A method for synthesizing 5-hydroxymethyloxazolidinone

Abstract

The present invention discloses a method for synthesizing 5-hydroxymethyloxazolidinone, belonging to the technical field of organic catalysis. The present invention proposes to use a bifunctional organic catalyst of a hydrogen bond donor / hydrogen bond acceptor to react epoxyamine with CO2 to generate 5-hydroxymethyloxazolidinone. The catalytic reaction conditions of the present invention are mild, the substrate scope is wide, and the product has no metal residue, having great potential for commercial application in the biomedical field.

Description

Technical Field

[0001] The present invention belongs to the technical field of organocatalysis, and particularly relates to a method for synthesizing 5-hydroxymethyloxazolidinone. Background Art

[0002] Oxazolidinone is a class of five-membered heterocyclic compounds containing both oxygen and nitrogen, which are structurally cyclic carbamates and important pharmaceutically active intermediates. The cores of many marketed or clinical drugs contain this structure, such as the bacterial protein synthesis inhibitor linezolid, the selective 5-hydroxytryptamine receptor agonist zolmitriptan, the drug rivaroxaban for treating venous thrombosis, and the antibiotic delpazolid. This compound was first synthesized in 1958, and many novel synthetic strategies have since been developed for the synthesis of oxazolidinone. Among them are: the [3+2] coupling of epoxides and isocyanates to prepare oxazolidinone (CN112851597B); the cycloaddition of aziridine and CO2 (ChemSusChem 2019, 12, 3296); the addition reaction of amino alcohol and carbon dioxide (RSCAdv. 2014, 4, 50851); the addition reaction of glycidol and isocyanate (CN113200932B), etc. It is worth mentioning that in previous synthetic strategies, the target products were mostly non-post-modifiable 4-substituted oxazolidinones, while in current drug molecules containing the oxazolidinone core, they are mostly 5-substituted functional groups. Therefore, the method for synthesizing 5-hydroxymethyloxazolidinone proposed in the present invention obtains the target compound with a modifiable side chain in one step through the cycloaddition reaction of simply prepared epoxyamine and CO2, which is suitable for post-modification reactions for various different purposes.

[0003] The one-step preparation of 5-hydroxymethyloxazolidinone by the catalytic reaction of epoxylamine with CO2 using an organic molecule is an efficient and atom-economic reaction, and is also an effective means of chemically fixing CO2 into high-value-added products. Considering from the aspects of economic benefits and environmental protection, it has great industrial application prospects. At present, the cycloaddition reaction of epoxylamine with CO2 has not been fully developed, and only two forms of metal catalysis and organic catalysis are mainly used in the existing research work. Metal catalysis mostly uses metal complexes or metal inorganic salts as catalysts (Org. Lett., 2018, 20, 5036; Angew. Chem., Int. Ed., 2016, 55, 3972; Chem. Commun., 2021, 57, 6672–6675). Metal catalysts are highly efficient and highly active, but the introduction of metal residues is generally considered to limit the high-end applications of products in the field of pharmaceutical research and development. At the same time, the disadvantages of metal catalysts, such as complex structure, long preparation route, and high price, are also very obvious. There are few reports on the use of organic catalysis. Currently, the only known case is the use of triethylamine as a catalyst (CN113461629A).

[0004] Based on the above research and conclusions, we propose a neutral organic ion pair catalyst, tris(dialkylamino)cyclopropenium ion halide (TDAC·X), to achieve the efficient conversion of epoxylamine and CO2 into 5-hydroxymethyloxazolidinone under mild conditions. Different from the catalytic mechanism of the above-mentioned organic base triethylamine, the halogen anion of TDAC·X acts as a hydrogen bond acceptor (HBA) to coordinate with the amino group by hydrogen bonding, enhancing the nucleophilicity of the nitrogen atom by attracting the hydrogen nucleus. At the same time, the cyclopropenium cation part acts as a hydrogen bond donor (HBD) to form a hydrogen bond with the oxygen atom of the epoxy group, activating the epoxy group and making it more easily subjected to nucleophilic ring opening. During the intramolecular cyclization process, by double-activating the nucleophilic site (N–H) and the electrophilic site (C–O–C) of the substrate, the target compound is obtained with high selectivity and high efficiency. We believe that this catalyst provides a bifunctional hydrogen bond of hydrogen bond donor / hydrogen bond acceptor, promoting the intramolecular cyclization of epoxylamine to obtain the target compound. Summary of the Invention

