CN118146134A - 3-Hydroxypyrrolidine derivative, and preparation method and application thereof - Google Patents

3-Hydroxypyrrolidine derivative, and preparation method and application thereof Download PDF

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CN118146134A
CN118146134A CN202410174163.5A CN202410174163A CN118146134A CN 118146134 A CN118146134 A CN 118146134A CN 202410174163 A CN202410174163 A CN 202410174163A CN 118146134 A CN118146134 A CN 118146134A
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hydroxypyrrolidine
copper
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李航
李观容
谭华强
杨渭光
王忱
曾俊
张冬英
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Southern Marine Science and Engineering Guangdong Laboratory Zhanjiang
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Abstract

The invention discloses a 3-hydroxypyrrolidine derivative, and a preparation method and application thereof. The structural formula of the 3-hydroxypyrrolidine derivative is shown as a formula (I) or a formula (II):

Description

3-Hydroxypyrrolidine derivative, and preparation method and application thereof
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a 3-hydroxypyrrolidine derivative, and a preparation method and application thereof.
Background
Macrophages are widely distributed in tissues and organs of the body, play an important role in pathogen defense, inflammatory response, steady state maintenance and injury repair, and can activate lymphocytes or other immune cells to react with pathogens and foreign particles, participate in immune response, help the immune system identify and clear invaders, and can also be used as professional antigen presenting cells to process and present antigen to activate adaptive immune response. However, modern biomedical research has shown that macrophage proliferation is involved in certain severe proliferative diseases, such as lymphomas, cardiovascular diseases, renal sclerosis, etc., where macrophage syndrome refers to a malignant tumor of the blood system caused by excessive proliferation and activation of macrophages in immune cells. The pyrrolidine alkaloid is an organic alkali compound containing a pyrrole ring structure, and has wide biological activity and medical value. The pyrrolidine alkaloid has the main medicinal effects: antitumor, antibacterial, analgesic, and antidepressant effects. Although pyrrolidine alkaloids have antitumor effects, there are few reports on the effects of pyrrolidine organisms on macrophages.
In addition, the current 3-hydroxypyrrolidine derivatives are mainly synthesized by three methods: the first is addition or oxidative hydroxylation of pyrroline containing double bonds; the second is to take malic acid as raw material to synthesize by cyclization and reduction; the third is by pyrrolidone reduction. The method is characterized by multi-step synthesis, use of a reducing agent or an explosive oxidizing agent which is easy to absorb moisture, low reaction efficiency and low yield. Thus, there is a need to develop pyrrolidines for the treatment of proliferative diseases, and to develop new green and efficient synthetic methods for 3-hydroxypyrrolidine.
Disclosure of Invention
In order to overcome the problems of the prior art, it is an object of the present invention to provide a 3-hydroxypyrrolidine derivative. The second object of the present invention is to provide a process for preparing such 3-hydroxypyrrolidine derivatives. It is a further object of the present invention to provide the use of such 3-hydroxypyrrolidine derivatives.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
The first aspect of the invention provides a 3-hydroxypyrrolidine derivative, wherein the structural formula of the 3-hydroxypyrrolidine derivative is shown as a formula (I) or a formula (II):
wherein the 3-hydroxypyrrolidine derivatives represented by the formula (I) and the formula (II) are diastereoisomers;
In formula (I) and formula (II), each of R 1 or R 2 is independently selected from H, phenyl or substituted phenyl; each R 3 is independently selected from the group consisting of aliphatic hydrocarbons or halogenated aliphatic hydrocarbons; the R 4 groups are each independently selected from phenyl, substituted phenyl, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons.
Preferably, in formula (I) and formula (II), each of R 1 or R 2 is independently selected from H, phenyl, C 1-C4 alkylphenyl, halophenyl, hydroxyphenyl, cyanophenyl, methoxyphenyl, nitrophenyl;
preferably, in formula (I) and formula (II), each R 3 is independently selected from C 1-C6 alkyl, C 5-C6 cycloalkyl;
Preferably, in formula (I) and formula (II), each R 4 is independently selected from phenyl, C 1-C4 alkylphenyl, halophenyl, hydroxyphenyl, cyanophenyl, methoxyphenyl, nitrophenyl, C 1-C6 alkyl, and halogenated C 1-C6 alkyl.
