3-hydroxypyrrolidine derivatives, processes for their preparation and use
The one-pot synthesis of 3-hydroxypyrrolidine derivatives via copper catalysis solves the problems of low synthesis efficiency and high safety risks in existing technologies, realizing a high-yield green synthesis route and providing a drug application for inhibiting macrophage proliferation.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SOUTHERN MARINE SCIENCE & ENGINEERING GUANGDONG LABORATORY (ZHANJIANG)
- Filing Date
- 2024-02-07
- Publication Date
- 2026-07-07
AI Technical Summary
Existing methods for synthesizing 3-hydroxypyrrolidine derivatives suffer from problems such as multiple steps, use of explosive and hygroscopic reagents, low reaction efficiency, and low yield. Furthermore, there are few reports on the effects of pyrrolidine alkaloids on macrophages, and there is a lack of effective, green, and efficient synthetic methods.
The diastereomers of 3-hydroxypyrrolidine were synthesized in a one-pot reaction using copper-catalyzed reactions of α-aminoacetone compounds, terminal acetyl ketone compounds, and sulfonyl azide compounds, avoiding the use of oxidizing or reducing agents and optimizing reaction conditions to improve yield.
The green and efficient synthesis of 3-hydroxypyrrolidine derivatives has been achieved, with improved yield, providing potential drug applications for inhibiting macrophage proliferation and solving the problems of low synthesis efficiency and high safety risks in existing technologies.
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Figure CN118146134B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a 3-hydroxypyrrolidine derivative, its preparation method, and its application. Background Technology
[0002] Macrophages are widely distributed in the body's tissues and organs, playing a crucial role in pathogen defense, inflammatory responses, homeostasis maintenance, and damage repair. Macrophages can activate lymphocytes or other immune cells, enabling them to respond to pathogens and foreign particles. They also participate in immune responses, helping the immune system recognize and eliminate invaders, and can serve as professional antigen-presenting cells to process and present antigens to activate adaptive immune responses. However, modern biomedical research indicates that macrophage proliferation is involved in certain serious proliferative diseases, such as lymphoma, cardiovascular disease, and nephrosclerosis. Macrophage syndrome, in particular, refers to a malignant hematologic malignancy caused by excessive proliferation and activation of macrophages in immune cells. Pyrrolidine alkaloids are a class of organic base compounds containing a pyrrole ring structure, possessing broad biological activity and medicinal value. The main medicinal effects of pyrrolidine alkaloids include antitumor, antibacterial, analgesic, and antidepressant effects. Although pyrrolidine alkaloids have antitumor effects, reports on their effects on macrophages are scarce.
[0003] Currently, 3-hydroxypyrrolidine derivatives are mainly synthesized through three methods: the first involves addition or oxidative hydroxylation of pyrrolidine containing a double bond; the second uses malic acid as a starting material through cyclization and reduction; and the third involves reduction via pyrrolidone. All of these methods involve multi-step synthesis, use hygroscopic reducing agents or explosive oxidizing agents, and have low reaction efficiency and low yields. Therefore, it remains necessary to develop pyrrolidine compounds for treating proliferative diseases, as well as to develop new, green, and efficient synthetic methods for 3-hydroxypyrrolidine. Summary of the Invention
[0004] To overcome the problems existing in the prior art, one objective of the present invention is to provide a 3-hydroxypyrrolidine derivative. A second objective of the present invention is to provide a method for preparing this 3-hydroxypyrrolidine derivative. A third objective of the present invention is to provide applications of this 3-hydroxypyrrolidine derivative.
[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:
[0006] The first aspect of the present invention provides a 3-hydroxypyrrolidine derivative, the structural formula of which is shown in formula (I) or formula (II):
[0007]
[0008] Among them, the 3-hydroxypyrrolidine derivatives shown in formula (I) and formula (II) are diastereomers of each other;
[0009] In equations (I) and (II), the R 1 or R 2 Each is independently selected from H, phenyl, or substituted phenyl; the R 3 Each is independently selected from aliphatic hydrocarbons or halogenated aliphatic hydrocarbons; the R 4 Each is independently selected from phenyl, substituted phenyl, aliphatic hydrocarbon, and halogenated aliphatic hydrocarbon.