[0005] The object of the present invention is to provide a method for synthesizing 5-hydroxymethyloxazolidinone. By using a newly designed catalyst, the intramolecular cycloaddition reaction of epoxylamine with CO2 is catalyzed to efficiently prepare 5-hydroxymethyloxazolidinone. The catalytic reaction conditions are mild, the substrate scope is wide, the product has no metal residue, and it has great commercial application potential in the biomedical field.

[0006] The present invention first proposes to use a bifunctional organic catalyst of a hydrogen bond donor / hydrogen bond acceptor to generate 5-hydroxymethyloxazolidinone from epoxyamine and CO2. The target catalyst is directly obtained by reacting commercially available pentachlorocyclopropane with common secondary amines. The steps are simple, the treatment is convenient, and the yield is high. The crude product can be directly used for catalysis after filtration and drying, without other post-treatment.

[0007] In order to expand the application of oxazolidinone in the fields of pharmaceutical research and development, etc., the present invention discovers and solves problems from actual needs, and uses different cyclopropenium ions containing different types of hydrogen bond donors to catalytically synthesize a variety of N-substituted 5-hydroxymethyloxazolidinones. This organic ion pair catalytic system is first applied to the cycloaddition of epoxyamine and CO2 to prepare oxazolidinone. The overall reaction has the characteristics of mild conditions, high yield, and no metal residue.

[0008] The technical solution to achieve the above object is as follows:

[0009] A method for synthesizing oxazolidinone is carried out under the catalysis of a catalyst shown in Formula I, and 5-hydroxymethyloxazolidinone is generated from the epoxyamine shown in Formula II and carbon dioxide:

[0010]

[0011] Wherein

[0012] X is selected from Cl, Br or I;

[0013] Wherein R 1 –R 6 is selected from hydrogen, phenyl, methyl, ethyl, butyl, piperidyl, diethanolamine group, cyclohexyl.

[0014] When the substituent is piperidyl, then R–R on the same N atom is the same piperidyl, that is, R 1 and R 2 are the same piperidyl, R 3 and R 4 、R 5 and R 6 are the same; when R 1 –R 6 is selected from methyl, ethyl, butyl, R 1 and R 2 are the same, R 3 and R 4 are the same, R 5 and R 6 are the same; when R 1 、R 3 and R 5 are selected from hydrogen, R 2 、R 4 、R 6 are phenyl; when R 1 and R2 When it is diethanolamino, R 3 –R 6 is cyclohexyl.

[0015] Preferably, R 1 –R 6 is selected from methyl, ethyl, butyl, R 1 and R 2 are the same, R 3 and R 4 are the same, R 5 and R 6 are the same. More preferably, R 1 –R 6 is selected from ethyl.

[0016] The epoxyamine described above is selected from the structure of Formula II:

[0017]

[0018] wherein R 7 –R 11 is selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, isopropyl. When R 7 –R 11 one of the substituents is selected from fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, the other substituents are selected from hydrogen; when R 8 and R 10 are both selected from chlorine at the same time, the other substituents are selected from hydrogen; when R 7 and R 11 are both isopropyl at the same time, the other substituents are selected from hydrogen; when R 7 , R 9 and R 11 are selected from methyl, the other substituents are selected from hydrogen.

[0019] Preferably, R 7 –R 11 is selected from hydrogen, fluorine, chlorine, bromine, methyl. When R 7 –R 11 one of them is selected from fluorine, chlorine, bromine, methyl, the other substituents are selected from hydrogen; when R 8 and R 10 are both selected from chlorine at the same time, the other substituents are selected from hydrogen. More preferably, R 7 –R 11 is selected from hydrogen.

