A novel compound of a sulfonylcarbamate-modified substituted benzoylaminourea and a preparation method thereof

Abstract

The application discloses a kind of sulfuryl amino methyl carbonate base modified substituted benzamide urea new compounds and preparation method thereof, belong to heterocyclic compound technical field. With the key intermediate 4-[2-(2-amino-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid of synthesizing pemetrexed disodium as mother nucleus, using NHS / EDC system activation mother nucleus carboxyl, make it react with the modifier containing free amino, so as to introduce glutamic acid recognition site and hydrophobic sulfuryl amino methyl carbonate tert-butyl ester fragment in structure;Modifier is lysine as connecting chain, glutamic acid and lysine are connected by amide bond, chlorosulfonyl amino methyl carbonate tert-butyl ester is grafted to lysine side chain by nucleophilic substitution reaction, while retaining pemetrexed recognition site, improve the hydrophobicity of molecular structure.

Description

Technical Field

[0001] This invention relates to the field of heterocyclic compound technology, specifically to a novel substituted benzoylaminourea compound modified with a sulfonyl carbamate group and its preparation method. Background Technology

[0002] Pemetrexed disodium is an antifolate agent with a core pyrrolopyrimidine group. It inhibits cell replication and thus tumor growth by disrupting normal folate-dependent metabolic processes within cells. Its main targets are thymidine synthase (TS), dihydrofolate reductase (DHFR), and glycine nucleotide transformylase (GARFT). By inhibiting these key enzymes, it affects the synthesis of purines and pyrimidines, thereby inhibiting DNA synthesis. Clinical studies have demonstrated its effectiveness as a monotherapy or in combination with other drugs against various tumors, including non-small cell lung cancer, malignant pleural mesothelioma, head and neck tumors, gastric cancer, bladder cancer, breast cancer, and cervical cancer. Pemetrexed has a broad-spectrum anticancer effect, showing definite efficacy against many solid tumors, and its side effects can be prevented or mitigated. Currently, the main dosage form of pemetrexed is disodium salt, primarily in magnesium, calcium, meglumine, and glucosamine salt forms. Among these salts, meglumine and glucosamine salts are highly hygroscopic and inconvenient to store; ethylenediamine salts are highly toxic. Therefore, there is a need to develop a new compound for antitumor purposes.

[0003] 4-[2-(2-amino-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid is a key intermediate in the synthesis of pemetrexed disodium. Its structure is similar to that of folic acid, and it has potential anti-tumor application value. Summary of the Invention

[0004] The purpose of this invention is to provide a novel substituted benzoylcarbamate compound modified with a sulfonylcarbamate group and its preparation method. Using 4-[2-(2-amino-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid, a key intermediate in the synthesis of pemetrexed disodium, as the parent nucleus, the carboxyl group is activated using a system of 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysuccinimide (NHS). This reacts with a modifier containing a free amino group, introducing a glutamate recognition site and a hydrophobic sulfonylcarbamate tert-butyl ester fragment into the structure. This enhances the overall hydrophobicity of the molecular structure, thereby affecting the permeability of tumor cell membranes.

[0005] To achieve the above objectives, in a first aspect, the present invention provides a novel substituted benzoylcarbamate compound modified with a sulfonylcarbamate group. The novel compound comprises a parent core and a modifier. The parent core is 4-[2-(2-amino-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid; the modifier is a lysine-linked glutamic acid and sulfonylcarbamate tert-butyl ester structure; the parent core and the modifier are connected by an amide bond. The structural formula of the novel compound is as follows: .

[0006] Secondly, the present invention provides a method for preparing a novel substituted benzoylaminourea compound modified with a sulfonyl carbamate group, comprising the following steps:

[0007] S1. The parent nucleus is reacted with benzyl chloroformate in anhydrous N,N-dimethylformamide (DMF) with triethylamine as a pH adjuster to prepare an amino-protected parent nucleus.

[0008] S2. Activate the carboxyl group of the amino protected parent nucleus in anhydrous DMF using the NHS / EDC system to obtain reaction solution 1;

[0009] S3. Dissolve the modifier and N,N-diisopropylethylamine in anhydrous DMF to obtain a modifier solution; add the modifier solution to reaction solution 1, stir, quench the reaction with anhydrous acetic acid, and after post-treatment, obtain product 2;

[0010] S4. Product 2 was reacted with 10 wt.% palladium on carbon in methanol and hydrogen. After separation and purification, a new substituted benzoylaminourea compound modified with sulfonyl carbamate group was obtained.

[0011] Further, in S1, the mass-to-volume ratio of the parent nucleus, benzyl chloroformate, and DMF is 1 g: (0.85~0.9) g: (20~40) mL; the reaction speed is 400~600 rpm, and the reaction time is 2~4 h.

[0012] Further, in S1, 4-[2-(2-amino-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid is dissolved in anhydrous DMF to obtain a nucleus solution; the pH of the nucleus solution is adjusted to 8 with triethylamine, and after cooling to 4°C, benzyl chloroformate is added in an ice-water bath, and the reaction is stirred; after the reaction is completed, the solution is distilled under reduced pressure until the solvent is evaporated to dryness, and 10 times the volume of ethyl acetate is added to the evaporated solid, and the mixture is stirred until the solid is completely dissolved to obtain a residue solution; The residue solution was transferred to a separatory funnel, and an equal volume of 5% citric acid aqueous solution was added. After vigorous shaking, the mixture was allowed to stand and separate into layers. The organic phase was collected. The aqueous phase was extracted twice with an equal volume of ethyl acetate, and the organic phases were combined. The organic phase was washed once with an equal volume of saturated sodium bicarbonate solution and once with saturated brine. After standing and separating into layers, the organic phase was collected. Anhydrous sodium sulfate was added to the organic phase, and the mixture was allowed to stand and dry for 30 min. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to remove the solvent, yielding the amino-protected nucleus.

[0013] Further, in S2, the NHS / EDC system includes NHS and EDC·HCl; the mass-to-volume ratio of the amino-protected core, NHS, EDC·HCl and anhydrous DMF is 1g:(1.0~1.1)g:(0.85~0.9)g:(30~50)mL; the activation temperature is 15~20℃, the activation speed is 200~400rpm, and the activation time is 1~2h.

[0014] Further, in S3, the mass-to-volume ratio of the modifier, N,N-diisopropylethylamine, and anhydrous DMF is 1 g : (0.17~0.18) g : (10~20) mL; the volume ratio of the modifier solution to reaction solution 1 is (15~25) : (30~50); the stirring temperature is 20~25℃, the stirring speed is 400~500 rpm, and the stirring time is 8~12 h; the volume ratio of anhydrous acetic acid to reaction solution 1 is 1 : (10~15).

