A method for preparing 2,5-diketopiperazine from diglycine
Through the stirring reaction of diglyene in a specific solvent and the recycling of mother liquor, the synthesis process of 2,5-diketopiperazine is optimized, and the problems of easy deliques of the catalyst and high wastewater are solved, achieving efficient and simple synthesis process and High yield.
Patent Information
- Application Number
- CN202310285661.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-03-22
- Publication Date
- 2024-12-31
- Estimated Expiration
- 2043-03-22
AI Technical Summary
In the existing 2,5-diketopiperazine synthesis method, the catalyst is prone to dehydration and needs to be evaporated and recovered. The process is complicated, there is a lot of wastewater, and it is difficult to deal with.
The stirring reaction of diglyene in a specific solvent is used to optimize the operating conditions and realize the efficient synthesis of 2,5-dionepiperazine through the recycling of mother liquor, including stirring reaction at 150-195°C, cooling and precipitation, suction filtration and washing and drying. And use the circulating filtrate as the next solvent to reduce the formation of wastewater.
The reaction product yield is improved, the operation process is simplified, the wastewater generation is reduced, and the treatment difficulty is reduced, achieving high selectivity and efficient 2,5-dionepiperazine synthesis.
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Figure BDA0004139743720000021
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of fine organic synthesis and specifically discloses a synthesis method of 2,5-diketopiperazine. Background Art
[0002] 2,5-Diketopiperazine, also known as glycine anhydride, has a chemical formula of C4H6N2O2 and is the smallest cyclic peptide in nature. 2,5-Diketopiperazine is a biochemical reagent and an important raw material for the preparation of glyphosate-piperazine, a systemic, spectrally active herbicide, using glycine as a raw material (such as patent CN105884700A).
[0003] U.S. Patent 2004 / 0024180 discloses a synthetic method for preparing 2,5-diketopiperazine by cyclization of glycine, wherein a glycine organic solvent is heated at a temperature between about 50-200°C, particularly including a temperature between about 80°C and about 150°C, wherein the solvent for the cyclodimerization of glycine is preferably a solvent that can form a low-boiling azeotrope with water, such as acetonitrile, allyl alcohol, benzene, benzyl alcohol, n-butanol, 2-butanol, tert-butanol, butyl acetate, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, diethyl acetal, dimethyl acetal, ethyl acetate, heptane, methyl isobutyl ketone, 3-pentanol, toluene and xylene; and the pH range at which the cyclodimerization reaction occurs is advantageously between about 2 and about 9 and preferably between about 3 and about 7.
[0004] Patent CN109317194 discloses a method for synthesizing cyclodipeptides (2,5-diketopiperazine derivatives) in one step by preparing a highly active titanium salt catalyst to catalyze the dimerization of N-hydrocarbon-substituted amino acids. The catalyst for synthesizing cyclodipeptides in one step in this application is prepared by a metal titanium compound and an organic superacid through a double decomposition reaction. In Example 2 of the patent, the catalyst prepared in Example 1 is used to dehydrate and cyclize glycine molecules in one step to obtain 2,5-diketopiperazine. Although the method disclosed in Patent CN109317194 does not require the protection of the carbon end or nitrogen end of the amino acid separately, and the synthesis steps are simplified, the catalyst powder or particles are easily deliquescent, and the mother liquor needs to be evaporated to dryness to recover the catalyst. Summary of the invention
[0005] In view of the shortcomings or improvement needs of the prior art, the present invention aims to provide a method for preparing 2,5-diketopiperazine from diglycyl peptide. By recycling the mother liquor and optimizing the operating conditions of the key synthesis process, compared with other 2,5-diketopiperazine synthesis methods, the method has the advantages of high yield of the target reaction product, simple operation, less wastewater and low treatment difficulty.
[0006] To achieve the purpose of the invention, the present invention provides a method for preparing 2,5-diketopiperazine from diglycine, which adopts the following technical scheme:
[0007] The di-Gly peptide is stirred in a solvent for reaction, and after the reaction is completed, a large amount of solid is precipitated by cooling, and then filtered, washed and dried to obtain the product.
[0008] The solvent includes any one of ethylene glycol, glycerol, N-methyl pyrrolidone, octanol, and octyl acetate, or a mixture of any two of them.
[0009] The mass concentration range of the reactant diGly-peptide in the solvent is 15-300 mg / mL; more preferably, the mass concentration range of the reactant diGly-peptide in the solvent is 50-250 mg / mL.