[0020] The synthesis method of Formula II is improved with reference to the method of Reference (Synlett, 2011(2011)1831–1834). Using aniline without substituents as the template substrate, the synthesis route is shown in the following reaction formula. In the first step of the original method, zinc perchlorate hexahydrate is added as a catalyst and chloroform is used as a solvent; in the second step, potassium fluoride supported on diatomaceous earth is added as a catalyst to synthesize the target epoxyamine of Formula II.

[0021]

[0022] The specific improvement is shown in the following reaction formula. Using a method without additives, in the first step, isopropanol is used as the solvent, and after the reaction is completed, the intermediate product is obtained by column chromatography. In the second step, an excess of potassium hydroxide is added, stirred vigorously, and after filtration and drying, the epoxyamine of formula II can be directly obtained.

[0023]

[0024] Aniline with different substituents and epichlorohydrin are added to a reaction flask containing an appropriate amount of isopropanol in a ratio of 1:1.1 and stirred at room temperature for 24 hours. Then, the first-step product is obtained by column chromatography (n-hexane:ethyl acetate = 4:1). After adding an excess of potassium hydroxide and stirring vigorously for 12 hours, the pure epoxyamine of formula II can be obtained by filtration and drying.

[0025] Preferably, the catalyst shown in formula I is selected from the following structures:

[0026]

[0027] Particularly preferably, the catalyst shown in formula I is selected from tris(diethylamino)cyclopropenium ion hydrochloride.

[0028] Preferably, the epoxyamine shown in formula II is selected from phenyl epoxyamine, p-tolyl epoxyamine, o-tolyl epoxyamine, m-tolyl epoxyamine, p-chlorophenyl epoxyamine, p-bromophenyl epoxyamine, o-chlorophenyl epoxyamine, m-chlorophenyl epoxyamine, p-trifluoromethylphenyl epoxyamine, p-methoxyphenyl epoxyamine, 2,6-diisopropylphenyl epoxyamine, 2,4,6-trimethylphenyl epoxyamine, etc.

[0029] The structure of the epoxyamine is shown in the following table:

[0030]

[0031] Preferably, the reaction temperature of the preparation method is 25 to 60 °C, the reaction time is 1 to 4 hours, and the ratio of the catalyst to the epoxyamine is 1:100 to 1:10.

[0032]

[0033] Preferably, the reaction temperature is 60 °C, the reaction time is 1 hour, and the ratio of the catalyst to the epoxyamine is 1:100.

[0034] The specific method for synthesizing 5-hydroxymethyloxazolidinone is as follows: Under the protection of an inert gas or nitrogen, the catalyst shown in Formula I and the epoxyamine shown in Formula II are added to a reactor in a ratio of 1:10 - 1:100. An organic solvent is added, and 1 atm of CO2 is introduced. The reactor is placed at (25°C - 60°C) and reacted for 1 - 4 hours. The reaction solution is cooled, subjected to column chromatography, and then dried to obtain the product.

[0035] Under the protection of an inert gas or nitrogen, the catalyst shown in Formula I and the epoxyamine shown in Formula II are added to a reactor in a ratio of 1:10 - 1:100. 0.5 mL of an organic solvent is added, and after evacuating and replacing the gas with CO2 three times under a vacuum environment, 1 standard atmosphere (i.e., 1 atm) of carbon dioxide is introduced. The reactor is placed at 60°C and reacted for 1 hour to obtain a solution containing the product.

[0036] The organic solvents used in the above synthesis method are toluene, N,N-dimethylformamide (DMF), and 1,4-dioxane.

[0037] The epoxyamine substrate shown in Formula II used is synthesized and improved according to the method reported in the literature (Synlett, 2011(2011)1831 - 1834).

[0038] Beneficial effects

[0039] Adopting the technical solution of the present invention can achieve at least one of the following beneficial effects:

[0040] (1) Through the above catalytic system, the present invention can efficiently synthesize the drug active intermediate 5-hydroxymethyloxazolidinone with modifiable side chain groups. Compared with the 5-hydroxymethyloxazolidinone synthesized by metal catalysis in the prior art, it has the characteristics of no metal residue and mild conditions. It has great potential for commercial application in fields such as biomedicine where strict requirements are imposed on metal residues.

