A pomalidomide-linked urea feed additive and its preparation method and application

Abstract

The present invention discloses a pomalidomide-linked urea feed additive and its preparation method and application, belonging to the technical field of functional feed additive synthesis. The technical solution of the present invention is as follows: the pomalidomide-linked urea feed additive molecule has a structure of 2-Boc aminobenzoic acid as the starting material, first reacting to obtain 2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline-1,3-dione, and then converting the amine group on the structure into azide, and obtaining the target compound through a click reaction. The compound is loaded with exosomes by a supercritical method, has a certain inhibitory effect on cattle urease, and can be used as a potential feed additive.

Description

Technical Field

[0001] The present invention belongs to the technical field of synthesis of feed additives, and in particular relates to a pomalidomide-linked urea feed additive, a preparation method thereof, and an application thereof. Background Art

[0002] Pomalidomide, chemically known as (RS)-4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, is an oral small molecule derivative and a newly launched third-generation immunomodulator. Developed and manufactured by Celgene Corporation in the United States, it is a modified version of the first-generation IMiD thalidomide. It can enhance immune responses mediated by T cells and natural killer cells, inhibit the production of proinflammatory cytokines, and induce tumor cell apoptosis. It has garnered widespread attention in the treatment of various malignancies and immune diseases. It is a widely used thalidomide derivative. Compared to thalidomide, the amino group attached to the benzene ring of pomalidomide makes it more chemically stable and exhibits stronger immunomodulatory effects than thalidomide. Furthermore, in clinical practice, pomalidomide offers a higher safety profile and fewer adverse reactions than thalidomide. It is virtually teratogenic and neurotoxic, and is effective against a variety of hematologic malignancies and solid tumors.

[0003] Urea is an organic compound composed of carbon, nitrogen, oxygen, and hydrogen. Urea was first isolated from urine in the 18th century. In the 19th century, scientists discovered that urea could be synthesized from the inorganic ammonium cyanate, overturning the traditional theory of "vitality" and opening a new chapter in organic chemistry. Urea structural fragments are important backbones for drug development and are widely used in the pharmaceutical field. Currently marketed anti-tumor drugs containing urea structures include Lenvatinib, a tyrosine kinase inhibitor used to treat renal and thyroid cancers, which can effectively slow or prevent tumor cell growth; and sorafenib, a novel multi-targeted oral cancer treatment. It is used to treat gastrointestinal stromal tumors and metastatic renal cells that are unresponsive or intolerant to standard therapies. It selectively targets receptors for certain proteins and is believed to act as a molecular switch in tumor growth. It has received Fast Track designation from the FDA for these indications in the United States.

[0004] In our previous work, we modified the structures of pomalidomide, thalidomide, and lenalidomide to make them useful as feed additives. This present invention modifies pomalidomide by converting its amine group into an azide group, which is then linked to a urea compound through a click reaction. Because the polarity increases after the two groups are superimposed, we load them through exosomes to better enable their entry into cells, hoping to improve their application as feed additives. Summary of the Invention

[0005] The technical problem solved by the present invention is to provide a preparation method of pomalidomide-linked urea derivatives.

[0006] The present invention adopts the following technical solution to solve the above technical problems: a method for preparing a pomalidomide-linked urea derivative, wherein the structure of the pomalidomide-linked urea derivative is:

[0007]