[0015] The core of quenching the condensation of amino and carboxyl groups in EDC lies in rapidly inactivating excess condensing agents and hydrolyzing unreacted activated ester / acylurea intermediates using acidic / weakly alkaline aqueous solutions, while simultaneously washing away byproducts and additives. Conventional one-step aqueous quenching, where water is directly added to the DMF reaction solution, leads to violent hydrolytic deothermia and a rapid increase in local temperature between EDC and NHS esters, easily triggering side reactions such as amide bond hydrolysis and racemic NHS ester reactions. Therefore, adding a small amount of anhydrous acetic acid to the reaction system creates a weakly acidic environment, achieving the desired quenching effect.

[0016] Further, the post-processing in S3 is as follows: Anhydrous acetic acid is added to reaction solution 1 to obtain reaction solution 2; a large amount of ice water is added to reaction solution 2, and after stirring and mixing, it is extracted three times with ethyl acetate of the same volume as the ice water. The organic phases are combined, anhydrous sodium sulfate is added to the organic phase, and after standing and drying, the desiccant is removed by filtration; the solvent is removed by vacuum distillation of the filtrate, and the product obtained by vacuum distillation is separated by silica gel column chromatography. The solvent is removed by rotary evaporation of the eluent of the separated product to obtain product 2.

[0017] Further, in S4, the mass-to-volume ratio of product 2, 10 wt.% palladium on carbon, and methanol is 1 g: (0.05~0.1) g: (10~20) mL; the pressure of the hydrogen gas is 1~2 bar.

[0018] Further, the separation and purification process in S4 is as follows: palladium on carbon is removed by filtration, the filter cake is washed with anhydrous methanol, the filtrates are combined, and the distillation is carried out under reduced pressure in the dark until the distillation rate of the distillate slows down significantly; methanol with a volume twice that of the concentrate is added to the concentrate, and the distillation is carried out under reduced pressure in the dark again until the distillation rate of the distillate slows down significantly; the residue is dissolved in ethyl acetate with a volume twice that of the residue, the mixture is transferred to a separatory funnel, an equal volume of pure water is added, the mixture is gently shaken and allowed to stand for separation, and the organic phase is retained; the aqueous phase is back-extracted three times with the same organic solvent, all organic phases are combined, the organic phase is washed with supersaturated brine, anhydrous sodium sulfate is added to the organic phase, the mixture is allowed to stand and dry for 30 min, the desiccant is removed by filtration, and the solvent is removed by reduced pressure distillation of the filtrate.

[0019] Thirdly, the present invention provides a method for preparing the modified body described in step S3, comprising the following steps:

[0020] A1. Cross-protection of the amino group on lysine is performed to obtain lysine with protected amino group; the carboxyl group of lysine with protected amino group is activated in anhydrous DMF using an NHS / EDC system to obtain reaction solution A.

[0021] A2. Disperse L-glutamic acid dibenzyl ester hydrochloride and N,N-diisopropylethylamine in anhydrous DMF and stir to obtain a glutamic acid solution; add the glutamic acid solution to reaction solution A, mix, and obtain reaction solution B;

[0022] A3. Add piperazine and 1,8-diazabicyclo[5.4.0]undec-7-ene to reaction solution B, stir, and purify to obtain reactant C;

[0023] A4. Reactant C reacts with tert-butyl chlorosulfonyl carbamate in anhydrous acetonitrile, using N,N-diisopropylethylamine as a base, and after separation and purification, reactant D is obtained.

[0024] A5. Reactant D was dissolved in dichloromethane, and trifluoroacetic acid and anisole were added. After stirring and purification, the modified product was obtained.

[0025] Furthermore, in A1, the process of cross-protecting the amino group on lysine to obtain lysine with protected amino groups is as follows:

[0026] Formation of B1 lysine-copper complex: 1 eq of lysine was dissolved in 0.5 mol / L hydrochloric acid solution, and 1.1 eq of basic copper carbonate was added. After stirring evenly, a reaction solution was obtained. The reaction solution was refluxed at 95℃ for 30 min, filtered, and the pH of the filtrate was adjusted to 8 with 10 wt.% sodium carbonate solution to obtain reaction solution L1.

[0027] Protection of the ℇ-amino group of lysine in complex B2: 1,4-dioxane and anhydrous DMF were added to reaction solution L1. After cooling to 0°C, 1 eq of 9-fluorenemethyl-N-succinimide carbonate (Fmoc-OSu) was added. The mixture was stirred at 200 rpm for 30 min at 0°C. After naturally warming to room temperature, the mixture was stirred at 200 rpm for 12 h. The mixture was filtered, and the precipitate was washed with ether and water. After vacuum drying, a blue powdery monoprotected complex was obtained. The monoprotection was the protection of the ℇ-amino group of lysine by Fmoc.

[0028] Decomposition of B3 complex: The copper complex is decomposed using any one of the following methods: ethylenediaminetetraacetic acid (EDTA), hydrochloric acid, hydrogen sulfide, or tetrahydrothiazothione. The tetrahydrothiazothione method is preferred, and the specific operation is as follows:

[0029] 1 eq of the monoprotected complex was dissolved in methanol to form a methanol solution of the monoprotected complex. A methanol solution of tetrahydrothiazothione was added dropwise to the methanol solution of the monoprotected complex, with the amount of tetrahydrothiazothione added being 5 eq. The mixture was stirred at 150 rpm for 5 min, filtered, and the filtrate was distilled under reduced pressure until all the solvent was evaporated. The residue was recrystallized from methanol-water to obtain monoprotected lysine.

[0030] α-Amino protection of B4 lysine: 1 eq of monoprotected lysine was dispersed in a mixed solvent of DMF and 10 wt.% sodium carbonate solution at a volume ratio of 1:2. After cooling to 0°C, 2 eq of di-tert-butyl dicarbonate was added, and the mixture was stirred at 150 rpm at room temperature for 12 h. Then, 10 times the volume of water was added to obtain reaction solution L2. The pH of reaction solution L2 was adjusted to 3 with 2 mol / L hydrochloric acid solution to obtain reaction solution L3. Reaction solution L3 was extracted with ethyl acetate, and the organic phase was collected. The organic phase was washed once with an equal volume of water and saturated brine. Anhydrous sodium sulfate was added to the organic phase, and the mixture was allowed to stand and dry for 30 min. The drying agent was removed by filtration, and the solvent was removed by vacuum distillation. The residue was recrystallized from ethyl acetate and petroleum ether to obtain lysine with amino protection.