[0041] (2) The catalytic system of the present invention catalyzes the cycloaddition of epoxyamine and carbon dioxide to synthesize 5-hydroxymethyloxazolidinone through bifunctional activation of a hydrogen bond donor / hydrogen bond acceptor. Compared with the synthesis of 5-hydroxymethyloxazolidinone under other conditions such as high temperature, high pressure, and high catalyst loading, the reaction conditions of the present invention are very mild.

[0042] (3) The catalytic system used in the present invention is easy to prepare, and the catalyst has high catalytic efficiency, short reaction time, and high conversion rate, featuring high efficiency.

[0043] In summary, compared with the existing other catalytic systems, the present invention has obvious advantages such as mildness, high efficiency, easy preparation, and metal-free. Description of the drawings

[0044] The embodiments of the present invention will be described in detail with reference to the accompanying drawings, where

[0045] Figures 1 to 2 : 1H-NMR and 13C-NMR spectra of the oxazolidinones obtained in Examples 1 to 13

[0046] Figures 3 to 14 : 1H-NMR and 13C-NMR spectra of the oxazolidinones obtained in Examples 14 to 19 respectively

[0047] Figures 15 to 28 : 1H-NMR spectra of catalysts 1 to 7 used in Examples 1 to 7

[0048] Figure 29 : 1H-NMR spectrum of the reaction mixture in Example 1 Detailed implementation manners

[0049] The present invention can be further illustrated by the following examples, which are for illustration purposes only and do not limit the present invention. Any ordinary technician in the art can understand that these examples do not limit the present invention in any way, and appropriate modifications and data transformations can be made without departing from the essence and scope of the present invention.

[0050] The 1H-NMR spectra involved in the examples were measured using a Bruker Ascend TM-400 1H-NMR spectrometer from Bruker Corporation, and the deuterated reagents used were deuterated chloroform (CDCl3) and deuterated dimethyl sulfoxide (DMSO-d6).

[0051] The raw materials used in the following examples were all purchased from Energy Chemical.

[0052] The structures of the catalytic systems used in the examples are as follows:

[0053]

[0054] The structures of the epoxyamines used in the examples are as follows:

[0055]

[0056] Example 1:

[0057] Perform standard Schlenk operation on the reaction flask to remove water and oxygen from the reaction system. Pump the reaction flask to vacuum and fill it with CO2 at 1 atm, then repeat this operation three times to ensure that the reaction flask is filled with a carbon dioxide atmosphere. Add catalyst 1 (7.2 mg, 0.025 mmol, 0.05 equiv), N,N-dimethylformamide (0.5 mL), and finally add epoxyamine A (75 mg, 0.05 mmol, 1 equiv). React the reaction flask on a heating stirrer at a stirring rate of 400 revolutions per minute and 60 °C for 1 hour. After the reaction is completed, take out the reaction tube and let it cool naturally. After separation by column chromatography (petroleum ether:ethyl acetate = 1:1), a mixed solution is obtained. It is roughly dried on a rotary evaporator and dried to a constant weight in a vacuum drying oven at 45 °C to obtain a slightly yellow oily substance with a yield of 96%. Take 0.1 mL of the reaction solution and analyze it by 1H NMR. The results are as shown in Figure 29 . Except for DMF (peak positions at 7.79 ppm, 2.75 ppm, and 2.65 ppm), only the characteristic peaks corresponding to epoxyamine A are monitored. That is, through 1H NMR analysis, the reaction selectivity is greater than 99%. The 1H NMR spectrum of the product is as shown in Figure 1 , and the 13C NMR spectrum is as shown in Figure 2 . The spectral data are: δ 7.51–7.44 (m, 2H), 7.36–7.26 (m, 2H), 7.08 (ddt, J = 8.5, 7.3, 1.1 Hz, 1H), 4.68 (dddd, J = 8.8, 7.1, 4.2, 3.3 Hz, 1H), 4.03–3.87 (m, 3H), 3.70 (ddd, J = 12.5, 6.8, 4.1 Hz, 1H), 2.21 (t, J = 6.5 Hz, 1H).