[0008] The specific steps are as follows: adding a certain amount of 2-N-Boc aminobenzoic acid to the acylating reagent, stirring for a period of time under nitrogen protection, and then concentrating the reaction system in vacuo. The concentrate is dissolved with dichloromethane, and then slowly dropping a dichloromethane solution containing dimethyl 2-aminoglutarate hydrochloride under stirring. After the addition is complete, stirring is continued for a period of time, and then the reaction system is concentrated. N, N-dimethylformyl is added, and after complete dissolution, a certain amount of tert-butyl lithium, barium hydroxide, cesium carbonate and palladium catalyst are added under nitrogen protection. The nitrogen atmosphere is maintained, and the reaction is transferred to a high-pressure reactor. The high-pressure reactor is fully protected with nitrogen, and then stirred at room temperature for a period of time to replace the gas in the reactor with carbon dioxide, and then carbon dioxide is introduced to make the pressure in the reactor reach a certain value, and slowly heated to a certain temperature. The reaction is continued for a period of time. After a certain time, carbon dioxide is removed in vacuo, and the temperature is lowered to a certain temperature. Ammonia is then introduced to make the pressure in the autoclave reach a certain value. The temperature and pressure are maintained and stirred for a period of time, and the reaction is cooled to room temperature. Water and dichloromethane are then added to the reaction system. After stirring, the reaction liquid is filtered to separate the organic phase. The aqueous phase is washed with dichloromethane for multiple times, and then the organic phase is separated. 2 mol / L dilute hydrochloric acid is added to the organic phase, and the reaction system is heated to 30° C. and stirred for a period of time. After that, a saturated potassium carbonate solution is used to adjust the reaction system to neutrality. The organic phase is separated again, concentrated, and separated and purified by silica gel column chromatography to obtain 2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline-1,3-dione. The acylating agent is thionyl chloride or phosphorus oxychloride; and the palladium catalyst is palladium acetate or palladium (II) chlorobis(acetonitrile).

[0009] 2. Add a certain amount of pomalidomide to hydrochloric acid, stir, then add sodium nitrite, stir for a period of time, maintain the temperature at 0°C, add an aqueous solution of sodium azide, continue stirring for a period of time, add dichloromethane to the reaction system, stir, separate the organic phase, extract the aqueous phase with dichloromethane several times, combine the organic phases, and concentrate to obtain pomalidomide-azide compound; the mass ratio of the pomalidomide to sodium nitrite and sodium azide is 10:3-5:2-5.

[0010] 3. Use a silicon carbide microchannel reactor, prepare a dichloromethane solution containing a certain amount of 3-amino-3-methyl-1-butyne and mark it as A, prepare a mixed solution of tert-butanol and dichloromethane containing a certain amount of pomalidomide-azide compound and copper catalyst and mark it as B, connect solution A and solution B to the two feed pumps of the reactor respectively, and enter the reactor at a certain speed at the same time. The reactor is set to 40°C. The two reaction solutions are mixed and reacted in the reactor and then flow into dichloromethane containing phenyl isocyanate compounds and triethylamine through the discharge port. Stir while adding. When the microchannel reactor is heated to 40°C, the reaction mixture is stirred. The solution flows out completely, and the stirring is continued for a period of time. The reaction liquid is filtered to separate the organic phase, and the aqueous phase is extracted with dichloromethane for multiple times. The organic phases are combined, dried over anhydrous magnesium sulfate, concentrated, and finally dried to obtain the product; the molar ratio of the 3-amino-3-methyl-1-butyne to the pomalidomide-azide compound is 1:1; the mass ratio of the pomalidomide-azide compound to the copper catalyst is 10:0.3-0.5; the molar ratio of the 3-amino-3-methyl-1-butyne to the isocyanate phenyl compound is 1:1; and the copper catalyst is cuprous iodide or cuprous chloride.

[0011] 4. The supernatant of laboratory-cultured Dunaliella cells was collected and ultracentrifuged in an ultrahigh-speed centrifuge. The exosome pellet was resuspended in phosphate buffer and the exosomes were incubated with the obtained compound in supercritical carbon dioxide. The specific conditions were as follows: the purified exosomes and the compound at a concentration of 90 μM were added to a 20 mL supercritical carbon dioxide reaction vessel. The carbon dioxide cylinder was opened, the inlet valve was opened, the carbon dioxide pump was turned on, and carbon dioxide was introduced. When the pressure in the reactor reached 6.5-7.5 MPa, liquid appeared inside the reaction vessel. This pressure condition was maintained. During the reaction, the temperature and pressure changes in the reactor were carefully observed. After slow stirring, the carbon dioxide in the reactor was slowly released. After the pressure was completely released, the reactor was opened and the mixture was centrifuged in a high-speed centrifuge (10,000 × g, 10 min) to preliminarily remove the drug that was not encapsulated in the exosomes. Finally, the above mixture was added to the exosome purification column and centrifuged at low speed (750 × g, 10 min) to completely remove the excess compound to obtain the loaded exosomes. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 This is the H NMR spectrum of pomalidomide linked to a urea derivative.

