Synthesis and application of 3-substituted pyroglutamic acid derivatives

Abstract

This invention discloses the synthesis of 3-substituted pyroglutamic acid derivatives, comprising: a first step, subjecting an unsaturated carboxylic acid ester represented by Formula II and a glycine imine ester represented by Formula III to a Michael addition reaction under alkaline conditions to obtain a substituted glutamic acid ester represented by Formula IV; a second step, subjecting the substituted glutamic acid ester represented by Formula IV to a benzophenone protecting group removal under acidic conditions, followed by thermal cyclization in triethylamine and toluene to obtain a pyroglutamic acid ester represented by Formula V; a third step, subjecting the pyroglutamic acid ester represented by Formula V to acidic hydrolysis to obtain 3-substituted pyroglutamic acid represented by Formula VI; a fourth step, subjecting the 3-substituted pyroglutamic acid represented by Formula VI to a piperazine protected by a tert-butoxycarbonyl group under the action of condensing agents EDCI and HOBt to obtain a compound represented by Formula VII; and a fifth step, subjecting the compound represented by Formula VII to acidic hydrolysis, followed by reaction with acryloyl chloride to obtain a 3-substituted pyroglutamic acid derivative represented by Formula I. Specifically, this invention provides a method for synthesizing a 3-substituted pyroglutamic acid derivative with anti-cerebral edema activity.

Description

Technical Field

[0001] This invention relates to a method for synthesizing derivatives, specifically a method for synthesizing a 3-substituted pyroglutamic acid derivative with anti-cerebral edema activity. Background Technology

[0002] Cerebral edema is one of the most common and important emergencies in neurology. It can be caused by a variety of diseases, including stroke, traumatic brain injury, acute high-altitude encephalopathy, and brain tumors, and can be localized or diffuse. The World Health Organization estimates that there are approximately 60 million brain and spinal cord injuries and 15 million strokes worldwide each year. Therefore, the incidence of cerebral edema is extremely high. Severe and persistent cerebral edema often leads to irreversible loss of neurological function and can even be life-threatening.

[0003] Cerebral edema can be divided into vasogenic edema and cytotoxic edema. Vasogenic edema is caused by increased extracellular fluid content due to cerebral vascular injury, increased permeability of the blood-brain barrier, and obstruction of venous and cerebrospinal fluid return, with blood-brain barrier disruption being the most common cause. Cytotoxic edema is caused by ion imbalance, disruption of the osmotic pressure balance across the cell membrane, leading to cell swelling and increased intracellular fluid content. Neurons and astrocytes are both susceptible cells for cytotoxic edema. In the human brain, astrocytes are far more numerous than neurons and are the main components of the blood-brain barrier, considered the primary cells affected by cytotoxic edema. In most pathological cases, cytotoxic edema occurs earlier than vasogenic edema. During the development of edema, vasogenic and cytotoxic edema occur alternately, jointly causing clinical cerebral edema.

[0004] Although cerebral edema has been understood for over a century, current clinical treatments are very limited. Drugs for treating cerebral edema, such as mannitol, glycerol saline, and hypertonic saline, primarily target vasogenic edema. For cytotoxic edema, which occurs earlier than vasogenic edema, there are still no effective treatments or clinically available drugs. Therefore, the development of anti-cytotoxic cerebral edema drugs is of great significance in both basic medicine and clinical treatment. Summary of the Invention

[0005] In view of the above-mentioned technical deficiencies, the purpose of this invention is to provide a synthesis method for 3-substituted pyroglutamic acid derivatives, thereby solving the existing problems.

[0006] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0007] This invention provides a method for synthesizing a 3-substituted pyroglutamic acid derivative represented by Formula I.

[0008]

[0009] The method includes:

[0010] The first step involves a Michael addition reaction between the unsaturated carboxylic acid ester represented by Formula II and the glycine imine ester represented by Formula III under basic conditions to obtain the substituted glutamate ester represented by Formula IV.

[0011]

[0012] In the second step, the substituted glutamate ester represented by Formula IV is deprotected by benzophenone under acidic conditions, and then undergoes thermal cyclization in triethylamine (Et3N) and toluene to obtain the pyroglutamate ester represented by Formula V.

[0013]

[0014] The third step involves acid hydrolysis of the pyroglutamic acid ester represented by formula V to obtain 3-substituted pyroglutamic acid represented by formula VI.