[0031] The glutamic acid structure in the pemetrexed compound is the main recognition site for TS (transferase inhibitors), linked to the benzene ring via an amide bond. To retain this recognition site and ensure the modified compound retains its anticancer effect, a small molecule linker bond was inserted between the glutamic acid and benzene ring. Lysine contains a carboxyl group, an α-amino group, and... The amino group is an ideal linking structure; the carboxyl group in its molecular structure can be linked to the amino group of glutamic acid via an amide bond, and the terminal amino group can be linked to the parent nucleus via an amide bond. It can also undergo nucleophilic substitution reactions with tert-butyl chlorosulfonylcarbamate to introduce a tert-butyl sulfonylcarbamate structure. To avoid... The amino group is attached to the parent nucleus, resulting in excessive intercalation of linkages between the parent nucleus and glutamic acid, selectively protecting the amino group of lysine through cross-protection. The carboxyl and α-amino groups of lysine can form stable complexes with metals; therefore, basic copper carbonate is first used to form a lysine-copper complex with the carboxyl and α-amino groups of lysine, thus protecting the amino group in the lysine structure. The amino group is free, and lysine is protected by Fmoc. The amino group is further decomposed into a complex, which releases the α-amino and carboxyl groups in the lysine structure. The α-amino group of lysine is then protected by a tert-butoxycarbonyl (Boc) group, forming lysine with the amino group protected.

[0032] Further, in A1, the NHS / EDC system includes NHS and EDC·HCl; the mass-to-volume ratio of the amino-protected lysine, NHS, EDC·HCl, and anhydrous DMF is 1 g : (0.9~1.0) g : (0.75~0.85) g : (30~50) mL; the activation temperature is 15~20℃, the activation rotation speed is 200~400 rpm, and the activation time is 1~2 h.

[0033] Further, in A2, the mass-to-volume ratio of L-glutamic acid dibenzyl ester hydrochloride, N,N-diisopropylethylamine, and anhydrous DMF is 1 g : (0.36~0.38) g : (10~15) mL; the stirring speed is 100~200 rpm, and the stirring time is 5~10 min; the volume ratio of glutamic acid solution to reaction solution A is (10~15) : (30~50); the mixing temperature is 20~25℃, the mixing speed is 300~500 rpm, and the mixing time is 6~8 h.

[0034] Further, in A3, the mass-to-volume ratio of the reaction solution B, piperazine, and 1,8-diazabicyclo[5.4.0]undec-7-ene is (45~60) mL : (2.25~3) g : (0.45~0.6) g; the stirring speed is 200~300 rpm, the stirring temperature is 20~25℃, and the stirring time is 20~30 min.

[0035] Further, in A3, the purification process is as follows: piperazine and 1,8-diazabicyclo[5.4.0]undec-7-ene are added to reaction solution B to obtain reaction solution B1; reaction solution B1 is poured into 10 times the volume of ice water and stirred until a solid precipitates; the solid product is collected by vacuum filtration, and the filter cake is washed sequentially with deionized water, 5wt.% sodium bicarbonate solution, water, and diethyl ether; the washed filter cake is then vacuum dried to obtain product C.

[0036] Further, in A4, the mass-to-volume ratio of reactant C, tert-butyl chlorosulfonyl carbamate, N,N-diisopropylethylamine, and anhydrous acetonitrile is 1 g : (0.65~0.7) g : (0.38~0.43) g : 10 mL; the reaction speed is 200~300 rpm, and the reaction time is 50~70 min.

[0037] Further, in A4, reactant C and N,N-diisopropylethylamine are dispersed in anhydrous acetonitrile and cooled to 0°C under nitrogen protection; an anhydrous acetonitrile solution of tert-butyl chlorosulfonyl carbamate is added dropwise at 1 mL / min at 4°C. After the addition is completed, the mixture is protected from light and allowed to naturally warm to room temperature. The mixture is then stirred to obtain reaction solution C.

[0038] Further, in A4, the purification process is as follows: saturated ammonium chloride solution is added to the reaction solution C after the reaction is completed to quench the reaction, and the mixture is stirred for 10 min to obtain reaction solution C1; an equal volume of ethyl acetate is added to the reaction solution C1 for extraction three times, the organic phases are combined, and the organic phases are washed successively with water, saturated sodium bicarbonate, and saturated brine; anhydrous sodium sulfate is added to the organic phase, and the mixture is allowed to stand and dry for 30 min, the desiccant is removed by suction filtration, and the solvent is removed by vacuum distillation of the filtrate to obtain the crude product; the crude product is purified by silica gel column chromatography to obtain reactant D.

[0039] Further, in A5, the mass-to-volume ratio of reactant D, dichloromethane, trifluoroacetic acid, and anisole is 1g:(30~40)mL:(3~4)mL:(0.09~0.1)mL; the stirring speed is 200~300rpm, the stirring temperature is 20~25℃, and the stirring time is 1~3h.

[0040] Further, in A5, the purification process is as follows: After the reaction is completed, the distillation is carried out under reduced pressure until the distillation rate of the distillate slows down significantly, and a residue is obtained; toluene is added to the residue at a mass-to-volume ratio of 1g:10mL, and the distillation is carried out under reduced pressure again until the distillation rate of the distillate slows down significantly, and a concentrate is obtained; diethyl ether is added dropwise to the stirred concentrate at a stirring rate of 600rpm, and the amount of diethyl ether added is 20 times the volume of the concentrate. After the solid precipitates, stirring is continued for 30min; the solid is collected by suction filtration, the filter cake is washed three times with diethyl ether, and the modified body is obtained after vacuum drying.

[0041] Reactant D contains two Boc protecting groups: one attached to the α-amino group of lysine (Boc1), and the other to the Boc group of tert-butyl sulfonylcarbamate (Boc2). To retain Boc2, Boc1 is selectively removed. Since the nitrogen atom attached to Boc1 is only bonded to the electron-donating alkyl carbon, its electron cloud density is high. This allows it to donate electrons to the carbonyl oxygen of Boc1 through a conjugation effect, significantly increasing the basicity of the carbonyl oxygen. Conversely, the nitrogen atom attached to Boc2 is directly bonded to the strongly electron-withdrawing sulfonyl group, resulting in a lower electron cloud density. This transforms Boc2 from an electron donor to a strongly electron-withdrawing group, leading to a decrease in its basicity. Under normal acidic conditions, Boc2 is almost impossible to protonate, exhibiting higher acid stability than Boc1, and hardly decomposes under mild awakening conditions. Therefore, the debonding conditions can be controlled to achieve the selective removal of Boc1.