More preferably, the 3-hydroxypyrrolidine derivative is selected from the group of compounds of the following structure:
In a second aspect, the present invention provides a method for preparing the 3-hydroxypyrrolidine derivative according to the first aspect of the present invention, in the presence of a copper compound, reacting an α -aminoethanone compound represented by formula (II I), a terminal alkyne compound represented by formula (IV), and a sulfonyl azide compound represented by formula (V), to obtain the 3-hydroxypyrrolidine diastereomers represented by formulas (I) and (II); wherein, the reaction formula of the preparation method is as follows:
In the preparation method, firstly, a terminal alkyne ketone compound (IV) and a sulfonyl azide compound (V) generate an intermediate A of triazole under the catalysis of copper, the intermediate A undergoes ring opening rearrangement to obtain ketene imine B, then undergoes nucleophilic addition with alpha-aminoacetophenone (II) to obtain an intermediate C, and then undergoes intramolecular cyclization reaction to obtain target products, namely 3-hydroxypyrrolidine diastereoisomers (I) and (II), wherein the reaction mechanism is as follows:
Preferably, the copper compound is selected from one or more of copper acetate, copper chloride, copper bromide, copper acetylacetonate, copper trifluoroacetate, copper triflate, copper oxide, copper iodide, copper bromide, copper chloride, copper thiophene-2-carboxylate, and copper acetate.
Preferably, the molar ratio of the alpha-amino ethanone compound to the copper compound is 1 (0.05-0.2).
Preferably, the molar ratio of the alpha-amino ethanone compound to the terminal acetylenic ketone compound is 1 (1-3).
Preferably, the molar ratio of the alpha-amino ethanone compound to the sulfonyl azide compound is 1 (1-3).
Preferably, the reaction temperature of the reaction is 60-120 ℃. More preferably, the reaction temperature is 60-80 ℃.
Preferably, the reaction time of the reaction is 0.5 to 8 hours. More preferably, the reaction time is 2 to 6 hours.
Preferably, the reaction is carried out in an organic solvent comprising any one or more of acetonitrile, dichloroethane, N-dimethylformamide, N-dimethylacetamide, dichloromethane, chlorobenzene, benzene, xylene, dimethyl sulfoxide, N-methylpyrrolidone.
More preferably, the dosage ratio of the alpha-amino ethanone compound to the organic solvent is 1mmol:5-15mL.
The reaction further comprises a post-treatment step after the reaction is finished. The post-treatment comprises any one treatment means or a combination of a plurality of treatment means in extraction, concentration, crystallization, recrystallization and column chromatography purification.
As an exemplary post-treatment means, for example, there may be: after the reaction is completed, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline in an equal volume ratio, oscillating and extracting for 2-4 times, collecting an organic layer, drying, rotationally evaporating and concentrating to obtain a crude product, subjecting the crude product to 200-300 mesh silica gel column chromatography, and taking the mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:5-10, thereby obtaining the 3-hydroxypyrrolidine diastereoisomer shown in the formula (I).
The third aspect of the invention also provides the use of the 3-hydroxypyrrolidine derivatives according to the first aspect of the invention in the manufacture of a medicament candidate for the treatment of a proliferative disease.
Preferably, the 3-hydroxypyrrolidine derivatives are for use in inhibiting macrophage proliferation.
More preferably, the 3-hydroxypyrrolidine derivatives are used for inhibiting proliferation of RAW264.7 macrophages.
The beneficial effects of the invention are as follows:
the 3-hydroxypyrrolidine derivative provided by the invention can inhibit proliferation of RAW264.7 cells, and further inhibit excessive proliferation of macrophages in immune cells to a certain extent, so that the 3-hydroxypyrrolidine derivative has a great application prospect in preparation of candidate medicines for proliferative diseases.