[0015]

[0016] In the fourth step, the 3-substituted pyroglutamic acid represented by formula VI and the piperazine protected by tert-butoxycarbonyl are reacted with condensing agents EDCI and HOBt to obtain the compound represented by formula VII.

[0017]

[0018] In the fifth step, the compound represented by formula VII is acidically hydrolyzed and then reacted with acryloyl chloride to obtain the 3-substituted pyroglutamic acid derivative represented by formula I.

[0019]

[0020] Specifically, the first step is as follows: Dissolve 10.0 mmol of the unsaturated carboxylic acid ester represented by formula II and 10.0 mmol of the glycine imine ester represented by formula III in 100 mL of dry tetrahydrofuran, and add 1.0 mmol of 1,8-diazabicyclo[5.4.0]undec-7-ene and 10.0 mmol of anhydrous lithium bromide in sequence, and stir the reaction at room temperature for 8 h.

[0021] Solid matter was removed by filtration under normal pressure. The filtrate was evaporated to dryness to obtain a yellow gelatinous residue. This residue was dissolved in dichloromethane and subjected to rapid column chromatography to obtain 5.13 g of a pale yellow transparent gelatinous pure product of formula IV substituted glutamate ester, with a yield of 96%. The eluent was n-hexane and ethyl acetate in a volume ratio of 20:1.

[0022] Specifically, the second step involves dissolving 5.0 mmol of the substituted glutamate represented by formula IV in 50 mL of dichloromethane, slowly adding 10 mL of 20.0 mmol of HCl aqueous solution, stirring at room temperature for 0.5 h, diluting the reaction solution with 100 mL of dichloromethane, adding 10 g of anhydrous sodium sulfate and drying, evaporating the solvent to obtain a yellow gelatinous residue, dissolving this residue in 20 mL of triethylamine and 80 mL of toluene, heating to 80 °C and stirring for 2 h, and filtering under normal pressure to remove the solid matter after the reaction solution has cooled to room temperature. The resulting filtrate is evaporated to dryness to obtain a yellow solid, and rapid column chromatography yields 1.38 g of a pale yellow powder of pure pyroglutamate represented by formula V, with a yield of 85%. The eluent is n-hexane and ethyl acetate in a volume ratio of 5:1.

[0023] Specifically, the third step involves dissolving 0.8 g of pyroglutamic acid ester (2.5 mmol) represented by formula V in 10 mL of dichloromethane (DCM), slowly adding 1.0 mL of trifluoroacetic acid (TFA, 10.0 mmol), stirring at room temperature for 2 h, and evaporating the solvent to obtain 0.67 g of pyroglutamic acid (yellow solid) represented by formula VI, which is directly used in the next step of the reaction.

[0024] Specifically, the fourth step involves dissolving 2.5 mmol of pyroglutamic acid (represented by formula VI) in 50 mL of dichloromethane. Then, 3 mmol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3 mmol of 1-hydroxybenzotriazole, and 2.7 mmol of tert-butoxycarbonyl-protected piperazine are added sequentially. The mixture is stirred at room temperature for 8 hours. The reaction solution is diluted with 100 mL of dichloromethane and washed sequentially with 20 mL of water and 20 mL of saturated saline solution. After drying with 15 g of anhydrous sodium sulfate, the solvent is evaporated to obtain a yellow gelatinous residue. This residue is then subjected to rapid column chromatography to obtain 0.90 g of a white powder of the compound represented by formula VII, with a yield of 81%. The eluent is a 1:1 volume ratio of n-hexane and ethyl acetate.

[0025] Specifically, the fifth step is as follows: Dissolve 2.0 mmol of the compound represented by formula VII in 10 mL of dichloromethane, slowly add 8.0 mmol of trifluoroacetic acid, stir at room temperature for 2 h, evaporate the solvent and dissolve the residue in 30 mL of dry dichloromethane, cool to -10 °C, slowly add 10 mL of triethylamine, stir for 0.5 h, then slowly add 0.18 g of acryloyl chloride, stir for 0.5 h, naturally warm to room temperature, and continue stirring for 1 h.