[0042] Compared with the prior art, the beneficial effects achieved by the present invention are as follows:

[0043] This invention provides a novel substituted benzoylaminourea compound modified with sulfonyl carbamate group and its preparation method, wherein the hydrophobicity of the novel compound is improved compared with that of pemetrexed. Using the folic acid analog 4-[2-(2-amino-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid as the parent nucleus, a lysine structure was inserted between the benzoyl group and glutamic acid, and the ℇ-amino group of lysine was replaced by tert-butyl chlorosulfonyl carbamate. This fully preserved the core pharmacophore of pemetrexed and the double free carboxyl group structure necessary for folic acid receptor recognition, ensuring the basic antitumor activity and folic acid receptor targeting ability of the new compound. By introducing the hydrophobic structural unit of tert-butyl chlorosulfonyl carbamate, the problem of insufficient passive cell membrane penetration caused by the strong hydrophilicity of the original drug was alleviated. This enabled the new compound to simultaneously possess two tumor cell uptake pathways: active targeting of folic acid receptors and passive diffusion of the phospholipid bilayer. It can achieve targeted enrichment of folic acid receptor-positive tumors through the double carboxyl group structure of glutamic acid, and can also penetrate the tumor cell membrane using the hydrophobic structural unit. Attached Figure Description

[0044] Figure 1 This is a schematic diagram of the chemical structure of the parent nucleus in this invention.

[0045] Figure 2 This is a schematic diagram of the chemical structure of the novel sulfonyl carbamate-modified substituted benzoyl urea compound prepared in this invention. Detailed Implementation

[0046] The technical solution of the present invention will be described in detail below through specific embodiments. It should be understood that the embodiments of the present invention and the specific features in the embodiments are detailed descriptions of the technical solution of the present invention, rather than limitations on the technical solution of the present invention. In the absence of conflict, the embodiments of the present invention and the technical features in the embodiments can be combined with each other.

[0047] The term "and / or" simply describes the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A alone, A and B simultaneously, or B alone. Additionally, the character " / " generally indicates that the preceding and following related objects have an "or" relationship.

[0048] This invention provides cross-protection for the amino group on lysine. The process for preparing lysine with protected amino groups is as follows:

[0049] Formation of B1 lysine-copper complex: 1 eq of lysine was dissolved in 0.5 mol / L hydrochloric acid solution, and 1.1 eq of basic copper carbonate was added. After stirring evenly, a reaction solution was obtained. The reaction solution was refluxed at 95℃ for 30 min, filtered, and the pH of the filtrate was adjusted to 8 with 10 wt.% sodium carbonate solution to obtain reaction solution L1.

[0050] Protection of the ℇ-amino group of lysine in complex B2: 1,4-dioxane and anhydrous DMF were added to reaction solution L1. After cooling to 0°C, 1 eq of 9-fluorenemethyl-N-succinimide carbonate (Fmoc-OSu) was added. The mixture was stirred at 200 rpm for 30 min at 0°C. After naturally warming to room temperature, the mixture was stirred at 200 rpm for 12 h. The mixture was filtered, and the precipitate was washed with ether and water. After vacuum drying, a blue powdery monoprotected complex was obtained. The monoprotection was the protection of the ℇ-amino group of lysine by Fmoc.

[0051] Decomposition of B3 complex: The preferred method is the tetrahydrothiazolium thione method. 1 eq of the monoprotected complex is dissolved in methanol to form a methanol solution of the monoprotected complex. A methanol solution of tetrahydrothiazolium thione is added dropwise to the methanol solution of the monoprotected complex, with the amount of tetrahydrothiazolium thione added being 5 eq. The mixture is stirred at 150 rpm for 5 min, filtered, and the filtrate is distilled under reduced pressure until all the solvent is evaporated. The residue is recrystallized from methanol-water to obtain monoprotected lysine.

[0052] α-Amino protection of B4 lysine: 1 eq of monoprotected lysine was dispersed in a mixed solvent of DMF and 10 wt.% sodium carbonate solution at a volume ratio of 1:2. After cooling to 0°C, 2 eq of di-tert-butyl dicarbonate was added, and the mixture was stirred at 150 rpm at room temperature for 12 h. Then, 10 times the volume of water was added to obtain reaction solution L2. The pH of reaction solution L2 was adjusted to 3 with 2 mol / L hydrochloric acid solution to obtain reaction solution L3. Reaction solution L3 was extracted with ethyl acetate, and the organic phase was collected. The organic phase was washed once with an equal volume of water and saturated brine. Anhydrous sodium sulfate was added to the organic phase, and the mixture was allowed to stand and dry for 30 min. The drying agent was removed by filtration, and the solvent was removed by vacuum distillation. The residue was recrystallized from ethyl acetate and petroleum ether to obtain lysine with amino protection.

[0053] Example 1

[0054] A modified body, the preparation method of which includes:

[0055] A1. Dissolve 0.96g NHS in 40mL anhydrous DMF, add 1g of amino-protected lysine prepared as described above, stir at 150rpm for 15min, cool to 4℃, add 0.79g EDC·HCl in an ice-water bath, and react at 300rpm at 17℃ for 1.5h to obtain reaction solution A.

[0056] A2. Disperse 1g of L-glutamic acid dibenzyl ester hydrochloride and 0.37g of N,N-diisopropylethylamine in 12mL of anhydrous DMF and stir at 150rpm for 7min to obtain a glutamic acid solution; add 11.5mL of the glutamic acid solution to 40mL of reaction solution A and stir at 400rpm at 22℃ for 7h to obtain reaction solution B;

[0057] A3. Add 2.57 g piperazine and 0.51 g 1,8-diazabicyclo[5.4.0]undec-7-ene to 51.5 mL of reaction solution B. Stir at 250 rpm for 25 min at 22 °C to obtain reaction solution B1. Pour reaction solution B1 into 10 times its volume of ice water and stir until a solid precipitates. Collect the solid product by vacuum filtration. Wash the filter cake sequentially with deionized water, 5 wt.% sodium bicarbonate solution, water, and diethyl ether. Dry the washed filter cake under vacuum to obtain product C.

[0058] A4. Mix 1g of reactant C with 0.4g of... N,N-Diisopropylethylamine was dispersed in 5 mL of anhydrous acetonitrile and cooled to 0 °C under nitrogen protection. An anhydrous acetonitrile solution of tert-butyl chlorosulfonate was added dropwise at 1 mL / min at 4 °C. The anhydrous acetonitrile solution of tert-butyl chlorosulfonate was prepared by dispersing 0.68 g of tert-butyl chlorosulfonate in 5 mL of anhydrous acetonitrile. After the addition was complete, the mixture was protected from light and allowed to naturally warm to room temperature. The mixture was stirred at 250 rpm for 60 min to obtain reaction solution C. A saturated ammonium chloride solution was added to reaction solution C to quench the reaction, and the mixture was stirred for 10 min to obtain reaction solution C1. An equal volume of ethyl acetate was added to reaction solution C1 for extraction three times. The organic phases were combined and washed successively with water, saturated sodium bicarbonate, and saturated brine. Anhydrous sodium sulfate was added to the organic phase, and the mixture was allowed to stand and dry for 30 min. The drying agent was removed by filtration, and the solvent was removed by vacuum distillation of the filtrate to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain reactant D.