[0058] The preparation method of catalyst 1 is as follows: Add diethylamine (1.33 mL, 12.9 mmol) to dichloromethane of pentachlorocyclopropane (0.55 mL, 4.3 mmol) and stir for 6 hours, gradually forming a turbid white precipitate. After the solution is extracted with 1 M dilute hydrochloric acid solution (3 × 50 mL) and saturated brine (3 × 50 mL), anhydrous sodium sulfate is added and dried overnight. The solvent is removed to obtain the pure product. The 1H NMR spectrum of the product is as shown in Figure 15 , and the 13C NMR spectrum is as shown in Figure 16 . The spectral data are: 1 1H NMR (400 MHz, Chloroform-d) δ 3.41 (q, J = 7.2 Hz, 12H), 1.25 (t, J = 7.2 Hz, 18H).

[0059] Example 2:

[0060] Perform standard Schlenk operation on the reaction flask to remove water and oxygen from the reaction system. Pump the reaction flask to vacuum and fill it with CO2 at 1 atm, then repeat this operation three times to ensure that the reaction flask is filled with a carbon dioxide atmosphere. Add catalyst 2 (8.3 mg, 0.025 mmol, 0.05 equiv), N,N-dimethylformamide (0.5 mL), and finally add epoxyamine A (75 mg, 0.05 mmol, 1 equiv). React the reaction flask on a heating stirrer at a stirring rate of 400 revolutions per minute and 60 °C for 1 hour. After the reaction is completed, take out the reaction tube and let it cool naturally. After separation by column chromatography (petroleum ether: ethyl acetate = 1:1), a mixed solution is obtained. It is roughly dried on a rotary evaporator and dried to a constant weight in a vacuum drying oven at 45 °C to obtain a slightly yellow oil, and the yield reaches 78%.

[0061] The preparation method of catalyst 2 is as follows: Add catalyst 1 (287.89 mg, 1 mmol) under an inert gas atmosphere, add 5 mL of HBr (48 w / w% aqueous solution), react at room temperature for 24 hours, extract the reaction solution with 10 mL of dichloromethane, and then wash it with 48% HBr and water (5 mL × 3) until the pH is neutral. After drying overnight in a vacuum drying oven, a dark brown solid (78%) is obtained. The 1H NMR spectrum of the product is as attached Figure 17 as shown, and the 13C NMR spectrum is as attached Figure 18 as shown. The spectral data are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 3.45 (q, J = 7.1 Hz, 12H), 1.30 (t, J = 7.1 Hz, 18H).

[0062] Example 3:

[0063] Perform standard Schlenk operation on the reaction flask to remove water and oxygen from the reaction system. Pump the reaction flask to vacuum and fill it with CO2 at 1 atm, then repeat this operation three times to ensure that the reaction flask is filled with a carbon dioxide atmosphere. Add catalyst 3 (9.5 mg, 0.025 mmol, 0.05 equiv), N,N-dimethylformamide (0.5 mL), and finally add epoxyamine A (75 mg, 0.05 mmol, 1 equiv). React the reaction flask on a heating stirrer at a stirring rate of 400 revolutions per minute and 60 °C for 1 hour. After the reaction is completed, take out the reaction tube and let it cool naturally. After separation by column chromatography (petroleum ether: ethyl acetate = 1:1), a mixed solution is obtained. It is roughly dried on a rotary evaporator and dried to a constant weight in a vacuum drying oven at 45 °C to obtain a slightly yellow oil, and the yield reaches 62%.

[0064] The preparation method of catalyst 3 is as follows: Add the acetone solution of catalyst 1 (287.89 mg, 1 mmol, 1 eq) into a 100 mL reaction flask, then add the acetone solution of sodium iodide (0.18 g, 1.2 mmol, 1.2 eq), and stir at room temperature for 2 hours. After filtering the precipitate, add sodium iodide (0.18 g, 1.2 mmol, 1.2 eq) again, and stir at room temperature for 30 minutes. If no precipitate precipitates, the reaction ends. The solution is rotary evaporated to obtain the crude product, and then the crude product is completely dissolved in dichloromethane. After filtering the precipitate, it is dried to obtain the pure product of catalyst 3. The 1H NMR spectrum of the product is as attached Figure 19 as shown, and the 13C NMR spectrum is as attached Figure 20 as shown. The spectral data are as follows: 1 1H NMR (400 MHz, Chloroform-d) δ 3.43 (q, J = 7.2 Hz, 12H), 1.29 (t, J = 7.2 Hz, 18H).