[0026] Evaporating the solvent yielded a yellow gelatinous residue. Rapid column chromatography was performed on this residue to obtain 0.78 g of a white solid pure 3-substituted pyroglutamic acid derivative represented by formula I, with the eluent being n-hexane and ethyl acetate in a volume ratio of 1:1.

[0027] On the other hand, the present invention provides an application of a 3-substituted pyroglutamic acid derivative represented by Formula I, applied to anti-cytotoxic cerebral edema, which alleviates the symptoms of cerebral edema by reducing the occurrence of programmed necrosis.

[0028] The beneficial effects of the present invention are as follows: the method of the present invention has the advantages of high yield, simple process flow, simple post-processing, high product purity and low cost. The 3-substituted pyroglutamic acid derivative produced has excellent anti-cytotoxic cerebral edema effect. Further studies have shown that it targets and inhibits mixed lineage kinase domain-like protein (MLKL) to exert anti-cytotoxic cerebral edema efficacy. Attached Figure Description

[0029] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0030] Figure 1 The 1H NMR spectrum of the 3-substituted pyroglutamic acid derivative in this invention ( 1 H-NMR spectrum;

[0031] Figure 2 Carbon NMR spectra of 3-substituted pyroglutamic acid derivatives 13 C-NMR spectrum;

[0032] Figure 3 This is a schematic diagram illustrating the changes in programmed necrosis-related molecules in the mouse brain under a high-altitude hypoxia-edema model.

[0033] Figure 4 This is a schematic diagram of brain water content in mice after MLKL knockout.

[0034] Figure 5 A schematic diagram of the blood-brain barrier after MLKL knockout in the mouse brain;

[0035] Figure 6 Evens-Blue diffusion reflects the extent of blood-brain barrier damage, which can be used to assess the degree of cerebral edema. The figure below shows that the 3-substituted pyroglutamic acid derivative represented by Formula I can significantly reduce blood-brain barrier damage and cerebral edema symptoms.

[0036] Figure 7 This is a schematic diagram showing the expression level of MLKL after primary mouse astrocytes were extracted and subjected to OGD (oxygen-glucose deprivation) experiment. Detailed Implementation

[0037] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0038] Example 1: A method for synthesizing a 3-substituted pyroglutamic acid derivative represented by Formula I.

[0039]

[0040]

[0041] The method includes:

[0042] The first step involves a Michael addition reaction between the unsaturated carboxylic acid ester represented by Formula II and the glycine imine ester represented by Formula III under basic conditions to obtain the substituted glutamate ester represented by Formula IV.

[0043]

[0044] In the second step, the substituted glutamate ester represented by Formula IV is deprotected by benzophenone under acidic conditions, and then undergoes thermal cyclization in triethylamine (Et3N) and toluene to obtain the pyroglutamate ester represented by Formula V.

[0045]

[0046] The third step involves acid hydrolysis of the pyroglutamic acid ester represented by formula V to obtain 3-substituted pyroglutamic acid represented by formula VI.

[0047]

[0048] In the fourth step, the 3-substituted pyroglutamic acid represented by formula VI and the piperazine protected by tert-butoxycarbonyl are reacted with condensing agents EDCI and HOBt to obtain the compound represented by formula VII.

[0049]

[0050] In the fifth step, the compound represented by formula VII is acidically hydrolyzed and then reacted with acryloyl chloride to obtain the 3-substituted pyroglutamic acid derivative represented by formula I.

[0051]

[0052] Specifically, the first step is as follows: Dissolve 10.0 mmol of the unsaturated carboxylic acid ester represented by formula II and 10.0 mmol of the glycine imine ester represented by formula III in 100 mL of dry tetrahydrofuran, and add 1.0 mmol of 1,8-diazabicyclo[5.4.0]undec-7-ene and 10.0 mmol of anhydrous lithium bromide in sequence, and stir the reaction at room temperature for 8 h.

[0053] Solid matter was removed by filtration under normal pressure. The filtrate was evaporated to dryness to obtain a yellow gelatinous residue. This residue was dissolved in dichloromethane and subjected to rapid column chromatography to obtain 5.13 g of a pale yellow transparent gelatinous pure product of formula IV substituted glutamate ester, with a yield of 96%. The eluent was n-hexane and ethyl acetate in a volume ratio of 20:1.