[0013] Figure 2 This is the NMR carbon spectrum of pomalidomide linked to urea derivatives. DETAILED DESCRIPTION

[0014] The above contents of the present invention are further described in detail below through examples, but this should not be understood as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above contents of the present invention fall within the scope of the present invention.

[0015] Example 1

[0016]

[0017] In a reaction flask with a stirring device, 2.4 g of 2-N-Boc aminobenzoic acid was added to 50 mL of dichlorothionyl, stirred under nitrogen protection for 1 hour, and then the reaction system was concentrated in vacuo. The concentrate was stirred and dissolved with 100 mL of dichloromethane, and then 70 mL of a dichloromethane solution containing 2.3 g of 2-amino-1,5-pentanedioic acid dimethyl ester hydrochloride was slowly added dropwise at 0 ° C. After the addition was complete, the mixture was heated to room temperature and stirred for 5 hours. The reaction system was concentrated in vacuo, and then added to 200 mL of N, N-dimethylformamide and stirred. After complete dissolution, 1.28 g of tert-butyl lithium, 3.4 g of barium hydroxide, 6.5 g of cesium carbonate and 0.45 g of palladium acetate were added under nitrogen protection. The nitrogen atmosphere was maintained and the reaction was transferred to a high-pressure reactor. The autoclave was fully protected with nitrogen, and then stirred at room temperature for 10 minutes. The gas in the autoclave was replaced with carbon dioxide. Then, carbon dioxide was introduced to make the pressure in the autoclave reach 0.2MPa, and the mixture was slowly heated to 100°C. After reacting for 20h, the carbon dioxide was removed by vacuum replacement and the temperature was lowered to 70°C. Then, ammonia was introduced to make the pressure in the autoclave reach 0.1MPa. The temperature and pressure were maintained and stirred for 15h, and then the mixture was cooled to room temperature. 200mL of water and 200mL of dichloromethane were added to the reaction system. After stirring, the reaction liquid was filtered and the organic phase was separated. The aqueous phase was washed four times with 100mL of dichloromethane, and then the organic phase was separated. 50mL of 2mol / L dilute hydrochloric acid was added to the organic phase, and the mixture was heated to 30°C and stirred for 2h. The reaction system was then adjusted to neutral with a saturated solution of potassium carbonate, and the organic phase was separated. After concentration, 2.31g of 2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline-1,3-dione was obtained by separation and purification by silica gel column chromatography. 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),7.48(s,1H),7.02(s,2H),6.53(s,2H),5.06(s,1H),3.11-2.58(m,3H),2.04(s,1H).

[0018] Example 2

[0019]

[0020] In a reaction flask with a stirring device, 2.4 g of 2-N-Boc aminobenzoic acid and 3.1 g of phosphorus oxychloride were added to 100 mL of dichloromethane, heated under reflux and stirred for 45 minutes under nitrogen protection, and then the reaction system was concentrated in vacuo. The concentrate was stirred and dissolved with 100 mL of dichloromethane, and then 70 mL of a dichloromethane solution containing 2.3 g of 2-amino-1,5-pentanedioic acid dimethyl ester hydrochloride was slowly added dropwise at 0 ° C. After the addition was complete, the mixture was heated to room temperature and stirred for 5 hours. The reaction system was concentrated in vacuo, and then added to 200 mL of N, N-dimethylformamide and stirred. After complete dissolution, 1.28 g of tert-butyl lithium, 3.4 g of barium hydroxide, 6.5 g of cesium carbonate and 0.26 g of palladium (II) chloride bis (acetonitrile) were added under nitrogen protection. The nitrogen atmosphere was maintained and the mixture was transferred to a high-pressure reactor. The autoclave was fully protected with nitrogen and then stirred at room temperature for 10 minutes. The gas in the autoclave was replaced with carbon dioxide, and then carbon dioxide was introduced to make the pressure in the autoclave reach 0.2MPa. The mixture was slowly heated to 90°C, and after reacting for 12h, carbon dioxide was removed by vacuum replacement. At the same time, the temperature was lowered to 70°C, and then ammonia was introduced to make the pressure in the autoclave reach 0.1MPa. The temperature and pressure were maintained and stirred for 15h, and then cooled to room temperature. 200mL of water and 200mL of dichloromethane were added to the reaction system. After stirring, the reaction liquid was filtered and the organic phase was separated. The aqueous phase was washed four times with 100mL of dichloromethane, and then the organic phase was separated. 50mL of 2mol / L dilute hydrochloric acid was added to the organic phase, and the mixture was heated to 30°C and stirred for 2h. The reaction system was then adjusted to neutral with a saturated solution of potassium carbonate. The organic phase was separated and concentrated, and then purified by silica gel column chromatography to obtain 2.57g of 2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline-1,3-dione; 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),7.48(s,1H),7.02(s,2H),6.53(s,2H),5.06(s,1H),3.11-2.58(m,3H),2.04(s,1H).

