine copper complex in 20 mL of methanol (pH = 7.7), add hydrochloric acid, control the pH value to 4.5, filter and obtain the precipitate, which is the final product glycine. 2.78 g of solid is obtained, with a yield of 97.5% and a purity of 99.0%.

[0034] Example 6 (1) The diketopiperazine mother liquor (pH = 4.2, glycine content 38%) was first subjected to a heating liquid concentration pretreatment to remove the water in the mother liquor. Then, 2.55 g of copper chloride (0.5 equivalent) was added and heated and stirred at 80 °C for 4 h to obtain a dark blue solution. The solution was concentrated, cooled, and filtered to obtain 3.86 g of diglycine copper complex with a yield of 97.4%.

[0035] (2) Dissolve the diglycine copper complex in 20 mL of methanol (pH = 7.8), add hydrochloric acid, control the pH value to 4.7, and filter to obtain the precipitate, which is the final product glycine. 2.79 g of solid was obtained with a yield of 98.0% and a purity of 98.7%.

[0036] Example 7 (1) The diketopiperazine mother liquor (pH = 4.2, glycine content 38%) was first subjected to a heating liquid concentration pretreatment to remove the water in the mother liquor. Then 3.79 g of copper acetate (0.5 equivalent) was added and heated and stirred at 80 °C for 4 h to obtain a dark blue solution. The solution was concentrated, cooled and filtered to obtain 3.79 g of diglycine copper complex with a yield of 95.6%.

[0037] (2) Dissolve the diglycine copper complex in 20 mL of methanol (pH = 8.5), add hydrochloric acid, control the pH value to 5.0, and filter to obtain the precipitate, which is the final product glycine. 2.73 g of solid was obtained with a yield of 95.9% and a purity of 98.2%.

[0038] From the experimental data of the above Examples 1-7, it can be seen that when the pH of the diketopiperazine mother liquor is 4.0, the inorganic copper compound (the dosage is 0.5 times) is one of copper carbonate, copper hydroxide, basic copper carbonate, copper sulfate, copper chloride and copper acetate, the reaction temperature is 80 ° C, and hydrochloric acid is added to control the pH to between 4.0 and 5.0, the separation and purification method of glycine of the present invention can be achieved to obtain glycine with high purity and high yield. Among them, the experimental parameter combination in Example 1 is better, and the yield of glycine can reach 98.5% and the purity is 99.5%. For specific spectrum information, see Figure 1 , 2, 3.

[0039] Examples 8-14 are based on Example 1, with only a single parameter changed, that is, the amount of copper carbonate, reaction time and temperature in step (1), and no change to the solvent, acid and pH value added in step (2). Therefore, the experimental steps are not described in detail. The experimental parameters and results of Examples 1 and 8-14 are summarized as follows, see Table 1 below.

[0040] From the data of Examples 8-14, it can be seen that when the amount of copper carbonate is greater than or less than 0.5 times the equivalent, the formation of the complex will be affected compared to Example 1. If the reaction time is too short, the formation of the complex will be affected, while if the reaction time is extended, the formation of the complex will not be affected. When the reaction temperature is room temperature, the polymerization of glycine acid anion and copper ion will be affected. Raising the temperature is a promoting process for this process, while if the temperature is too high, the dissociation of the complex may be caused.

[0041] Examples 15-21 are based on Example 1, with only a single parameter changed, that is, the solvent, acid and pH value added in step (2) are changed, and the amount of copper carbonate, reaction time and temperature in step (1) are not changed. Therefore, the experimental steps are not described in detail. The experimental parameters and results of Examples 1 and 15-21 are summarized as follows, see Table 2 below: Table 2

[0042] From Examples 15-21, it can be seen that, compared with Example 1, when different acids are added to different solvents to adjust the different pH values ​​of the complex solution, the dissociation degree of the complex is affected, thereby affecting the yield of glycine. Compared with the method used in the above examples, in Example 21, when water is used as the solvent, the yield of glycine is 0, because all glycine is dissolved in water and no precipitate is obtained. The filtrate is concentrated and recrystallized, and finally glycine can be obtained, with a yield of 96.4% and a purity of 99.3%.