[0054] Specifically, the second step involves dissolving 5.0 mmol of the substituted glutamate represented by formula IV in 50 mL of dichloromethane, slowly adding 10 mL of 20.0 mmol of HCl aqueous solution, stirring at room temperature for 0.5 h, diluting the reaction solution with 100 mL of dichloromethane, adding 10 g of anhydrous sodium sulfate and drying, evaporating the solvent to obtain a yellow gelatinous residue, dissolving this residue in 20 mL of triethylamine and 80 mL of toluene, heating to 80 °C and stirring for 2 h, and filtering under normal pressure to remove the solid matter after the reaction solution has cooled to room temperature. The resulting filtrate is evaporated to dryness to obtain a yellow solid, and rapid column chromatography yields 1.38 g of a pale yellow powder of pure pyroglutamate represented by formula V, with a yield of 85%. The eluent is n-hexane and ethyl acetate in a volume ratio of 5:1.

[0055] Specifically, the third step involves dissolving 0.8 g of pyroglutamic acid ester (2.5 mmol) represented by formula V in 10 mL of dichloromethane (DCM), slowly adding 1.0 mL of trifluoroacetic acid (TFA, 10.0 mmol), stirring at room temperature for 2 h, and evaporating the solvent to obtain 0.67 g of 3-substituted pyroglutamic acid (yellow solid) represented by formula VI, which is directly used in the next step of the reaction.

[0056] Specifically, the fourth step involves dissolving 2.5 mmol of 3-substituted pyroglutamic acid (represented by formula VI) in 50 mL of dichloromethane. Then, 3 mmol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3 mmol of 1-hydroxybenzotriazole, and 2.7 mmol of tert-butoxycarbonyl-protected piperazine are added sequentially. The mixture is stirred at room temperature for 8 hours. The reaction solution is diluted with 100 mL of dichloromethane and washed sequentially with 20 mL of water and 20 mL of saturated saline solution. After drying with 15 g of anhydrous sodium sulfate, the solvent is evaporated to obtain a yellow gelatinous residue. This residue is then subjected to rapid column chromatography to obtain 0.90 g of a white powder of the compound represented by formula VII, with a yield of 81%. The eluent is a 1:1 mixture of n-hexane and ethyl acetate.

[0057] Specifically, the fifth step is as follows: Dissolve 2.0 mmol of the compound represented by formula VII in 10 mL of dichloromethane, slowly add 8.0 mmol of trifluoroacetic acid, stir at room temperature for 2 h, evaporate the solvent and dissolve the residue in 30 mL of dry dichloromethane, cool to -10 °C, slowly add 10 mL of triethylamine, stir for 0.5 h, then slowly add 0.18 g of acryloyl chloride, stir for 0.5 h, naturally warm to room temperature, and continue stirring for 1 h.

[0058] Evaporating the solvent yielded a yellow gelatinous residue. Rapid column chromatography was performed on this residue to obtain 0.78 g of a white solid pure 3-substituted pyroglutamic acid derivative represented by formula I, with the eluent being n-hexane and ethyl acetate in a volume ratio of 1:1.

[0059] In another embodiment, the present invention provides the application of a 3-substituted pyroglutamic acid derivative represented by Formula I, applied to combat cytotoxic cerebral edema, reduce the occurrence of programmed necrosis, and alleviate the symptoms of cerebral edema.

[0060] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

[0061] The characterization data of the 3-substituted pyroglutamic acid derivatives represented by Formula I are as follows (e.g.) Figure 1-2 As shown):

[0062] White solid. 1 H-NMR(400MHz,Chloroform-d)δ7.39(d,J=7.8Hz,1H),7.32-7.21(m,1H),7.13-6.89(m,3H),6.67-6.49(m,1H),6.33(d,J=16.8Hz,1H),5.76( d,J=10.6Hz,1H),4.76(s,1H),4.13-3.95(m,2H),3.95-3.53(m,8H),3.04-2.88(m,1H),2.68(dd,J=17.2.8.5Hz,1H),2.01(d,J=17.2Hz,1H); 13 C-NMR (101MHz, Chloroform-d) δ177.7,169.9,165.6,153.5,130.6,128.7,128. 1,127.0,122.5,113.4,69.8,55.6,45.9,42.5,38.7,31.7; HRMS(ESI:m / Z):M+Na +calcd for C19H22N3O4CINa + :414.1197,found:414.1195