[0021] Example 3

[0022]

[0023] In a stirred reaction flask, add 3 g of pomalidomide to 100 mL of hydrochloric acid, stir, then add 0.9 g of sodium nitrite, stir for 30 min, maintain at 0°C, add 50 mL of an aqueous solution containing 0.8 g of sodium azide, continue stirring for 4 h, add 100 mL of dichloromethane to the reaction system, stir, separate the organic phase, extract the aqueous phase several times with 50 mL of dichloromethane, combine the organic phases, and concentrate to obtain 2.87 g of pomalidomide-azide compound.

[0024] Example 4

[0025]

[0026] A silicon carbide microchannel reactor from Chemttrix, Germany, was used. 10 mL of a dichloromethane solution containing 0.85 g of 3-amino-3-methyl-1-butyne was prepared and labeled A. A mixed solution containing 3 g of pomalidomide-azide and 0.1 g of cuprous iodide in 10 mL of tert-butanol and 30 mL of dichloromethane was prepared and labeled B. Solution A and solution B were connected to the two feed pumps of the reactor, respectively, and fed into the reactor at a rate of 1 mL / min and 4 mL / min, respectively. The reactor temperature was set to The temperature was 50° C. The two reaction solutions were mixed and reacted in the reactor and then flowed into 20 mL of dichloromethane dissolved with 2.0 g of 4-bromoisocyanate and 1 g of triethylamine through the discharge port. Stirring was continued while adding. When the solution in the microchannel reactor was completely discharged, stirring was continued for 40 minutes. 30 mL of water was added. After stirring, the reaction solution was filtered to separate the organic phase. The aqueous phase was extracted several times with 10 mL of dichloromethane. The organic phases were combined and dried with 3 g of anhydrous magnesium sulfate and concentrated. Finally, 5.32 g of the product was obtained after drying. 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),8.64(d,J=13.2Hz,2H),8.21(p,J=3.6Hz,1H),8.08(d,J=4.8Hz,2H),7.32(q,J=8.8Hz ,4H),6.70(s,1H),5.19(dd,J=12.9,5.4Hz,1H),2.93-2.88(m,1H),2.60(d,J=18.0Hz,2H),2.08-2.02(m,1H),1.72(s,6H). 13 C NMR(150MHz,DMSO-d6)δ173.17,170.02,169.49,166.41,165.19,154.61,154.35,154.04,140.26,136.90,1 33.44,133.26,131.79,131.00,124.31,122.59,119.90,112.69,50.57,49.65,40.54,31.35,28.90,22.32.

[0027] Example 5

[0028]