[0059] A5. Dissolve 1g of reactant D in 35mL of dichloromethane, add 3.5mL of trifluoroacetic acid and 0.095mL of anisole, and stir at 250rpm at 22℃ for 2h to obtain reaction solution D; distill reaction solution D under reduced pressure until the distillation rate of the distillate slows down significantly to obtain a residue; add toluene to the residue at a mass-to-volume ratio of 1g:10mL, and distill under reduced pressure again until the distillation rate of the distillate slows down significantly to obtain a concentrate; add diethyl ether dropwise to the stirred concentrate at a stirring rate of 600rpm, with the amount of diethyl ether added being 20 times the volume of the concentrate; after the solid precipitates, continue stirring for 30min; collect the solid by suction filtration, wash the filter cake three times with diethyl ether, and dry under vacuum to obtain the modified body.

[0060] Example 2

[0061] A modified body, the preparation method of which includes:

[0062] A1. Dissolve 0.9g NHS in 30mL anhydrous DMF, add 1g of amino-protected lysine prepared as described above, stir at 200rpm for 10min, cool to 4℃, add 0.75g EDC·HCl in an ice-water bath, and react at 20℃ for 2h at 200rpm to obtain reaction solution A.

[0063] A2. Disperse 1g of L-glutamic acid dibenzyl ester hydrochloride and 0.38g of N,N-diisopropylethylamine in 15mL of anhydrous DMF and stir at 200rpm for 5min to obtain a glutamic acid solution; add 15mL of the glutamic acid solution to 30mL of reaction solution A and stir at 500rpm at 20℃ for 6h to obtain reaction solution B;

[0064] A3. Add 2.25 g piperazine and 0.45 g 1,8-diazabicyclo[5.4.0]undec-7-ene to 45 mL of reaction solution B. Stir at 300 rpm for 20 min at 20 °C to obtain reaction solution B1. Pour reaction solution B1 into 10 times its volume of ice water and stir until a solid precipitates. Collect the solid product by vacuum filtration. Wash the filter cake sequentially with deionized water, 5 wt.% sodium bicarbonate solution, water, and diethyl ether. Dry the washed filter cake under vacuum to obtain product C.

[0065] A4. Mix 1g of reactant C with 0.38g of... N,N-Diisopropylethylamine was dispersed in 5 mL of anhydrous acetonitrile and cooled to 0 °C under nitrogen protection. An anhydrous acetonitrile solution of tert-butyl chlorosulfonate was added dropwise at 1 mL / min at 4 °C. The anhydrous acetonitrile solution of tert-butyl chlorosulfonate was prepared by dispersing 0.65 g of tert-butyl chlorosulfonate in 5 mL of anhydrous acetonitrile. After the addition was complete, the mixture was protected from light and allowed to naturally warm to room temperature. The mixture was stirred at 200 rpm for 70 min to obtain reaction solution C. A saturated ammonium chloride solution was added to reaction solution C to quench the reaction, and the mixture was stirred for 10 min to obtain reaction solution C1. An equal volume of ethyl acetate was added to reaction solution C1 for extraction three times. The organic phases were combined and washed successively with water, saturated sodium bicarbonate, and saturated brine. Anhydrous sodium sulfate was added to the organic phase, and the mixture was allowed to stand and dry for 30 min. The drying agent was removed by filtration, and the solvent was removed by vacuum distillation of the filtrate to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain reactant D.

[0066] A5. Dissolve 1g of reactant D in 30mL of dichloromethane, add 3mL of trifluoroacetic acid and 0.09mL of anisole, and stir at 300rpm at 20℃ for 1h to obtain reaction solution D; distill reaction solution D under reduced pressure until the distillation rate of the distillate slows down significantly to obtain a residue; add toluene to the residue at a mass-to-volume ratio of 1g:10mL, and distill under reduced pressure again until the distillation rate of the distillate slows down significantly to obtain a concentrate; add diethyl ether dropwise to the stirred concentrate at a stirring rate of 600rpm, with the amount of diethyl ether added being 20 times the volume of the concentrate; after the solid precipitates, continue stirring for 30min; collect the solid by suction filtration, wash the filter cake three times with diethyl ether, and dry under vacuum to obtain the modified body.

[0067] Example 3

[0068] A modified body, the preparation method of which includes:

[0069] A1. Dissolve 1.0 g NHS in 50 mL of anhydrous DMF, add 1 g of amino-protected lysine prepared as described above, stir at 100 rpm for 20 min, cool to 4 °C, add 0.85 g EDC·HCl in an ice-water bath, and react at 15 °C for 1 h at 400 rpm to obtain reaction solution A.

[0070] A2. Disperse 1g of L-glutamic acid dibenzyl ester hydrochloride and 0.36g of N,N-diisopropylethylamine in 10mL of anhydrous DMF to obtain a glutamic acid solution; add 10mL of aminourea solution to 50mL of reaction solution A, and stir at 300rpm at 25℃ for 8h to obtain reaction solution B.

[0071] A3. Add 3g piperazine and 0.6g 1,8-diazabicyclo[5.4.0]undec-7-ene to 60mL of reaction solution B. Stir at 200rpm for 30min at 25℃ to obtain reaction solution B1. Pour reaction solution B1 into 10 times its volume of ice water and stir until a solid precipitates. Collect the solid product by filtration. Wash the filter cake sequentially with deionized water, 5wt.% sodium bicarbonate solution, water, and diethyl ether. Dry the washed filter cake under vacuum to obtain product C.

[0072] A4. Mix 1g of reactant C with 0.43g of... N,N-Diisopropylethylamine was dispersed in 5 mL of anhydrous acetonitrile and cooled to 0 °C under nitrogen protection. An anhydrous acetonitrile solution of tert-butyl chlorosulfonate was added dropwise at 1 mL / min at 4 °C. This anhydrous acetonitrile solution of tert-butyl chlorosulfonate was prepared by dispersing 0.7 g of tert-butyl chlorosulfonate in 5 mL of anhydrous acetonitrile. After the addition was complete, the mixture was protected from light and allowed to naturally warm to room temperature. The mixture was stirred at 300 rpm for 50 min to obtain reaction solution C. A saturated ammonium chloride solution was added to reaction solution C to quench the reaction, and the mixture was stirred for 10 min to obtain reaction solution C1. An equal volume of ethyl acetate was added to reaction solution C1 for extraction three times. The organic phases were combined and washed successively with water, saturated sodium bicarbonate, and saturated brine. Anhydrous sodium sulfate was added to the organic phase, and the mixture was allowed to stand and dry for 30 min. The drying agent was removed by filtration, and the solvent was removed by vacuum distillation of the filtrate to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain reactant D.