[0063] Regarding the anti-cytotoxic cerebral edema activity of 3-substituted pyroglutamate derivatives:

[0064] Western blot analysis revealed that in a high-altitude hypoxia-edema model (mice were housed in a hypobaric chamber at an altitude of 5500m for 3 days), molecules related to programmed necrosis were upregulated in the mouse brain, such as... Figure 3 As shown in the figure. The degree of brain edema was reflected by detecting brain water content after brain edema in mice. Knockout of mixed lineage kinase domain-like protein (MLKL) significantly reduced brain water content, as shown in the figure. Figure 4 As shown. Brain water content = (wet weight - dry weight) / wet weight × 100% (wet weight is the mass of fresh brain tissue, and dry weight is the mass after drying in a 37℃ oven for 3 days).

[0065] The degree of blood-brain barrier disruption in a high-altitude hypoxia model mouse was assessed by tail vein injection of 2% Evens-Blue (200 μL / 20 g, E808783, MACKLIN) to reflect the extent of cerebral edema. Knockout of MLKL significantly reduced blood-brain barrier damage. Figure 5 As shown.

[0066] Through testing and screening of the anti-cerebral edema activity of synthesized 3-substituted pyroglutamic acid derivatives, it was found that the 3-substituted pyroglutamic acid derivative represented by Formula I can target and inhibit MLKL to resist cerebral edema, such as... Figure 6 As shown in the figure, administration of the 3-substituted pyroglutamic acid derivative represented by Formula I to mice with cerebral edema under a high-altitude hypoxia model significantly reduced kidney damage to the blood-brain barrier.

[0067] OGD (oxygen-glucose deprivation) assays performed on primary mouse astrocytes revealed a significant upregulation of pMLKL expression. Adding a 3-substituted pyroglutamate derivative (Formula I) to cell culture after OGD significantly reduced pMLKL expression levels. Figure 7 As shown.

[0068] In vivo experimental dosing procedures and data for 3-substituted pyroglutamic acid derivatives:

[0069] 3-Substituted pyroglutamic acid derivative 100 mg / kg Solutol HS-15 (polyethylene glycol-15-hydroxystearate), a commercially available solubilizer. The drug is typically dissolved in 5% DMSO, 10% Solutol, and 85% Saline to form a clear solution. Mice were placed in a high-altitude oxygen chamber for three days to establish the hypoxia model. The drug was administered on the second and third days. On the third day, after removal from the chamber, mice were injected with 2% Evans blue for 30 minutes, followed by brain perfusion for observation.

[0070] The 3-substituted pyroglutamic acid derivative represented by Formula I was found to have excellent anti-cytotoxic cerebral edema effects. Further studies have shown that it exerts its anti-cytotoxic cerebral edema efficacy by targeting and inhibiting MLKL.

Claims

1. A 3-substituted pyroglutamic acid derivative represented by Formula I, 。 2. A method for synthesizing a 3-substituted pyroglutamic acid derivative represented by Formula I, the method comprising: The first step involves a Michael addition reaction between the unsaturated carboxylic acid ester represented by Formula II and the glycine imine ester represented by Formula III under basic conditions to obtain the substituted glutamate ester represented by Formula IV. ； The second step involves removing the benzophenone protecting group from the substituted glutamate represented by formula IV under acidic conditions, followed by thermal cyclization in triethylamine and toluene to obtain the pyroglutamate represented by formula V. ； The third step involves acid hydrolysis of the pyroglutamic acid ester represented by formula V to obtain 3-substituted pyroglutamic acid represented by formula VI. ； In the fourth step, the 3-substituted pyroglutamic acid represented by formula VI and the piperazine protected by tert-butoxycarbonyl are reacted with condensing agents EDCI and HOBt to obtain the compound represented by formula VII. ； In the fifth step, the compound represented by formula VII is acidically hydrolyzed and then reacted with acryloyl chloride to obtain the 3-substituted pyroglutamic acid derivative represented by formula I. 。 3. The method for synthesizing the 3-substituted pyroglutamic acid derivative as described in claim 2, characterized in that, The specific steps of the first step are as follows: 10.0 mmol of the unsaturated carboxylic acid ester represented by Formula II and 10.0 mmol of the glycine imine ester represented by Formula III are dissolved in 100 mL of dry tetrahydrofuran, and 1.0 mmol of 1,8-diazabicyclo[5.4.0]undec-7-ene and 10.0 mmol of anhydrous lithium bromide are added sequentially, and the mixture is stirred at room temperature for 8 h. Solid matter was removed by filtration under normal pressure. The filtrate was evaporated to dryness to obtain a yellow gelatinous residue. This residue was dissolved in dichloromethane and subjected to rapid column chromatography to obtain 5.13 g of a pale yellow transparent gelatinous pure product of formula IV substituted glutamate ester, with a yield of 96%. The eluent was n-hexane and ethyl acetate in a volume ratio of 20:

1.