[0010] Preferably, in formulas (I) and (II), the R 1 or R 2 Each of the following is independently selected from H, phenyl, C1-C4 alkylphenyl, halophenyl, hydroxyphenyl, cyanophenyl, methoxyphenyl, and nitrophenyl;
[0011] Preferably, in formulas (I) and (II), the R 3 They are independently selected from C1-C6 alkyl groups and C5-C6 cycloalkyl groups, respectively;
[0012] Preferably, in formulas (I) and (II), the R 4 Each of the following is independently selected from phenyl, C1-C4 alkylphenyl, halophenyl, hydroxyphenyl, cyanophenyl, methoxyphenyl, nitrophenyl, C1-C6 alkyl, and haloC1-C6 alkyl.
[0013] More preferably, the 3-hydroxypyrrolidine derivative is selected from compounds with the following structures:
[0014]
[0015]
[0016] The second aspect of this invention provides a method for preparing the 3-hydroxypyrrolidine derivative described in the first aspect of this invention. In the presence of a copper compound, an α-aminoacetone compound of formula (III), a terminal acetylene ketone compound of formula (IV), and a sulfonyl azide compound of formula (V) are reacted to obtain the 3-hydroxypyrrolidine diastereomers of formulas (I) and (II); wherein the reaction formulas of the preparation method are as follows:
[0017]
[0018] In the preparation method of this invention, firstly, a terminal acetyl ketone compound (IV) reacts with a sulfonyl azide compound (V) under copper catalysis to generate a triazole intermediate A. A undergoes ring-opening rearrangement to obtain an enone imine B, which then undergoes nucleophilic addition with α-aminoacetophenone (II) to obtain intermediate C. Subsequently, an intramolecular cyclization reaction occurs to obtain the target product, 3-hydroxypyrrolidine diastereomers (I) and (II). The reaction mechanism is as follows:
[0019]
[0020] Preferably, the copper compound is selected from one or more of copper acetate, copper chloride, copper bromide, copper acetylacetone, copper trifluoroacetate, copper trifluoromethanesulfonate, copper oxide, cuprous iodide, cuprous bromide, cuprous chloride, copper thiophene-2-carboxylate, and cuprous acetate.
[0021] Preferably, the molar ratio of the α-aminoacetone compound to the copper compound is 1:(0.05-0.2).
[0022] Preferably, the molar ratio of the α-aminoacetone compound to the terminal acetylene compound is 1:(1-3).
[0023] Preferably, the molar ratio of the α-aminoethyl ketone compound to the sulfonyl azide compound is 1:(1-3).
[0024] Preferably, the reaction temperature is 60-120°C. More preferably, the reaction temperature is 60-80°C.
[0025] Preferably, the reaction time is 0.5-8 hours. More preferably, the reaction time is 2-6 hours.
[0026] Preferably, the reaction is carried out in an organic solvent, which includes any one or more of acetonitrile, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, chlorobenzene, benzene, xylene, dimethyl sulfoxide, and N-methylpyrrolidone.
[0027] More preferably, the ratio of the α-aminoethyl ketone compound to the organic solvent is 1 mmol: 5-15 mL.
[0028] The reaction process includes a post-processing step. The post-processing includes any one or a combination of extraction, concentration, crystallization, recrystallization, and column chromatography purification.