[0010] The stirring reaction temperature ranges from 150 to 195°C, and the stirring reaction time ranges from 0.5 to 10.0 hours;
[0011] The more preferred reaction temperature is 170-180°C, and the stirring reaction time is 1.0-3.0 hours.
[0012] After the reaction is completed, the reaction is cooled to 0-4°C and maintained at this temperature for 6.0-24.0 hours; more preferably, maintained at 3-4°C for 6.0-12.0 hours.
[0013] The filtrate obtained by suction filtration is used as mother liquor and directly used in the next step reaction to replace the solvent used.
[0014] The mother liquor is used as a solvent in a volume fraction of 50-100% to participate in the next cycle reaction.
[0015] The mother liquor is circulated 1-5 times, and more preferably 2-3 times. Before being recycled, the mother liquor is first dehydrated with anhydrous sodium sulfate.
[0016] The filter cake obtained after the suction filtration is washed with any one of ethanol, methanol, petroleum ether and tetrahydrofuran.
[0017] On the other hand, the present invention also provides a 2,5-diketopiperazine, which is prepared by the above-mentioned method for preparing 2,5-diketopiperazine from diglycine.
[0018] The present invention uses diglycine as a raw material to prepare 2,5-diketopiperazine, which has the characteristics of high reaction selectivity, simple operation, less wastewater and low treatment difficulty compared with the prior art. The main reactions and mechanisms involved are as follows:
[0019] DETAILED DESCRIPTION
[0020] In order to more clearly illustrate the purpose, technical solutions and advantages of the present invention, the present invention is further described in detail in conjunction with the following examples. It should be understood that the following examples are only to help explain the present invention and do not limit the present invention in any way.
[0021] The method for preparing 2,5-diketopiperazine from diglycine peptide of the present invention is mainly achieved by the following steps:
[0022] The method comprises the following steps: sequentially adding the reaction materials di-Gly peptide and a solvent into a reactor equipped with a stirrer, a thermometer and a water-cooled condenser, stirring the contents of the reactor at a substantially constant temperature of 150-195° C., preferably about 170-180° C., for a reaction of 0.5-10.0 hours and more preferably about 1.0-3.0 hours; after the reaction is completed, cooling the contents of the high-temperature reactor to room temperature, and cooling at 0-4° C. for 6.0-24.0 hours, more preferably not less than 12.0 hours; filtering the precipitated 2,5-diketopiperazine solid from the reaction system, washing and drying the filter cake, and weighing the filter cake to calculate the yield; and recycling the filtrate as the mother liquor.
[0023] The solvent is any one of ethylene glycol, glycerol, N-methyl pyrrolidone, octanol, octyl acetate or a mixture of any two thereof, or a circulating mother liquor.
[0024] The filter cake washing solvent is any one of ethanol, methanol, petroleum ether and tetrahydrofuran.
[0025] The following examples under different conditions further illustrate the technical solution of the present invention for preparing 2,5-diketopiperazine from diGly peptide.
[0026] Example 1
[0027] 6.6 g of di-Gly peptide (0.05 mol) and 25 mL of ethylene glycol solvent were placed in a reaction flask. Under stirring conditions, the electric heating jacket was heated until the thermometer in the reaction flask rose to 175°C and kept warm for 1.0 hour. After the reaction was completed, the reaction solution was cooled to room temperature 25°C and kept at 4°C for 12 hours. The solid precipitated in the reaction solution was filtered after the solid precipitated. The collected filtrate was treated with anhydrous sodium sulfate as a mother liquor. The filter cake after filtration was washed with 30 mL of ethanol. After the solid was dried, 4.40 g of pure 2,5-diketopiperazine (yield = 77.2%) was produced.
[0028] Example 2
[0029] 6.6 g of di-Gly peptide (0.05 mol), 22 mL of the mother liquor obtained in Example 1 and 3 mL of ethylene glycol (25 mL in total) were placed in a reaction flask as a solvent. Under stirring conditions, the electric heating jacket was heated until the thermometer in the reaction flask rose to 175°C and kept warm for 1.0 hour. After the reaction was completed, the reaction solution was cooled to room temperature of 25°C and placed at 4°C for 12 hours. The solid precipitated in the reaction solution was filtered after the solid precipitated. The collected filtrate was treated with anhydrous sodium sulfate as the mother liquor. The filter cake after filtration was washed with 30 mL of ethanol. After the solid was dried, 4.89 g of 2,5-diketopiperazine (yield = 85.8%) was produced.