4. The method for synthesizing the 3-substituted pyroglutamic acid derivative as described in claim 2, characterized in that, The specific steps of the second step are as follows: 5.0 mmol of the substituted glutamate represented by formula IV was dissolved in 50 mL of dichloromethane, and 10 mL of 20.0 mmol of HCl aqueous solution was slowly added dropwise. The mixture was stirred at room temperature for 0.5 h. The reaction solution was diluted with 100 mL of dichloromethane, and 10 g of anhydrous sodium sulfate was added for drying. The solvent was evaporated to obtain a yellow gelatinous residue. This residue was dissolved in 20 mL of triethylamine and 80 mL of toluene, and the mixture was heated to 80 °C and stirred for 2 h. After the temperature of the reaction solution dropped to room temperature, the solid matter was removed by filtration under normal pressure. The filtrate was evaporated to obtain a yellow solid. Rapid column chromatography was used to obtain 1.38 g of a pale yellow powder of pure pyroglutamate represented by formula V, with a yield of 85%. The eluent was n-hexane and ethyl acetate in a volume ratio of 5:

1.

5. The method for synthesizing the 3-substituted pyroglutamic acid derivative as described in claim 2, characterized in that, The specific steps of the third step are as follows: Dissolve 2.5 mmol of pyroglutamic acid ester represented by formula V in 10 mL of dichloromethane, slowly add 10.0 mmol of trifluoroacetic acid, stir the reaction at room temperature for 2 h, evaporate the solvent to obtain 0.67 g of pyroglutamic acid represented by formula VI, which can be directly used in the next step of the reaction.

6. The method for synthesizing the 3-substituted pyroglutamic acid derivative as described in claim 2, characterized in that, The specific steps of the fourth step are as follows: 2.5 mmol of pyroglutamic acid represented by formula VI was dissolved in 50 mL of dichloromethane, and 3 mmol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3 mmol of 1-hydroxybenzotriazole, and 2.7 mmol of piperazine protected by tert-butoxycarbonyl were added sequentially. The mixture was stirred at room temperature for 8 h. The reaction solution was diluted with 100 mL of dichloromethane and washed sequentially with 20 mL of water and 20 mL of saturated saline solution, respectively. 15 g of anhydrous sodium sulfate was added for drying. The solvent was evaporated to obtain a yellow gelatinous residue. This residue was subjected to rapid column chromatography to obtain 0.90 g of the pure white powder of the compound represented by formula VII, with a yield of 81%. The eluent was n-hexane and ethyl acetate in a volume ratio of 1:

1.

7. The method for synthesizing the 3-substituted pyroglutamic acid derivative as described in claim 2, characterized in that, The specific steps of the fifth step are as follows: Dissolve 2.0 mmol of the compound represented by formula VII in 10 mL of dichloromethane, slowly add 8.0 mmol of trifluoroacetic acid, stir at room temperature for 2 h, evaporate the solvent and dissolve the residue in 30 mL of dry dichloromethane, cool to -10℃, slowly add 10 mL of triethylamine, stir for 0.5 h, then slowly add 0.18 g of acryloyl chloride, stir for 0.5 h, naturally warm to room temperature, and continue stirring for 1 h. Evaporating the solvent yielded a yellow gelatinous residue. Rapid column chromatography was performed on this residue to obtain 0.78 g of a white solid pure 3-substituted pyroglutamic acid derivative represented by formula I, with the eluent being n-hexane and ethyl acetate in a volume ratio of 1:

1.

8. An application of the 3-substituted pyroglutamic acid derivative represented by Formula I as described in claim 1, characterized in that, It is used in the preparation of drugs for treating cytotoxic cerebral edema.

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