[0029] A silicon carbide microchannel reactor from Chemttrix, Germany, was used. 10 mL of a dichloromethane solution containing 0.85 g of 3-amino-3-methyl-1-butyne was prepared and labeled A. A mixed solution containing 3 g of pomalidomide-azide and 0.1 g of cuprous chloride in 10 mL of tert-butanol and 30 mL of dichloromethane was prepared and labeled B. Solution A and solution B were connected to the two feed pumps of the reactor, respectively, and fed into the reactor at a rate of 1 mL / min and 4 mL / min, respectively. The reactor temperature was set to The temperature was 50° C. The two reaction solutions were mixed and reacted in the reactor and then flowed into 20 mL of dichloromethane dissolved with 2.0 g of 4-bromoisocyanate and 1 g of triethylamine through the discharge port. Stirring was continued while adding. When the solution in the microchannel reactor was completely discharged, stirring was continued for 40 minutes. 30 mL of water was added. After stirring, the reaction solution was filtered to separate the organic phase. The aqueous phase was extracted several times with 10 mL of dichloromethane. After the organic phases were combined, they were dried with 3 g of anhydrous magnesium sulfate and concentrated. Finally, 5.57 g of the product was obtained after drying. 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),8.64(d,J=13.2Hz,2H),8.21(p,J=3.6Hz,1H),8.08(d,J=4.8Hz,2H),7.32(q,J=8.8Hz ,4H),6.70(s,1H),5.19(dd,J=12.9,5.4Hz,1H),2.93-2.88(m,1H),2.60(d,J=18.0Hz,2H),2.08-2.02(m,1H),1.72(s,6H). 13 C NMR(150MHz,DMSO-d6)δ173.17,170.02,169.49,166.41,165.19,154.61,154.35,154.04,140.26,136.90,1 33.44,133.26,131.79,131.00,124.31,122.59,119.90,112.69,50.57,49.65,40.54,31.35,28.90,22.32.

[0030] Example 6

[0031] The supernatant of Dunaliella cells cultured in the laboratory was collected and ultracentrifuged in an ultrahigh-speed centrifuge. The exosome precipitate was resuspended in phosphate buffer and the obtained exosomes were incubated with the obtained compound in supercritical carbon dioxide. The specific conditions were as follows: 5000 μg of purified exosomes and 5 mL of the compound with a concentration of 90 μM (cell culture medium) were added to a 30 mL supercritical carbon dioxide reaction vessel. The carbon dioxide cylinder was opened, the air inlet valve was opened, the carbon dioxide pump was turned on, carbon dioxide was introduced, and the pressure range of the reactor was observed to reach 6.5-7.5 MPa. When the reaction vessel is filled with liquid, maintain this pressure condition and pay attention to the changes in temperature and pressure in the reactor during the reaction. After slow stirring for 1 hour, slowly release the carbon dioxide in the reactor. After the pressure is completely released, open the reactor and centrifuge the mixture in a high-speed centrifuge (10,000 × g, 10 min) to preliminarily remove the drug that is not encapsulated into the exosomes. Finally, add the above mixture to the exosome purification column and centrifuge at low speed (750 × g, 10 min) to completely remove the excess compound to obtain the loaded compound. Repeat the experiment several times to fully prepare the material.

[0032] Example 7

[0033] We conducted an in vitro urease inhibition assay using the target compound loaded with exosomes. Cattle aged approximately 12 months were selected. After feeding for one hour, 400 mL of rumen fluid was collected using a custom-designed rumen fluid collector via an artificial rumen fistula. The fluid was filtered through four layers of gauze and set aside. Each culture tube was added with the corresponding reagents in the amounts listed in the table, followed by four drops of liquid paraffin. The cells were then gently shaken in a (39.0 ± 0.5)°C water bath. The cultures were incubated for 8 hours. Four drops of saturated mercuric chloride solution were immediately added to the culture tubes from each group and shaken to terminate the reaction. Ammoniacal nitrogen content was determined using the Kjeldahl semi-micro-saturated magnesium oxide distillation method. We can find that the designed compounds before and after loading have increasingly significant inhibitory activity against urease over time, showing a very significant inhibitory effect. Moreover, through CCK8 experiments, at a concentration of 10 mg / mL, there is no obvious inhibitory effect on human renal epithelial cell line 293T cells. At the same concentration, the target compound without exosome loading has an inhibition rate of greater than 30% on human renal epithelial cell line 293T cells.

[0034] Group control group Experimental group 1 Experimental Group 2 Rumen fluid / mL 5 5 5 Artificial saliva / mL 5 5 5 Soluble starch / mg 6 6 6 Urea nitrogen / mg 5 5 5 Unloaded product / mg 0 4 8 Loaded product / mg 0 4 8

[0035] Inhibition rate (%) = (ammonia content of control group - ammonia content of test group) ÷ ammonia content of control group × 100%.