[0029] As an example of post-processing, the reaction can be carried out as follows: after the reaction is complete, the reaction system is naturally cooled to room temperature, a mixture of ethyl acetate and saturated brine in equal volume ratio is added, the mixture is shaken and extracted 2-4 times, the organic layer is collected, dried, concentrated by rotary evaporation, and the crude product is obtained. The crude product is then subjected to chromatographic chromatography on a 200-300 mesh silica gel column, using a mixture of ethyl acetate and petroleum ether as the eluent, wherein the volume ratio of ethyl acetate to petroleum ether is 1:5-10, thereby obtaining the 3-hydroxypyrrolidine diastereomer of formula (I).
[0030] The third aspect of the present invention also provides the use of the 3-hydroxypyrrolidine derivative described in the first aspect of the present invention in the preparation of candidate drugs for treating proliferative diseases.
[0031] Preferably, the 3-hydroxypyrrolidine derivative is used in inhibiting macrophage proliferation.
[0032] More preferably, the 3-hydroxypyrrolidine derivative is used in inhibiting the proliferation of RAW264.7 macrophages.
[0033] The beneficial effects of this invention are:
[0034] The 3-hydroxypyrrolidine derivative provided by this invention can inhibit the proliferation of RAW264.7 cells, and thus inhibit the excessive proliferation of macrophages in immune cells to a certain extent, thus showing great application potential in the preparation of candidate drugs for proliferative diseases.
[0035] This invention, by selecting suitable reaction substrates and using a copper catalyst, allows for a one-pot reaction to obtain the diastereomers of 3-hydroxypyrrolidine of formulas (I) and (II) without the addition of any oxidizing or reducing agents. The reaction conditions are simple, and good yields are achieved. This invention solves the problems of multi-step synthesis, high reaction risk, low reaction efficiency, and low yield in existing technologies. It provides a new and green synthetic route for the preparation of 3-hydroxypyrrolidine derivatives and has good application value and potential in industrial and pharmaceutical synthesis. Detailed Implementation
[0036] The present invention will be further described in detail below through specific embodiments. Unless otherwise specified, the raw materials used in the following embodiments can be obtained from conventional commercial channels or prepared and isolated through simple synthesis; unless otherwise specified, the processes employed are conventional processes in the art.
[0037] Example 1
[0038] Prepare 3-hydroxypyrrolidine derivatives according to the following reaction formula:
[0039]
[0040] Based on the above chemical reaction formula, the preparation process includes the following steps:
[0041] Compounds of formulas (1.3), (1.4), and (1.5) and copper acetate (Cu(OAc)2) were added to acetonitrile, and the mixture was heated to 60°C and stirred and sealed at that temperature for 4 hours.
[0042] The molar ratio of compound (1.3) to copper acetate (Cu(OAc)2) is 1:0.1; the molar ratio of compound (1.3) to compounds (1.4) and (1.5) is 1:1.5:1.5; and the ratio of compound (1.3) in millimoles (mmol) to acetonitrile in milliliters (mL) is 1:8.
[0043] After the reaction is complete, the reaction system is naturally cooled to room temperature. A mixture of ethyl acetate and saturated brine in equal volume ratio is added, and the mixture is extracted by shaking 2-4 times. The organic layer is collected, dried, and concentrated by rotary evaporation to obtain the crude product. The crude product is then subjected to chromatographic chromatography on a 200-300 mesh silica gel column using a mixture of ethyl acetate and petroleum ether as the eluent, wherein the volume ratio of ethyl acetate to petroleum ether is 1:5. This yields a white product, 3-hydroxypyrrolidine diastereomer, with a total yield of 96%. Formulas (1.1) and (1.2) can be separated and purified separately, wherein compound (C) of formula (1.1) is... 26 H 26 N2O5S), yield 42%, (1.2) compound (C 26 H 26 N2O5S), with a yield of 54%.
[0044] Nuclear magnetic resonance of compound (1.1): 1 HNMR(400MHz, CDCl3)δ7.68-7.66(m,2H),7.51-7.50(m,4H),7.36-7.34(m,5H),7.26-7.24(m, 1H),7.17-7.16(m,2H),4.88-4.81(m,2H),3.97-3.66(m,4H),3.0(s,3H),0.8(t,J=6.8Hz,3H).