[0030] Example 3
[0031] 6.6 g of di-Gly peptide (0.05 mole), 20 mL of the mother liquor obtained in Example 2 and 5 mL of ethylene glycol (25 mL in total) were placed in a reaction flask as a solvent, and the electric heating jacket was heated to 175° C. in the reaction flask under stirring conditions and kept warm for 1.0 hour. After the reaction was completed, the reaction solution was cooled to room temperature of 25° C. and placed at 4° C. for 12 hours. The solid precipitated in the reaction solution was filtered after the solid precipitated. The collected filtrate was treated with anhydrous sodium sulfate as the mother liquor. The filter cake after filtration was washed with 30 mL of ethanol, and the solid was dried to produce 5.11 g of 2,5-diketopiperazine (yield = 89.6%).
[0032] Example 4
[0033] 6.6 g of di-Gly peptide (0.05 mol), 20 mL of the mother liquor obtained in Example 3 and 5 mL of ethylene glycol (25 mL in total) were placed in a reaction flask as a solvent. Under stirring conditions, the electric heating jacket was heated until the thermometer in the reaction flask rose to 175°C and kept warm for 1.0 hour. After the reaction was completed, the reaction solution was cooled to room temperature 25°C and placed at 4°C for 12 hours. The solid precipitated in the reaction solution was filtered after the solid precipitated. The collected filtrate was treated with anhydrous sodium sulfate as the mother liquor. The filter cake after filtration was washed with 50 mL of ethanol. After the solid was dried, 5.13 g of 2,5-diketopiperazine (yield = 90.0%) was produced.
[0034] Example 5
[0035] 6.6 g of di-Gly peptide (0.05 mole), 15 mL of the mother liquor obtained in Example 4 and 10 mL of ethylene glycol (25 mL in total) were placed in a reaction flask as a solvent, and the electric heating jacket was heated to 175° C. in the reaction flask under stirring conditions and kept warm for 1.0 hour. After the reaction was completed, the reaction solution was cooled to room temperature of 25° C. and placed at 4° C. for 12 hours. The solid precipitated in the reaction solution was filtered after the solid precipitated. The collected filtrate was treated with anhydrous sodium sulfate as the mother liquor. The filter cake after filtration was washed with 60 mL of ethanol, and the solid was dried to produce 4.58 g of 2,5-diketopiperazine (yield = 80.4%).
[0036] Example 6
[0037] 6.6 g of di-Gly peptide (0.05 mol), 15 mL of the mother liquor obtained in Example 5 and 10 mL of ethylene glycol (25 mL in total) were placed in a reaction flask as a solvent, and the electric heating jacket was heated to 175° C. in the reaction flask under stirring conditions and kept warm for 1.0 hour. After the reaction was completed, the reaction solution was cooled to room temperature of 25° C. and placed at 4° C. for 12 hours. The solid precipitated in the reaction solution was filtered after the solid was precipitated. The filter cake obtained after the filtration was washed with 100 mL of ethanol, and the solid was dried to produce 4.31 g of 2,5-diketopiperazine (yield = 75.6%).
[0038] Example 7
[0039] 25.0g of diglycine (0.378 mol) and 250mL of glycerol solvent were placed in a reaction flask and stirred. The electric heating jacket was heated until the thermometer in the reaction flask rose to 170°C and kept warm for 3.0 hours. After the reaction was completed, the reaction solution was cooled to room temperature 25°C and placed at 4°C for 24 hours. The solid precipitated in the reaction solution, and the reaction solution was filtered after the solid precipitated. The collected filtrate was treated with anhydrous sodium sulfate and used as a mother liquor. The filter cake after filtration was washed with 100mL of methanol, and the solid was dried to produce 15.60g of 2,5-diketopiperazine (yield = 74.1%).
[0040] Example 8
[0041] 25.0g of di-Gly peptide (0.378 mol) was placed in a reaction flask, and 195mL of ethylene glycol and 55mL of N-methylpyrrolidone, a total of 250mL of solvent, were added and stirred. The electric heating jacket was heated until the thermometer in the reaction flask rose to 170°C and kept warm for 3.0 hours. After the reaction was completed, the reaction solution was cooled to room temperature 25°C and placed at 4°C for 24 hours. The solid precipitated in the reaction solution, after the solid precipitated, the reaction solution was filtered, and the collected filtrate was treated with anhydrous sodium sulfate and used as a mother liquor. The filter cake after filtration was washed with 100mL of tetrahydrofuran, and the solid was dried to produce 17.25g of 2,5-diketopiperazine (yield = 79.9%).