[0073] A5. Dissolve 1g of reactant D in 40mL of dichloromethane, add 4mL of trifluoroacetic acid and 0.1mL of anisole, and stir at 200rpm at 25℃ for 3h to obtain reaction solution D; distill reaction solution D under reduced pressure until the distillation rate of the distillate slows down significantly to obtain a residue; add toluene to the residue at a mass-to-volume ratio of 1g:10mL, and distill under reduced pressure again until the distillation rate of the distillate slows down significantly to obtain a concentrate; add diethyl ether dropwise to the stirred concentrate at a stirring rate of 600rpm, with the amount of diethyl ether added being 20 times the volume of the concentrate; after the solid precipitates, continue stirring for 30min; collect the solid by suction filtration, wash the filter cake three times with diethyl ether, and dry under vacuum to obtain the modified body.

[0074] Example 4

[0075] A novel substituted benzoylaminourea compound modified with a sulfonyl carbamate group, the preparation method of which includes:

[0076] S1, take 1g as... Figure 1 The 4-[2-(2-amino-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid shown was dissolved in 30 mL of anhydrous DMF to obtain a core solution. The pH of the core solution was adjusted to 8 with triethylamine, and after cooling to 4 °C, 0.87 g of benzyl chloroformate was added in an ice-water bath. The mixture was stirred at 500 rpm for 3 h. After the reaction was completed, the solvent was evaporated to dryness under reduced pressure. Ten times the volume of ethyl acetate was added to the evaporated solid, and the mixture was stirred until the solid was completely dissolved to obtain the final product. The residue solution was transferred to a separatory funnel, and an equal volume of 5% citric acid aqueous solution was added. After vigorous shaking, the mixture was allowed to stand and separate into layers. The organic phase was collected. The aqueous phase was extracted twice with an equal volume of ethyl acetate, and the organic phases were combined. The organic phase was washed once with an equal volume of saturated sodium bicarbonate solution and once with saturated brine. After standing and separating into layers, the organic phase was collected. Anhydrous sodium sulfate was added to the organic phase, and the mixture was allowed to stand and dry for 30 min. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to remove the solvent, yielding the amino-protected nucleus.

[0077] S2. Dissolve 1.07g NHS in 40mL of anhydrous DMF, add 1g of amino-protected core, stir at 150rpm for 15min, add 0.88g EDC·HCl in an ice bath, and react at 300rpm at 17℃ for 1.5h to obtain reaction solution 1.

[0078] S3. Dissolve 1g of the modified product prepared in Example 1 and 0.175g of N,N-diisopropylethylamine in 15mL of anhydrous DMF to obtain a modified product solution; add 20mL of the modified product solution to 40mL of reaction solution 1, stir at 450rpm for 10h, quench the reaction with anhydrous acetic acid, the volume ratio of anhydrous acetic acid to reaction solution 1 is 1:12, to obtain reaction solution 2; add 20 times the volume of ice water to reaction solution 2, stir and mix well, and extract three times with an equal volume of ethyl acetate, combine the organic phases, add anhydrous sodium sulfate to the organic phase, let stand and dry, and filter to remove the desiccant; remove the solvent by vacuum distillation of the filtrate, separate the product obtained by vacuum distillation by silica gel column chromatography, and remove the solvent by rotary evaporation of the eluent of the separated product to obtain product 2.

[0079] S4. Dissolve 1g of product 2 in 15mL of methanol, add 0.075g of 10% palladium on carbon, and purge with hydrogen gas at a pressure of 1.5 bar. Stir at 500rpm at 20℃ for 12h. After the reaction is complete, filter to remove the palladium on carbon, wash the filter cake with anhydrous methanol, combine the filtrates, and distill under reduced pressure in the dark until the distillation rate of the distillate slows down significantly. Add twice the volume of methanol to the concentrate, and distill under reduced pressure again in the dark until the distillation rate of the distillate slows down significantly. Dissolve the residue in twice the volume of ethyl acetate, transfer the mixture to a separatory funnel, add an equal volume of pure water, gently shake, and allow to stand for separation, retaining the organic phase. Back-extract the aqueous phase three times with the same organic solvent, combine all organic phases, wash the organic phase with supersaturated brine, add anhydrous sodium sulfate to the organic phase, let stand and dry for 30min, filter to remove the drying agent, and distill the filtrate under reduced pressure to remove the solvent, obtaining a product as shown in the figure. Figure 2 The novel substituted benzoylaminourea compound shown is modified with a sulfonyl carbamate group.

[0080] Example 5

[0081] A novel substituted benzoylaminourea compound modified with a sulfonyl carbamate group, the preparation method of which includes:

[0082] S1, take 1g as... Figure 1The 4-[2-(2-amino-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid shown was dissolved in 20 mL of anhydrous DMF to obtain a core solution. The pH of the core solution was adjusted to 8 with triethylamine, and after cooling to 4 °C, 0.85 g of benzyl chloroformate was added in an ice-water bath. The mixture was stirred at 400 rpm for 4 h. After the reaction was completed, the solvent was evaporated to dryness under reduced pressure. Ten times the volume of ethyl acetate was added to the evaporated solid, and the mixture was stirred until the solid was completely dissolved to obtain the final product. The residue solution was transferred to a separatory funnel, and an equal volume of 5% citric acid aqueous solution was added. After vigorous shaking, the mixture was allowed to stand and separate into layers. The organic phase was collected. The aqueous phase was extracted twice with an equal volume of ethyl acetate, and the organic phases were combined. The organic phase was washed once with an equal volume of saturated sodium bicarbonate solution and once with saturated brine. After standing and separating into layers, the organic phase was collected. Anhydrous sodium sulfate was added to the organic phase, and the mixture was allowed to stand and dry for 30 min. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to remove the solvent, yielding the amino-protected nucleus.

[0083] S2. Dissolve 1.0g NHS in 30mL of anhydrous DMF, add 1g of amino-protected parent nucleus, stir at 200rpm for 10min, add 0.85g EDC·HCl in an ice bath, and react at 400rpm at 15℃ for 1h to obtain reaction solution 1.