[0045] 13 CNMR(100MHz, CDCl3)δ166.8,163.1,142.5,139.9,138.6,137.9,129.3(2C),129.2(2C),129. 1,128.7(2C),127.3,126.6(2C),126.4(2C),124.4(2C).79.3,64.0,61.9,61.8,21.7,13.6..
[0046] Nuclear magnetic resonance of compound (1.2): 1 HNMR(400MHz, CDCl3)δ7.75-7.73(m,2H),7.39-7.33(m,9H),7.23-7.21(m,3H),4.93(s,1H),4.93(s,1H),4.3 8(d,J=11.2Hz,1H),4.27-4.22(m,2H),3.9(d,J=11.2Hz,1H),3.37(s,1H),2.39(s,3H),1.28(t,J=6.8Hz,3H).
[0047] 13 CNMR(100MHz, CDCl3)δ166.7,162.7,144.0,142.7,139.9,138.2,129.4(2C),129.3(2C),129 .2(2C),128.9,127.3,126.8(2C),124.5(2C),123.9(2C).77.2,63.4,62.4,60.5,21.7,14.3.
[0048] Example 2
[0049] The reaction formula is the same as in Example 1, and the specific preparation method is as follows:
[0050] Add the compounds of formulas (1.1), (1.2), and (1.3) above, along with copper acetate (Cu(OAc)2), to acetonitrile. Then, heat the mixture to 80°C and stir and seal it at this temperature for 8 hours.
[0051] The molar ratio of compound (1.3) to copper acetate (Cu(OAc)2) is 1:0.5; the molar ratio of compound (1.3) to compounds (1.4) and (1.5) is 1:2:2; and the ratio of compound (1.3) in millimoles (mmol) to acetonitrile in milliliters (ml) is 1:10.
[0052] After the reaction is complete, the reaction system is naturally cooled to room temperature. A mixture of ethyl acetate and saturated brine in equal volume ratio is added, and the mixture is extracted by shaking 2-4 times. The organic layer is collected, dried, and concentrated by rotary evaporation to obtain the crude product. The crude product is then subjected to chromatographic chromatography on a 200-300 mesh silica gel column using a mixture of ethyl acetate and petroleum ether as the eluent, wherein the volume ratio of ethyl acetate to petroleum ether is 1:6. This yields a white product, 3-hydroxypyrrolidine diastereomer, with a total yield of 92%. Formulas (1.1) and (1.2) can be separated and purified separately, wherein compound (C) of formula (1.1) is... 26 H 26 N2O5S), yield 40%, (1.2) compound (C26 H 26 N2O5S), with a yield of 52%.
[0053] The NMR data of the product compounds (1.1) and (1.2) are the same as in Example 1.
[0054] Example 3
[0055] Prepare 3-hydroxypyrrolidine derivatives according to the following reaction formula:
[0056]
[0057] Based on the above chemical reaction formula, the preparation process includes the following steps:
[0058] Compounds of formulas (2.3), (2.4), and (2.5) and cuprous iodide (CuI) were added to DMF, and the mixture was heated to 100°C and stirred and sealed at that temperature for 2 hours.
[0059] The molar ratio of compound (2.3) to cuprous iodide (CuI) is 1:0.15; the molar ratio of compound (2.3) to compounds (2.4) and (2.5) is 1:1.2:1.2; and the ratio of compound (2.3) in millimoles (mmol) to DMF in milliliters (ml) is 1:8.