According to the invention, through selecting a proper reaction substrate, under the action of a copper catalyst, the 3-hydroxypyrrolidine diastereoisomers of the formulas (I) and (II) can be obtained by a one-pot reaction without adding any oxidant or reducing agent, the reaction condition is simple, and meanwhile, good yield is obtained, the problems of multi-step synthesis, high reaction risk, low reaction efficiency and low yield in the prior art are solved, a novel green synthesis route is provided for preparing the 3-hydroxypyrrolidine derivative, and the preparation method has good application value and potential in industrial and pharmaceutical synthesis.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The starting materials used in the examples below, unless otherwise specified, were all available from conventional commercial sources or were isolated by simple synthetic preparation; the processes used, unless otherwise specified, are all conventional in the art.
Example 1
The 3-hydroxypyrrolidine derivatives are prepared according to the following reaction scheme:
according to the chemical reaction formula, the preparation process comprises the following steps:
To acetonitrile, the above formula (1.3), formula (1.4), formula (1.5) and copper acetate (Cu (OAc) 2) were added, then heated to 60 ℃, and the reaction was stirred at that temperature for 4 hours under sealed conditions.
Wherein the molar ratio of the compound of formula (1.3) to copper acetate (Cu (OAc) 2) is 1:0.1; the molar ratio of the compound of formula (1.3) to the compound of formula (1.4), (1.5) is 1:1.5:1.5; the ratio of the compound of formula (1.3) in millimoles (mmol) to acetonitrile in milliliters (mL) was 1:8.
After the reaction is completed, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline in an equal volume ratio, oscillating and extracting for 2-4 times, collecting an organic layer, drying, rotationally evaporating and concentrating to obtain a crude product, subjecting the crude product to 200-300 mesh silica gel column chromatography, and taking the mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:5, so that a white product 3-hydroxypyrrolidine diastereoisomer with the total yield of 96% is obtained. The compound (C 26H26N2O5 S) of the formula (1.1) and the compound (C 26H26N2O5 S) of the formula (1.2) can be separated and purified independently, wherein the yield of the compound (C 26H26N2O5 S) of the formula (1.1) is 42%, and the yield of the compound (C 26H26N2O5 S) of the formula (1.2) is 54%.
Nuclear magnetic resonance of the compound of formula (1.1) ：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).
13CNMR(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..
Nuclear magnetic resonance of the compound of formula (1.2) ：1HNMR(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),4.38(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).
13CNMR(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.
Example 2
The reaction formula is the same as in example 1, and the specific preparation method is as follows:
To acetonitrile, a compound of the above formula (1.1), (1.2), (1.3), copper acetate (Cu (OAc) 2) were added, then heated to 80 ℃, and the reaction was stirred at that temperature for 8 hours under sealed conditions.
Wherein the molar ratio of the compound of formula (1.3) to copper acetate (Cu (OAc) 2) is 1:0.5; the molar ratio of the compound of formula (1.3) to the compound of formula (1.4), (1.5) is 1:2:2; the ratio of the compound of formula (1.3) in millimoles (mmol) to acetonitrile in milliliters (ml) is 1:10.
After the reaction is completed, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline in equal volume ratio, oscillating and extracting for 2-4 times, collecting an organic layer, drying, rotationally evaporating and concentrating to obtain a crude product, subjecting the crude product to 200-300 mesh silica gel column chromatography, and taking the mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:6, so that a white product 3-hydroxypyrrolidine diastereoisomer with the total yield of 92% is obtained. The compound (C 26H26N2O5 S) of the formula (1.1) and the compound (C 26H26N2O5 S) of the formula (1.2) can be separated and purified independently, wherein the yield of the compound (C 26H26N2O5 S) of the formula (1.1) is 40%, and the yield of the compound (C 26H26N2O5 S) of the formula (1.2) is 52%.
Nuclear magnetic resonance data of the product compounds of formula (1.1) and formula (1.2) are the same as in example 1.
Example 3
The 3-hydroxypyrrolidine derivatives are prepared according to the following reaction scheme:
according to the chemical reaction formula, the preparation process comprises the following steps:
To DMF was added the compounds of the above formula (2.3), formula (2.4), formula (2.5) and copper iodide (CuI), and then heated to 100℃and the reaction was stirred at this temperature for 2 hours under sealed conditions.