[0065] Example 4:

[0066] Perform standard Schlenk operation on the reaction flask to remove water and oxygen from the reaction system. Evacuate the reaction flask to vacuum, fill it with CO2 at 1 atm, and then repeat this operation three times to ensure that the reaction flask is filled with a carbon dioxide atmosphere. Add catalyst 4 (8.1 mg, 0.025 mmol, 0.05 equiv), N,N-dimethylformamide (0.5 mL), and finally add epoxyamine A (75 mg, 0.05 mmol, 1 equiv). React the reaction flask on a heating stirrer at a stirring rate of 400 rpm and 60 °C for 1 hour. After the reaction ends, take out the reaction tube and let it cool naturally. After separation by column chromatography (petroleum ether: ethyl acetate = 1:1), a mixed solution is obtained. It is roughly dried on a rotary evaporator and dried to constant weight in a vacuum drying oven at 45 °C to obtain a slightly yellow oily substance, and the yield reaches 88%.

[0067] The preparation method of catalyst 4 is the same as that of catalyst 1. The 1H NMR spectrum of the product is as attached Figure 21 as shown, and the 13C NMR spectrum is as attached Figure 22 as shown. The spectral data are as follows: 1 1H NMR (400 MHz, Chloroform-d) δ 3.38 (q, J = 7.3 Hz, 12H), 1.24 (t, J = 7.2 Hz, 18H).

[0068] Example 5:

[0069] Perform standard Schlenk operation on the reaction flask to remove water and oxygen from the reaction system. Pump the reaction flask to vacuum, fill it with CO2 at 1 atm, and then repeat this operation three times to ensure that the reaction flask is filled with a carbon dioxide atmosphere. Add catalyst 5 (11.4 mg, 0.025 mmol, 0.05 equiv), N,N-dimethylformamide (0.5 mL), and finally add epoxyamine A (75 mg, 0.05 mmol, 1 equiv). React the reaction flask on a heating stirrer at a stirring rate of 400 rpm and 60 °C for 1 hour. After the reaction is completed, take out the reaction tube and let it cool naturally. After separation by column chromatography (petroleum ether:ethyl acetate = 1:1), a mixed solution is obtained. It is roughly dried on a rotary evaporator and dried to a constant weight in a vacuum drying oven at 45 °C to obtain a slightly yellow oil, with a yield of 76%.

[0070] The preparation method of catalyst 5 is as follows: the same as the preparation method of catalyst 1. The 1H NMR spectrum of the product is shown in the appendix Figure 23 as follows, and the 13C NMR spectrum is shown in the appendix Figure 24 as follows. The spectral data are as follows: 1 H NMR (400 MHz, CDCl3) δ 3.20 (m, 12H), 1.55 - 1.47 (m, 12H), 1.27 - 1.18 (m, 12H) 0.86 (t, J = 7.4 Hz, 18H).

[0071] Example 6:

[0072] Perform standard Schlenk operation on the reaction flask to remove water and oxygen from the reaction system. Pump the reaction flask to vacuum, fill it with CO2 at 1 atm, and then repeat this operation three times to ensure that the reaction flask is filled with a carbon dioxide atmosphere. Add catalyst 6 (8.7 mg, 0.025 mmol, 0.05 equiv), N,N-dimethylformamide (0.5 mL), and finally add epoxyamine A (75 mg, 0.05 mmol, 1 equiv). React the reaction flask on a heating stirrer at a stirring rate of 400 rpm and 60 °C for 1 hour. After the reaction is completed, take out the reaction tube and let it cool naturally. After separation by column chromatography (petroleum ether:ethyl acetate = 1:1), a mixed solution is obtained. It is roughly dried on a rotary evaporator and dried to a constant weight in a vacuum drying oven at 45 °C to obtain a slightly yellow oil, with a yield of 43%.