[0042] Example 9
[0043] 10.0g of di-Gly peptide (0.151 mol) was placed in a reaction flask, and 50mL of ethylene glycol and 50mL of octanol (a total of 100mL of solvent) were added and stirred. The electric heating jacket was heated until the thermometer in the reaction flask rose to 185°C and kept warm for 1.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature 25°C and placed at 4°C for 24 hours. The solid precipitated in the reaction solution, the reaction solution was filtered after the solid precipitated, and the collected filtrate was treated with anhydrous sodium sulfate and used as a mother liquor. The filter cake after filtration was washed with 100mL of ethanol, and the solid was dried to produce 5.32g of 2,5-diketopiperazine (yield = 70.0%).
[0044] Example 10
[0045] 10.0g of di-Gly peptide (0.151 mol) was placed in a reaction flask, and 50mL of ethylene glycol and 25mL of octyl acetate, a total of 75mL of solvent, were added and stirred. The electric heating jacket was heated until the thermometer in the reaction flask rose to 170°C and kept warm for 6.0 hours. After the reaction was completed, the reaction solution was cooled to room temperature 25°C and placed at 4°C for 24 hours. The solid precipitated in the reaction solution, the reaction solution was filtered after the solid precipitated, and the collected filtrate was treated with anhydrous sodium sulfate and used as a mother liquor. The filter cake after filtration was washed with 100mL of ethanol, and the solid was dried to produce 5.02g of 2,5-diketopiperazine (yield = 66.1%).
[0046] The above description is only a preferred embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that within the technical scope disclosed by the present invention, any change or replacement of the implementation method falls within the protection scope and disclosure scope of the present invention.
Claims
1. A method for preparing 2,5-diketopiperazine from diglycine, characterized in that: The steps include: (1) 6.6 g of di-Gly peptide and 25 mL of ethylene glycol solvent were placed in a reaction flask. Under stirring conditions, the electric heating mantle was heated until the thermometer in the reaction flask rose to 175°C and kept warm for 1.0 hour; After the reaction was completed, the reaction solution was cooled to room temperature 25°C and then kept at 4°C for 12 hours. The solid precipitated in the reaction solution was filtered out and the collected filtrate was treated with anhydrous sodium sulfate as the mother liquor. The filter cake after filtration was washed with 30 mL of ethanol and the solid was dried to produce 4.40 g of pure 2,5-diketopiperazine. (2) 6.6 g of Glycine Hydroxypropyl Methyl Peptide, 22 mL of the mother solution obtained in step (1) above and 3 mL of ethylene glycol (25 mL in total) were placed in a reaction flask as a solvent. Under stirring conditions, an electric heating mantle was used to heat the reaction flask until the thermometer in the flask rose to 175° C. and the temperature was kept at this temperature for 1.0 hour. After the reaction was completed, the reaction solution was cooled to room temperature 25°C and placed at 4°C for 12 hours. The solid precipitated in the reaction solution was filtered out after the solid precipitated. The collected filtrate was treated with anhydrous sodium sulfate as the mother liquor. The filter cake after filtration was washed with 30 mL of ethanol. The solid was dried to produce 4.89 g of 2,5-diketopiperazine. (3) 6.6 g of Glycine Hydroxypropyl Methyl Peptide, 20 mL of the mother solution obtained in step (2) and 5 mL of ethylene glycol (25 mL in total) were placed in a reaction flask as a solvent, and heated with an electric heating mantle until the thermometer in the reaction flask rose to 175° C. under stirring conditions and kept warm for 1.0 hour; After the reaction was completed, the reaction solution was cooled to room temperature 25°C and placed at 4°C for 12 hours. The solid precipitated in the reaction solution was filtered out after the solid precipitated. The collected filtrate was treated with anhydrous sodium sulfate as the mother liquor. The filter cake after filtration was washed with 30 mL of ethanol. The solid was dried to produce 5.11 g of 2,5-diketopiperazine; (4) 6.6 g of Glycine Hydroxypropyl Methyl Peptide, the mother solution obtained in step (3) and 5 mL of ethylene glycol (25 mL in total) were placed in a reaction flask as a solvent. Under stirring conditions, the electric heating mantle was heated until the thermometer in the reaction flask rose to 175° C. and the temperature was kept for 1.0 hour; After the reaction, the reaction solution was cooled to room temperature of 25°C and placed at 4°C for 12 hours. The solid precipitated in the reaction solution was filtered off and the collected filtrate was treated with anhydrous sodium sulfate as the mother liquor. The filter cake after filtration was washed with 50 mL of ethanol and the solid was dried to produce 5.13 g of 2,5-diketopiperazine.