Wherein the molar ratio of the compound of formula (2.3) to copper iodide (CuI) is 1:0.15; the molar ratio of the compound of formula (2.3) to the compound of formula (2.4), (2.5) is 1:1.2:1.2; the ratio of the compound of formula (2.3) in millimoles (mmol) to DMF in milliliters (ml) is 1:8.
After the reaction is completed, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline in equal volume ratio, oscillating and extracting for 2-4 times, collecting an organic layer, drying, rotationally evaporating and concentrating to obtain a crude product, subjecting the crude product to 200-300 mesh silica gel column chromatography, and taking the mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:8, so that a white product 3-hydroxypyrrolidine diastereoisomer with the total yield of 88% is obtained. The compound (C 26H26N2O5 S) of the formula (2.1) and the compound (C 26H26N2O5 S) of the formula (2.2) can be separated and purified independently, wherein the yield of the compound (C 26H26N2O5 S) of the formula (2.1) is 46%, and the yield of the compound (C 26H26N2O5 S) of the formula (2.2) is 42%.
Nuclear magnetic resonance of the compound of formula (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).
13CNMR(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..
Nuclear magnetic resonance of the compound of formula (2.2) ：1HNMR(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),4.38(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).
13CNMR(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.
Example 4
The reaction formula is the same as in example 3, and the specific preparation method is as follows:
To the dimethyl sulfoxide solvent, the compounds of the above formula (2.3), formula (2.4), formula (2.5) and copper iodide (CuI) were added, and then heated to 120 ℃ and the reaction was stirred and sealed at that temperature for 12 hours.
Wherein the molar ratio of the compound of formula (2.3) to copper iodide (CuI) is 1:0.25; the molar ratio of the compound of formula (2.3) to the compound of formula (2.4), (2.5) is 1:2.5:2.5; the ratio of the compound of formula (2.3) in millimoles (mmol) to dimethyl sulfoxide in milliliters (ml) was 1:12.
After the reaction is completed, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline in an equal volume ratio, oscillating and extracting for 2-4 times, collecting an organic layer, drying, rotationally evaporating and concentrating to obtain a crude product, subjecting the crude product to 200-300 mesh silica gel column chromatography, and taking the mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:7, so that a white product 3-hydroxypyrrolidine diastereoisomer with 86% total yield is obtained. The compound (C 26H26N2O5 S) of the formula (2.1) and the compound (C 26H26N2O5 S) of the formula (2.2) can be separated and purified independently, wherein the yield of the compound (C 26H26N2O5 S) of the formula (2.1) is 46%, and the yield of the compound (C 26H26N2O5 S) of the formula (2.2) is 40%.
Nuclear magnetic resonance data of the product compounds of formula (2.1) and formula (2.2) are the same as in example 3.
Examples 5 to 20
According to the correspondence shown in Table 1, the catalysts of examples 1 to 4, copper acetate (Cu (OAc) 2) or copper iodide (CuI), were replaced with the same molar amount of other copper compound, and the other operations were the same, and the obtained product yields are shown in Table 1.
TABLE 1 product yields over different catalysts
It can be seen that the type of catalyst has a significant effect on the product yield, with copper acetate (Cu (OAc) 2) or copper iodide (CuI) having the better catalytic effect and copper acetate (Cu (OAc) 2) having the best catalytic performance.
Examples 21 to 28
According to the correspondence shown in Table 2, the solvents of examples 1 to 4 were replaced with the same amount of other solvents, and the other operations were different, and the obtained product yields are shown in Table 2.
TABLE 2 yields of products in different solvents
It can be seen that the water-soluble solvent gave a relatively high yield of product and the water-insoluble solvent gave a relatively poor reaction effect in all solvents.
From the above, it is clear from all the examples that, when the method of the present invention is employed, three compounds of the raw materials can be smoothly reacted, wherein a plurality of factors such as the combination of the catalyst and the solvent act synergistically, thereby obtaining the objective product with good yield and simple post-treatment.