[0084] S3. Dissolve 1g of the modified product prepared in Example 2 and 0.17g of N,N-diisopropylethylamine in 10mL of anhydrous DMF to obtain a modified product solution; add 15mL of the modified product solution to 30mL of reaction solution 1, stir at 400rpm for 12h, quench the reaction with anhydrous acetic acid, the volume ratio of anhydrous acetic acid to reaction solution 1 is 1:10, to obtain reaction solution 2; add 25 times the volume of ice water to reaction solution 2, stir and mix well, and extract three times with an equal volume of ethyl acetate, combine the organic phases, add anhydrous sodium sulfate to the organic phase, let stand and dry, and filter to remove the desiccant; remove the solvent by vacuum distillation of the filtrate, separate the product obtained by vacuum distillation by silica gel column chromatography, and remove the solvent by rotary evaporation of the eluent of the separated product to obtain product 2.

[0085] S4. Dissolve 1g of product 2 in 10mL of methanol, add 0.05g of 10% palladium on carbon, and purge with hydrogen gas at a pressure of 1 bar. Stir at 500rpm at 20℃ for 12h. After the reaction is complete, filter to remove the palladium on carbon, wash the filter cake with anhydrous methanol, combine the filtrates, and distill under reduced pressure in the dark until the distillation rate of the distillate slows down significantly. Add twice the volume of methanol to the concentrate, and distill under reduced pressure again in the dark until the distillation rate of the distillate slows down significantly. Dissolve the residue in twice the volume of ethyl acetate, transfer the mixture to a separatory funnel, add an equal volume of pure water, gently shake, and allow to stand for separation, retaining the organic phase. Back-extract the aqueous phase three times with the same organic solvent, combine all organic phases, wash the organic phase with supersaturated brine, add anhydrous sodium sulfate to the organic phase, let stand and dry for 30min, filter to remove the drying agent, and distill the filtrate under reduced pressure to remove the solvent, obtaining a product as shown in the figure. Figure 2 The novel substituted benzoylaminourea compound shown is modified with a sulfonyl carbamate group.

[0086] Example 6

[0087] A novel substituted benzoylaminourea compound modified with a sulfonyl carbamate group, the preparation method of which includes:

[0088] S1, take 1g as... Figure 1 The 4-[2-(2-amino-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid shown was dissolved in 40 mL of anhydrous DMF to obtain a core solution. The pH of the core solution was adjusted to 8 with triethylamine, and after cooling to 4 °C, 0.9 g of benzyl chloroformate was added in an ice-water bath. The mixture was stirred at 600 rpm for 2 h. After the reaction was completed, the solvent was evaporated to dryness under reduced pressure. Ethyl acetate with a volume of 10 times that of the solid was added to the evaporated solid, and the mixture was stirred until the solid was completely dissolved to obtain the residue. The residue solution was transferred to a separatory funnel, and an equal volume of 5% citric acid aqueous solution was added. After vigorous shaking, the mixture was allowed to stand and separate into layers. The organic phase was collected. The aqueous phase was extracted twice with an equal volume of ethyl acetate, and the organic phases were combined. The organic phase was washed once with an equal volume of saturated sodium bicarbonate solution and once with saturated saline solution. After standing and separating into layers, the organic phase was collected. Anhydrous sodium sulfate was added to the organic phase, and the mixture was allowed to stand and dry for 30 min. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to remove the solvent, yielding the amino-protected nucleus.

[0089] S2. Dissolve 1.1g NHS in 50mL of anhydrous DMF, add 1g of amino-protected core, stir at 100rpm for 20min, add 0.9g EDC·HCl in an ice bath, and react at 20℃ for 2h at 200rpm to obtain reaction solution 1.

[0090] S3. Dissolve 1g of the modified product prepared in Example 3 and 0.18g of N,N-diisopropylethylamine in 20mL of anhydrous DMF to obtain a modified product solution; add 25mL of the modified product solution to 50mL of reaction solution 1, stir at 500rpm for 8h, quench the reaction with anhydrous acetic acid, the volume ratio of anhydrous acetic acid to reaction solution 1 is 1:15, to obtain reaction solution 2; add 10 times the volume of ice water to reaction solution 2, stir and mix well, and extract three times with an equal volume of ethyl acetate, combine the organic phases, add anhydrous sodium sulfate to the organic phase, let stand and dry, and filter to remove the desiccant; remove the solvent by vacuum distillation of the filtrate, separate the product obtained by vacuum distillation by silica gel column chromatography, and remove the solvent by rotary evaporation of the eluent of the separated product to obtain product 2;

[0091] S4. Dissolve 1g of product 2 in 20mL of methanol, add 0.1g of 10% palladium on carbon, and purge with hydrogen gas at a pressure of 2 bar. Stir at 500rpm at 20℃ for 12h. After the reaction is complete, filter to remove the palladium on carbon, wash the filter cake with anhydrous methanol, combine the filtrates, and distill under reduced pressure in the dark until the distillation rate of the distillate slows down significantly. Add twice the volume of methanol to the concentrate, and distill under reduced pressure again in the dark until the distillation rate of the distillate slows down significantly. Dissolve the residue in twice the volume of ethyl acetate, transfer the mixture to a separatory funnel, add an equal volume of pure water, gently shake, and allow to stand for separation, retaining the organic phase. Back-extract the aqueous phase three times with the same organic solvent, combine all organic phases, wash the organic phase with supersaturated brine, add anhydrous sodium sulfate to the organic phase, let stand and dry for 30min, filter to remove the drying agent, and distill the filtrate under reduced pressure to remove the solvent, obtaining a product as shown in the figure. Figure 2 The novel substituted benzoylaminourea compound shown is modified with a sulfonyl carbamate group.

[0092] Performance testing:

[0093] Water contact angle tests were conducted on the samples prepared in Examples 4 to 6 and pemetrexed according to the present invention. The samples were prepared into solutions and then cast into films. The static water contact angle was measured using a contact angle measuring instrument. The test results are shown in Table 1.

[0094] Table 1 Performance test results of Examples 4-6 and Pemetrexed

[0095]

[0096] As shown in Table 1, the water contact angles of the novel sulfonyl carbamate-modified substituted benzoyl urea compounds prepared in Examples 4-6 are all higher than those of pemetrexed, indicating that the overall hydrophobicity of the new compounds is improved compared to pemetrexed. However, due to the large proportion of polar groups, they still exhibit a hydrophilic surface in the solid state. A moderate increase in hydrophobicity helps improve the passive permeability of drugs to cell membranes, potentially leading to better permeation effects on tumor cells with low expression of reduced folic acid carriers or those resistant to drugs. The hydrophilic ends in the parent nucleus structure ensure the dissolution and transport of the drug in vivo.