[0060] After the reaction is complete, the reaction system is naturally cooled to room temperature. A mixture of ethyl acetate and saturated brine in equal volume ratio is added, and the mixture is extracted by shaking 2-4 times. The organic layer is collected, dried, and concentrated by rotary evaporation to obtain the crude product. The crude product is then subjected to chromatographic chromatography on a 200-300 mesh silica gel column using a mixture of ethyl acetate and petroleum ether as the eluent, wherein the volume ratio of ethyl acetate to petroleum ether is 1:8. This yields a white product, 3-hydroxypyrrolidine diastereomer, with a total yield of 88%. Formulas (2.1) and (2.2) can be separated and purified separately, wherein compound (C) of formula (2.1) is... 26 H 26 N2O5S), yield 46%, (2.2) compound (C 26 H 26 N2O5S), with a yield of 42%.
[0061] Nuclear magnetic resonance of compound (2.1): 1HNMR(400MHz, CDCl3)δ7.68-7.66(m,2H),7.51-7.50(m,4H),7.36-7.34(m,5H),7.26-7.24(m, 1H),7.17-7.16(m,2H),4.88-4.81(m,2H),3.97-3.66(m,4H),3.0(s,3H),0.8(t,J=6.8Hz,3H).
[0062] 13 CNMR(100MHz, CDCl3)δ166.8,163.1,142.5,139.9,138.6,137.9,129.3(2C),129.2(2C),129. 1,128.7(2C),127.3,126.6(2C),126.4(2C),124.4(2C).79.3,64.0,61.9,61.8,21.7,13.6..
[0063] Nuclear magnetic resonance of compound (2.2): 1 HNMR(400MHz, CDCl3)δ7.75-7.73(m,2H),7.39-7.33(m,9H),7.23-7.21(m,3H),4.93(s,1H),4.93(s,1H),4.3 8(d,J=11.2Hz,1H),4.27-4.22(m,2H),3.9(d,J=11.2Hz,1H),3.37(s,1H),2.39(s,3H),1.28(t,J=6.8Hz,3H).
[0064] 13 CNMR(100MHz, CDCl3)δ166.7,162.7,144.0,142.7,139.9,138.2,129.4(2C),129.3(2C),129 .2(2C),128.9,127.3,126.8(2C),124.5(2C),123.9(2C).77.2,63.4,62.4,60.5,21.7,14.3.
[0065] Example 4
[0066] The reaction formula is the same as in Example 3, and the specific preparation method is as follows:
[0067] Compounds of formulas (2.3), (2.4), and (2.5) and cuprous iodide (CuI) were added to a dimethyl sulfoxide solvent, and the mixture was heated to 120°C and stirred and sealed at that temperature for 12 hours.
[0068] The molar ratio of compound (2.3) to cuprous iodide (CuI) is 1:0.25; the molar ratio of compound (2.3) to compounds (2.4) and (2.5) is 1:2.5:2.5; and the ratio of compound (2.3) in millimoles (mmol) to dimethyl sulfoxide in milliliters (ml) is 1:12.
[0069] After the reaction is complete, the reaction system is naturally cooled to room temperature. A mixture of ethyl acetate and saturated brine in equal volume ratio is added, and the mixture is extracted by shaking 2-4 times. The organic layer is collected, dried, and concentrated by rotary evaporation to obtain the crude product. The crude product is then subjected to chromatographic chromatography on a 200-300 mesh silica gel column using a mixture of ethyl acetate and petroleum ether as the eluent, wherein the volume ratio of ethyl acetate to petroleum ether is 1:7. This yields a white product, 3-hydroxypyrrolidine diastereomer, with a total yield of 86%. Formulas (2.1) and (2.2) can be separated and purified separately, wherein compound (C) of formula (2.1) is... 26 H 26 N2O5S), yield 46%, (2.2) compound (C 26 H 26 N2O5S), with a yield of 40%.
[0070] The NMR data of the product compounds (2.1) and (2.2) are the same as those in Example 3.
[0071] Example 5-20
[0072] According to the correspondence shown in Table 1, the catalysts copper acetate (Cu(OAc)2) or cuprous iodide (CuI) in Examples 1-4 were replaced with other copper compounds in the same molar amount, and other operations were the same. The product yields are shown in Table 1.