Activity test implementation section:
Cell resuscitation: firstly, preparing a high-sugar DEME culture medium on an ultra-clean workbench, taking out a frozen tube of Raw264.7 macrophages from a refrigerator at-80 ℃ and rapidly placing the frozen tube in a constant-temperature water bath at 37 ℃ to melt the frozen tube, placing the sterilized frozen tube in a 15mL centrifuge tube, transferring the sterilized frozen tube into the 15mL centrifuge tube, screwing a tube cover, and placing the sterilized frozen tube in a desk centrifuge for centrifugation at normal temperature (800 rpm,3 min). After centrifugation, the Raw264.7 macrophages are removed, the supernatant is discarded, and the cells are resuspended by gentle blowing with an appropriate amount of high-sugar DEME medium. The resuspended cell fluid was inoculated uniformly into a petri dish and immediately incubated in a cell incubator at 37℃with 5% CO 2.
And (3) cell subculture: when the growth of cells in the culture dish is observed under an inverted microscope to about 80%, the culture dish is taken out and placed on an ultra-clean workbench, the original culture medium is discarded, 3mL of prepared PBS buffer solution is added, the culture dish is rotated and washed and discarded, 3mL of high-sugar DEME culture medium is added after repeating the above operation for 2 times, the cells on the wall are blown down to fall completely, the cell suspension is transferred into a15 mL centrifuge tube by a pipetting gun for subculture according to the ratio of 1:2, and the cell state is observed every day for subculture again.
Cell cryopreservation: the cells in the observation dish grow to about 80%, the cells are taken out and placed on an ultra-clean workbench, the original culture medium is discarded, PBS buffer solution is added for washing for 2 times, high-sugar DEME culture medium is added for gently blowing down the cells, a15 mL centrifuge tube is used for collecting cell suspension, the cell suspension is placed for centrifugation (800 rmp,3 min), the supernatant fluid after centrifugation is removed, a proper amount of cell finished product frozen stock solution is added, and the cells are gently blown down for resuspension. The cell suspension is transferred to a sterile cryopreservation tube for labeling and cryopreservation.
Raw264.7 macrophage activity test: observing the cells under a microscope, and when the cells grow to 80% -90% by adhering to the wall, and the cell morphology is in a transparent small round shape, the cell morphology can be used for experimental detection. Placing the sterilized culture dish on an ultra-clean workbench, washing the culture dish for 2 times by using precooled PBS buffer solution, blowing the cells in the central area by using fresh culture medium, and transferring the cell suspension into a 15mL centrifuge tube; then, 10 mu L of cell suspension is sucked into a cell counting plate by a liquid-transferring gun, counted on a cell counter, the average value is taken as the cell concentration of the cell suspension of the tube, and fresh culture medium is added according to the concentration to dilute the cell suspension; adding 100 mu L of cell suspension into a 96-well plate, and placing the mixture into a CO 2 cell culture box to culture for 24 hours until cells adhere to the wall; the compounds to be tested were diluted with medium to the corresponding concentrations (6.25. Mu. Mol/L, 12.5. Mu. Mol/L, 25.0. Mu. Mol/L, 50. Mu. Mol/L, 100. Mu. Mol/L) and added to 96-well plates inoculated with Raw264.7 macrophages, 100. Mu.L of each well was added, 3 multiplex wells were placed in a cell incubator for continued culture. After 48h, 10 μl MTT was added to each well, after 4h incubation, the medium was removed from the wells by pipetting, 150 μl DMSO was added to each well, shaking on a shaker for 10min until formazan dissolved, detecting OD 570 values with a microplate reader, and calculating IC 50 (macrophage apoptosis 50% which concentration was referred to as 50% inhibition concentration) by GraphPad.
The four 3-hydroxypyrrolidine diastereomers prepared in example 1 and example 3 were tested for their inhibitory effect on raw264.7 macrophages using the MTT method described above, and as a result, four compounds were found to have inhibitory effects on raw264.7 cells, with IC 50 of 0.12 μm,0.23 μm,0.013 μm, and 0.018 μm, respectively. The 3-hydroxypyrrolidine derivative provided by the invention can inhibit proliferation of RAW264.7 cells, and further inhibit excessive proliferation of macrophages in immune cells to a certain extent, so that the 3-hydroxypyrrolidine derivative has a great application prospect in preparation of candidate medicines for proliferative diseases.