[0036]

[0037]

[0038] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for illustrating the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A pomalidomide-linked urea feed additive, characterized in that The structure of the pomalidomide-linked urea feed additive is:

2. A method for preparing a pomalidomide-linked urea feed additive according to claim 1, characterized in that: A silicon carbide microchannel reactor was used, and a dichloromethane solution containing 3-amino-3-methyl-1-butyne was prepared and marked as A. A mixed solution of tert-butanol and dichloromethane containing pomalidomide-azide compound and copper catalyst was prepared and marked as B. Solution A and solution B were respectively connected to the two feed pumps of the reactor. At the same time, solution A and solution B entered the reactor at a flow rate ratio of 1:

4. The reactor temperature was set to 40°C. The two reaction solutions were mixed and reacted in the reactor and then flowed into the dichloromethane solution containing phenyl isocyanate compound and triethylamine through the discharge port. Stirring was performed while adding. When the solution in the microchannel reactor was completely discharged, stirring was continued for a while. The reaction liquid is filtered, the organic phase is separated, the aqueous phase is extracted multiple times with dichloromethane, the organic phases are combined, dried over anhydrous magnesium sulfate, concentrated, and finally dried to obtain pomalidomide-linked urea feed additives; the molar ratio of the 3-amino-3-methyl-1-butyne to the pomalidomide-azide compound is 1:1; the mass ratio of the pomalidomide-azide compound to the copper catalyst is 10:0.3-0.5; the molar ratio of the 3-amino-3-methyl-1-butyne to the isocyanate phenyl compound is 1:1; the copper catalyst is cuprous iodide or cuprous chloride; the isocyanate phenyl compound is 4-bromophenylisocyanate.

3. The method according to claim 2, wherein Pomalidomide is added to hydrochloric acid, and sodium nitrite is added after stirring. The mixture is stirred for a period of time while maintaining the temperature at 0°C. An aqueous solution of sodium azide is added and the mixture is stirred for a period of time. Dichloromethane is added to the reaction system and the organic phase is separated after stirring. The aqueous phase is extracted with dichloromethane several times, and the organic phases are combined and concentrated to obtain a pomalidomide-azide compound. The mass ratio of the pomalidomide to sodium nitrite and sodium azide is 10:3-5:2-5.

4. The method according to claim 3, wherein A certain amount of 2-N-Boc aminobenzoic acid was added to the acylating reagent, stirred for a period of time under nitrogen protection, and then the reaction system was vacuum concentrated. The concentrate was dissolved with dichloromethane, and then a dichloromethane solution containing 2-aminoglutaric acid dimethyl ester hydrochloride was slowly added dropwise under stirring. After the addition was complete, the stirring reaction was continued for a period of time, and then the reaction system was concentrated. N, N-dimethylformyl was added, and after complete dissolution, a certain amount of tert-butyl lithium, barium hydroxide, cesium carbonate and palladium catalyst were added under nitrogen protection. The nitrogen atmosphere was maintained and the reaction was transferred to a high-pressure reactor. The autoclave was fully protected with nitrogen, and then stirred at room temperature for a period of time, and the gas in the autoclave was replaced with carbon dioxide. Then carbon dioxide was introduced to make the pressure in the autoclave reach 0.2MPa, and the reaction was slowly heated to 90°C. After a period of reaction, dioxygen was removed in vacuum. Carbon is evaporated, and the temperature is simultaneously lowered to 70°C, and then ammonia is introduced to make the pressure in the autoclave reach 0.1MPa. The temperature and pressure are maintained and stirred for a period of time, and then the reaction is cooled to room temperature. Water and dichloromethane are then added to the reaction system, and the reaction liquid is filtered after stirring to separate the organic phase. The aqueous phase is washed with dichloromethane for multiple times, and then the organic phase is separated. 2mol / L dilute hydrochloric acid is added to the organic phase, and the mixture is heated to 30°C and stirred for a period of time, and then a saturated potassium carbonate solution is used to adjust the reaction system to neutrality. The organic phase is separated again, concentrated, and separated and purified by silica gel column chromatography to obtain pomalidomide; the acylating agent is thionyl chloride or phosphorus oxychloride; the palladium catalyst is palladium acetate or palladium (II) chlorobis (acetonitrile); the molar ratio of the feeding amount of the 2-N-Boc aminobenzoic acid and the palladium catalyst is 1:0.05-0.

2.

5. Use of the pomalidomide-linked urea feed additive according to claim 1 in the preparation of a drug for inhibiting urease activity.

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