[0073] Table 1. Product yields under different catalysts
[0074]
[0075] It is evident that the type of catalyst has a significant impact on the product yield. Copper acetate (Cu(OAc)2) or cuprous iodide (CuI) exhibits better catalytic effects, while copper acetate (Cu(OAc)2) demonstrates the best catalytic performance.
[0076] Examples 21-28
[0077] According to the correspondence shown in Table 2, the solvents in Examples 1-4 were replaced with other solvents in the same amount, and other operations were different. The product yields are shown in Table 2.
[0078] Table 2. Product yields under different solvents
[0079]
[0080] Therefore, it can be seen that among all solvents, water-soluble solvents yield higher product yields, while non-water-soluble solvents produce poorer reaction results.
[0081] In summary, it is clear from all the above embodiments that when the method of the present invention is used, the three compounds of the raw materials can react smoothly, and the combined synergistic effect of multiple factors such as catalyst and solvent can lead to the target product with good yield and simple post-processing.
[0082] Activity testing implementation section:
[0083] Cell resuscitation: First, prepare high-glucose DEME medium in a clean bench. Remove the cryopreserved tubes of Raw264.7 macrophages from the -80℃ freezer and quickly place them in a 37℃ constant temperature water bath to thaw. After sterilization, transfer the cells to 15mL centrifuge tubes in a clean bench and tighten the caps. Centrifuge at room temperature (800rpm, 3min). After centrifugation, remove the Raw264.7 macrophages, discard the supernatant, and gently pipette the cells with an appropriate amount of high-glucose DEME medium to resuspend them. Evenly seed the resuspended cells into culture dishes and immediately incubate in a 37℃, 5% CO2 cell incubator.
[0084] Cell passage culture: When the cells in the culture dish have grown to about 80% under an inverted microscope, remove the culture dish and place it on a clean bench. Discard the original culture medium and add 3 mL of prepared PBS buffer. Rotate the culture dish to wash and discard the PBS buffer. Repeat the above operation twice. Then add 3 mL of high-glucose DEME medium and pipette the cells on the wall to make them fall off completely. Use a pipette to transfer the cell suspension to a 15 mL centrifuge tube and passage at a 1:2 ratio. Observe the cell status daily and passage again.
[0085] Cell cryopreservation: When cells in the observation dish reach approximately 80% confluence, remove them and place them in a clean bench. Discard the original culture medium, wash twice with PBS buffer, add high-glucose DEME medium, and gently pipette the cells off. Collect the cell suspension in a 15mL centrifuge tube and centrifuge (800 rpm, 3 min). Remove the supernatant after centrifugation, add an appropriate amount of pre-prepared cell cryopreservation solution, and gently pipette to resuspend the cells. Transfer the cell suspension to sterile cryovials, seal and label, and freeze for storage.
[0086] Raw264.7 Macrophage Activity Test: Observe the cells under a microscope. When the cells have adhered to the wall and grown to 80%-90% and the cells are translucent small round, they can be used for experimental detection. After sterilizing the culture dishes, place them on a clean bench and wash twice with pre-cooled PBS buffer. Use fresh culture medium to agitate the central cells, then transfer the cell suspension to a 15 mL centrifuge tube. Next, pipette 10 μL of the cell suspension into a cell counting chamber and count the cells using a cell counter. Take the average value as the cell concentration of that tube. Dilute the cell suspension with fresh culture medium according to the concentration. Add 100 μL of the cell suspension to a 96-well plate and incubate in a CO2 cell culture incubator for 24 h until the cells adhere. Dilute the compounds to be tested to the corresponding concentrations (6.25 μmol / L, 12.5 μmol / L, 25.0 μmol / L, 50 μmol / L, 100 μmol / L) with culture medium and add 100 μL to each well of a 96-well plate seeded with Raw264.7 macrophages, with 3 replicates. Continue incubation in a cell culture incubator. After 48 hours, remove the culture medium from each well and add 10 μl of MTT to each well. After culturing for 4 hours, remove the culture medium from each well and aspirate it. Add 150 μL of DMSO to each well and shake on a shaker for 10 minutes until the formazan dissolves. Measure the OD using a microplate reader. 570 Values, and calculate IC using GraphPad. 50 (50% macrophage apoptosis is called the 50% inhibition concentration).