Claims (10)

1. The 3-hydroxypyrrolidine derivative is characterized in that the structural formula of the 3-hydroxypyrrolidine derivative is shown as a formula (I) or a formula (II):
wherein the 3-hydroxypyrrolidine derivatives represented by the formula (I) and the formula (II) are diastereoisomers;
In formula (I) and formula (II), each of R 1 or R 2 is independently selected from H, phenyl or substituted phenyl; each R 3 is independently selected from the group consisting of aliphatic hydrocarbons or halogenated aliphatic hydrocarbons; the R 4 groups are each independently selected from phenyl, substituted phenyl, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons.
2. The 3-hydroxypyrrolidine derivative according to claim 1, wherein in formula (I) and formula (II), said R 1 or R 2 are each independently selected from H, phenyl, C 1-C4 alkylphenyl, halophenyl, hydroxyphenyl, cyanophenyl, methoxyphenyl, nitrophenyl;
And/or, each of said R 3 is independently selected from C 1-C6 alkyl, C 5-C6 cycloalkyl;
And/or, the R 4 is independently selected from phenyl, C 1-C4 alkylphenyl, halophenyl, hydroxyphenyl, cyanophenyl, methoxyphenyl, nitrophenyl, C 1-C6 alkyl, halo C 1-C6 alkyl.
3. 3-Hydroxypyrrolidine derivative according to claim 2, characterized in that said 3-hydroxypyrrolidine derivative is selected from compounds of the following structure:
4. A process for the preparation of a 3-hydroxypyrrolidine derivative according to any of claims 1 to 3, characterized by comprising the steps of: reacting an alpha-aminoethanone compound shown in formula (II I), a terminal alkyne compound shown in formula (IV) and a sulfonyl azide compound shown in formula (V) in the presence of a copper compound to obtain 3-hydroxypyrrolidine diastereoisomers shown in formulas (I) and (II); wherein, the reaction formula of the preparation method is as follows:
5. The method for producing a 3-hydroxypyrrolidine derivative according to claim 4, wherein the copper compound is one or more selected from copper acetate, copper chloride, copper bromide, copper acetylacetonate, copper trifluoroacetate, copper trifluoromethanesulfonate, copper oxide, copper iodide, copper bromide, copper chloride, thiophene-2-carboxylic acid copper, and copper acetate.
6. The method for producing a 3-hydroxypyrrolidine derivative according to claim 4, wherein the molar ratio of the α -aminoethanone compound to the copper compound is 1 (0.05-0.2);
And/or the molar ratio of the alpha-amino ethanone compound to the terminal acetylenic ketone compound is 1 (1-3);
and/or the molar ratio of the alpha-amino-ethanone compound to the sulfonyl azide compound is 1 (1-3).
7. The method for producing a 3-hydroxypyrrolidine derivative according to claim 4, wherein the reaction temperature of the reaction is 60 to 120 ℃;
and/or the reaction time of the reaction is 0.5-8h.
8. The method for producing a 3-hydroxypyrrolidine derivative according to claim 4, wherein the reaction is performed in an organic solvent comprising any one or more of acetonitrile, dichloroethane, N-dimethylformamide, N-dimethylacetamide, dichloromethane, chlorobenzene, benzene, xylene, dimethylsulfoxide, and N-methylpyrrolidone.
9. The method for preparing 3-hydroxypyrrolidine derivatives according to claim 8, wherein the dosage ratio of the α -aminoethanone compound to the organic solvent is 1mmol: (5-15) mL.
10. Use of a 3-hydroxypyrrolidine derivative according to any one of claims 1 to 3 for the preparation of a candidate medicament for the treatment of a proliferative disease.
CN202410174163.5A 2024-02-07 2024-02-07 3-Hydroxypyrrolidine derivative, and preparation method and application thereof Pending CN118146134A (en)

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