[0043] In Example 22, glycine was heated in ethylene glycol to synthesize diketopiperazine for a scale-up experiment. In the diketopiperazine mother liquor, 45% of glycine that did not participate in the reaction was also enriched, with a molar weight of 1.04 mol and a theoretical mass of 78.2 g.

[0044] (1) The diketopiperazine mother liquor (pH = 3.8, glycine content 45%) was first subjected to a heating liquid concentration pretreatment to remove the water in the mother liquor. Then 61.78 g of copper carbonate (0.5 equivalent) was added and heated and stirred at 80 °C for 4 h to obtain a dark blue solution. The solution was concentrated, cooled and filtered to obtain 101.03 g of diglycine copper complex with a yield of 96.7%.

[0045] (2) Dissolve the diglycine copper complex in 1 L of methanol (pH = 7.3), add hydrochloric acid, control the pH value to 4.8, and filter to obtain the precipitate, which is the final product glycine. 74.76 g of solid is obtained, with a yield of 95.6% and a purity of 98.9%.

[0046] Example 22 shows that the method of the present invention has no obvious amplification effect when used for large-scale experiments, and has good industrial application value.

[0047] The invention provides a separation and purification method of glycine. First, an inorganic copper compound is added, and a strongly coordinated diglycine copper complex is formed by using copper ions and glycine ions to crystallize and precipitate, thereby achieving the purpose of extracting glycine ions in a diketopiperazine mother liquor. The process of extracting glycine by distilling a high-boiling-point solvent is avoided. Then, by adding acid, the copper ions in the diglycine copper complex can be removed, and hydrogen ions are formed to form glycine with the dissociated glycine ions. After a simple post-treatment operation, high-purity and high-yield glycine can be recovered, thereby solving the problems of high difficulty in purifying glycine in the diketopiperazine mother liquor, low yield and purity, etc. By using the glycine separation and purification method provided by the invention, the purity of the glycine finally recovered can reach up to 99.5%, and the yield can reach up to 98.1%. In the amplification experiment, the amplification effect is not obvious, and the final glycine yield is 95.6%, and the purity is 98.9%, which significantly improves the purification efficiency. The process of the invention is simple, does not require special equipment, and can achieve efficient purification of glycine through concentration and filtration, which is suitable for large-scale industrial production.

[0048] The above-mentioned embodiments are only preferred technical solutions of the present invention and should not be regarded as limitations of the present invention. The embodiments and features in the embodiments of the present application can be arbitrarily combined with each other without conflict. The protection scope of the present invention shall be the technical solutions recorded in the claims, including the equivalent replacement solutions of the technical features in the technical solutions recorded in the claims. That is, equivalent replacement improvements within this scope are also within the protection scope of the present invention.

Claims

1. A method for separating and purifying glycine, characterized in that: The following steps are involved: Step (1): firstly pre-treating the mother liquor of diketopiperazine by heating and concentrating to remove water in the mother liquor, then adding a copper compound, heating and stirring, concentrating and cooling, and filtering to obtain a diglycine copper complex; Step (2): dissolving the diglycine copper complex in step (1) in a solution, adding acid, controlling the pH value, filtering, and obtaining glycine.

2. The method according to claim 1, characterized in that The mother liquor of diketopiperazine described in step (1) is the mother liquor obtained after heating glycine in ethylene glycol to obtain the diketopiperazine product, and the mother liquor is enriched with 30-40% of glycine that has not participated in the reaction.

3. The method according to claim 1, characterized in that The copper compound in step (1) is any one of copper chloride, copper nitrate, copper acetate, copper carbonate, copper hydroxide and copper sulfate.

4. The method according to claim 3, characterized in that: In step (1), the molar ratio of the inorganic copper compound to the glycine ion in the diketopiperazine mother liquor is 0.3-0.7:

1.

5. The method according to claim 1, characterized in that The temperature of heating and stirring in step (1) is 25-120°C.

6. The method according to claim 1, characterized in that The heating and stirring time in step (1) is 2-8 h.

7. The method according to claim 1, characterized in that The solution in step (2) is any one of methanol, ethanol, acetone, toluene, ethyl acetate and water.

8. The method according to claim 1, characterized in that: In step (2), the acid is any one or more of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, and oxalic acid.

9. The method according to claim 1, characterized in that: In step (2), the pH value of the diglycine copper complex solution is 3.0-5.0.

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