[0087] The inhibitory effects of the four 3-hydroxypyrrolidine diastereomers prepared in Examples 1 and 3 on Raw264.7 macrophages were tested using the MTT assay described above. The results showed that all four compounds had inhibitory effects on Raw264.7 cells, with an IC50 concentration of [missing value]. 50 The concentrations were 0.12 μM, 0.23 μM, 0.013 μM, and 0.018 μM, respectively. The 3-hydroxypyrrolidine derivative provided by this invention can inhibit the proliferation of RAW264.7 cells, and thus, to a certain extent, inhibit the excessive proliferation of macrophages in immune cells, thereby showing great promise in the preparation of candidate drugs for proliferative diseases.
Claims
1. A 3-hydroxypyrrolidine derivative, characterized in that, The structural formula of the 3-hydroxypyrrolidine derivative is shown in formula (I) or formula (II): 、 ； Among them, the 3-hydroxypyrrolidine derivatives shown in formula (I) and formula (II) are diastereomers of each other; In equations (I) and (II), the R 1 or R 2 Each of the following is independently selected from phenyl, C1-C4 alkylphenyl, halophenyl, hydroxyphenyl, cyanophenyl, methoxyphenyl, and nitrophenyl; R 3 Each is independently selected from C1-C6 alkyl groups; the R 4 Each of the following is independently selected from phenyl, C1-C4 alkylphenyl, halophenyl, hydroxyphenyl, cyanophenyl, methoxyphenyl, and nitrophenyl.
2. The 3-hydroxypyrrolidine derivative according to claim 1, characterized in that, The 3-hydroxypyrrolidine derivative is selected from compounds with the following structures: 、 、 、 、 、 、 、 。 3. The method for preparing the 3-hydroxypyrrolidine derivative according to any one of claims 1 to 2, characterized in that, The steps include: in the presence of a copper compound, as shown in formula (III) α - An aminoacetone compound, a terminal acetyl ketone compound as shown in formula (IV), and a sulfonyl azide compound as shown in formula (V) are reacted to obtain the 3-hydroxypyrrolidine diastereomers of formulas (I) and (II); wherein the reaction formulas of the preparation method are shown below: ； The reaction is carried out in an organic solvent selected from any one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.
4. The method for preparing the 3-hydroxypyrrolidine derivative according to claim 3, characterized in that, The copper compound is selected from one or more of copper acetate, copper chloride, copper bromide, copper acetylacetone, copper trifluoroacetate, copper trifluoromethanesulfonate, copper oxide, cuprous iodide, cuprous bromide, cuprous chloride, copper thiophene-2-carboxylate, and cuprous acetate.
5. The method for preparing the 3-hydroxypyrrolidine derivative according to claim 3, characterized in that, The α The molar ratio of aminoacetone compounds to copper compounds is 1:(0.05-0.2); And / or, the α The molar ratio of aminoacetone compounds to terminal acetylene compounds is 1:(1-3); And / or, the α The molar ratio of aminoethyl ketone compounds to sulfonyl azide compounds is 1:(1-3).
6. The method for preparing the 3-hydroxypyrrolidine derivative according to claim 3, characterized in that, The reaction temperature is 60-120℃; And / or, the reaction time is 0.5-8 h.
7. The method for preparing the 3-hydroxypyrrolidine derivative according to claim 3, characterized in that, The α The ratio of aminoethyl ketone compounds to organic solvents is 1 mmol:(5-15) mL.
8. The use of the 3-hydroxypyrrolidine derivative according to any one of claims 1 to 2 in the preparation of a medicament for treating macrophage overproliferation.