[0097] The embodiments of the present invention have been described above. However, the present invention is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of the present invention without departing from the spirit and scope of the claims. All of these forms are within the protection scope of the present invention.

Claims

1. A novel substituted benzoylaminourea compound modified with a sulfonyl carbamate group, characterized in that, The novel substituted benzoylaminourea compound modified with a sulfonyl carbamate group consists of a parent core and a modifier. The parent core is 4-[2-(2-amino-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid; the modifier is a lysine-linked glutamic acid and sulfonyl carbamate tert-butyl ester structure; the parent core and the modifier are connected by an amide bond. The structural formula of the novel substituted benzoylaminourea compound modified with a sulfonyl carbamate group is as follows: 。 2. A method for preparing a novel substituted benzoylaminourea compound modified with a sulfonyl carbamate group as described in claim 1, characterized in that, Includes the following steps: S1. The parent nucleus is reacted with benzyl chloroformate in anhydrous DMF, and triethylamine is used as a pH adjuster to prepare an amino-protected parent nucleus. S2. Activate the carboxyl group of the amino protected parent nucleus in anhydrous DMF using the NHS / EDC system to obtain reaction solution 1; S3. Dissolve the modifier and N,N-diisopropylethylamine in anhydrous DMF to obtain a modifier solution; add the modifier solution to reaction solution 1, stir, quench the reaction with anhydrous acetic acid, and after post-treatment, obtain product 2; S4. Product 2 was reacted with 10 wt.% palladium on carbon in methanol and hydrogen. After separation and purification, a new substituted benzoylaminourea compound modified with sulfonyl carbamate group was obtained.

3. The method for preparing a novel sulfonyl carbamate-modified substituted benzoylaminourea compound according to claim 2, characterized in that, In S1, the mass-to-volume ratio of the parent nucleus, benzyl chloroformate, and DMF is 1 g : (0.85~0.9) g : (20~40) mL; the reaction speed is 400~600 rpm, and the reaction time is 2~4 h.

4. The method for preparing a novel sulfonyl carbamate-modified substituted benzoylaminourea compound according to claim 2, characterized in that, In S2, the NHS / EDC system includes NHS and EDC·HCl; the mass-to-volume ratio of the amino-protected core, NHS, EDC·HCl and anhydrous DMF is 1g:(1.0~1.1)g:(0.85~0.9)g:(30~50)mL; the activation temperature is 15~20℃, the activation speed is 200~400rpm, and the activation time is 1~2h.

5. The method for preparing a novel substituted benzoylaminourea compound modified with a sulfonyl carbamate group according to claim 2, characterized in that, In step S3, the mass-to-volume ratio of the modifier, N,N-diisopropylethylamine, and anhydrous DMF is 1 g : (0.17~0.18) g : (10~20) mL; the volume ratio of the modifier solution to reaction solution 1 is (25~45) : (30~50); the stirring temperature is 20~25℃, the stirring speed is 400~500 rpm, and the stirring time is 8~12 h; the volume ratio of anhydrous acetic acid to reaction solution 1 is 1 : (10~15).

6. The method for preparing a novel sulfonyl carbamate-modified substituted benzoylaminourea compound according to claim 2, characterized in that, In step S4, the mass-to-volume ratio of product 2, 10 wt.% palladium on carbon, and methanol is 1 g: (0.05~0.1) g: (10~20) mL; the pressure of the hydrogen gas is 1~2 bar.

7. The method for preparing a novel sulfonyl carbamate-modified substituted benzoylaminourea compound according to claim 2, characterized in that, In step S3, the preparation of the modified body includes the following steps: A1. Cross-protect the amino group on lysine to obtain lysine with protected amino group; activate the carboxyl group of lysine with protected amino group in anhydrous DMF using an NHS / EDC system to obtain reaction solution A. A2. Disperse L-glutamic acid dibenzyl ester hydrochloride and N,N-diisopropylethylamine in anhydrous DMF and stir to obtain a glutamic acid solution; add the glutamic acid solution to reaction solution A, mix, and obtain reaction solution B; A3. Add piperazine and 1,8-diazabicyclo[5.4.0]undec-7-ene to reaction solution B, stir, and purify to obtain reactant C; A4. Reactant C reacts with tert-butyl chlorosulfonyl carbamate in anhydrous acetonitrile, using N,N-diisopropylethylamine as a base, and after separation and purification, reactant D is obtained. A5. Reactant D was dissolved in dichloromethane, and trifluoroacetic acid and anisole were added. After stirring and purification, the modified product was obtained.

8. The method for preparing a novel sulfonyl carbamate-modified substituted benzoylaminourea compound according to claim 7, characterized in that, In A1, the NHS / EDC system includes NHS and EDC·HCl; the mass-to-volume ratio of the amino-protected lysine, NHS, EDC·HCl and anhydrous DMF is 1 g : (0.9~1.0) g : (0.75~0.85) g : (30~50) mL; the activation temperature is 15~20℃, the activation speed is 200~400 rpm, and the activation time is 1~2 h.

9. The method for preparing a novel substituted benzoylaminourea compound modified with a sulfonyl carbamate group according to claim 7, characterized in that, In A2, the mass-to-volume ratio of L-glutamic acid dibenzyl ester hydrochloride, N,N-diisopropylethylamine, and anhydrous DMF is 1 g : (0.36~0.38) g : (10~15) mL; the stirring speed is 100~200 rpm, and the stirring time is 5~10 min; the volume ratio of glutamic acid solution to reaction solution A is (10~15) : (30~50); the mixing temperature is 20~25℃, the mixing speed is 300~500 rpm, and the mixing time is 6~8 h; In A3, the mass-to-volume ratio of reaction solution B, piperazine, and 1,8-diazabicyclo[5.4.0]undec-7-ene is (45~60) mL : (2.25~3) g : (0.45~0.6) g; the stirring speed is 200~300 rpm, the stirring temperature is 20~25℃, and the stirring time is 20~30 min.

10. The method for preparing a novel sulfonyl carbamate-modified substituted benzoylaminourea compound according to claim 7, characterized in that, In A4, the mass-to-volume ratio of reactant C, tert-butyl chlorosulfonyl carbamate, N,N-diisopropylethylamine, and anhydrous acetonitrile is 1 g : (0.65~0.7) g : (0.38~0.43) g : 10 mL; the reaction speed is 200~300 rpm, and the reaction time is 50~70 min; In A5, the mass-to-volume ratio of reactant D, dichloromethane, trifluoroacetic acid, and anisole is 1 g : (30~40) mL : (3~4) mL : (0.09~0.1) mL; the stirring speed is 200~300 rpm, the stirring temperature is 20~25℃, and the stirring time is 1~3 h.

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