[0073] The preparation method of catalyst 6 is as follows: Perform standard Schlenk operation on the reaction flask to remove water and oxygen in the reaction system. Add freshly prepared N,N-dimethylaniline (2.1 g, 12.9 mmol) to a 100 mL reaction flask, add 50 mL of dichloromethane, and slowly dropwise add pentachlorocyclopropane (0.55 mL, 4.3 mmol) at 0 °C, and react for 6 hours. After filtration, wash with dichloromethane, and then recrystallize in methanol to obtain the pure product of catalyst 6. The 1H NMR spectrum of the product is as shown in Figure 25 the attached, and the 13C NMR spectrum is as shown in Figure 26 the attached. The spectral data are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 3H), 7.43 - 7.34 (m, 12H), 7.18 - 7.15 (m, 3H).

[0074] Example 7:

[0075] Perform standard Schlenk operation on the reaction flask to remove water and oxygen in the reaction system. Evacuate the reaction flask to vacuum, fill it with CO2 at 1 atm, and then repeat this operation three times to ensure that the reaction flask is filled with a carbon dioxide atmosphere. Add catalyst 7 (13.4 mg, 0.025 mmol, 0.05 equiv), N,N-dimethylformamide (0.5 mL), and finally add epoxyamine A (75 mg, 0.05 mmol, 1 equiv). React the reaction flask on a heating stirrer at a stirring rate of 400 revolutions per minute and 60 °C for 1 hour. After the reaction is completed, take out the reaction tube and let it cool naturally. After separation by column chromatography (petroleum ether:ethyl acetate = 1:1), a mixed solution is obtained. It is roughly dried on a rotary evaporator and dried to a constant weight in a vacuum drying oven at 45 °C to obtain a slightly yellow oily substance, and the yield reaches 80%.

[0076] The preparation method of catalyst 7 is as follows: Add 100 mL of dichloromethane to a 250 mL reaction flask, add dicyclohexylamine (11.1 mL, 56 mmol), and slowly dropwise add pentachlorocyclopropane (1 mL, 7 mmol) in an ice bath. After reacting for 24 hours, add diethanolamine (1.341 mL, 14 mmol) and continue to react for 24 hours. After the reaction is completed, filter the solid, wash with dichloromethane, and collect the filtrate. Extract the filtrate with 1 M dilute hydrochloric acid (100 mL × 3) and saturated brine (100 mL × 3), collect the organic phase, add anhydrous sodium sulfate and dry overnight. Rotate and evaporate to remove the solution, add ethyl acetate and stir at 60 °C for 30 minutes, and filter to obtain the pure product of catalyst 7. The 1H NMR spectrum of the product is as shown in Figure 27 the attached, and the 13C NMR spectrum is as shown in Figure 28 the attached. The spectral data are as follows: 11H NMR (400 MHz, Chloroform-d) δ 3.88 (t, J = 4.6 Hz, 4H), 3.65 (t, J = 4.8 Hz, 4H), 3.51 (tt, J = 12.4, 3.5 Hz, 4H), 1.91–1.81 (m, 16H), 1.71–1.63 (m, 4H), 1.57 (dt, J = 12.6, 6.1 Hz, 8H), 1.32 (dt, J = 16.5, 13.0 Hz, 8H), 1.12 (ddt, J = 16.6, 13.2, 6.6 Hz, 4H).

[0077] Example 8:

[0078] Perform standard Schlenk operation on the reaction flask to remove water and oxygen from the reaction system. Pump the reaction flask to vacuum, fill it with CO2 at 1 atm, and then repeat this operation three times to ensure that the reaction flask is filled with a carbon dioxide atmosphere. Add catalyst 1 (7.2 mg, 0.025 mmol, 0.05 equiv), N,N-dimethylformamide (0.5 mL), and finally add epoxyamine A (75 mg, 0.05 mmol, 1 equiv). React the reaction flask on a heating stirrer at a stirring rate of 400 revolutions per minute and 25 °C for 1 hour. After the reaction is completed, take out the reaction tube and let it cool naturally. After separation by column chromatography (petroleum ether:ethyl acetate = 1:1), a mixed solution is obtained. It is roughly dried on a rotary evaporator and dried to a constant weight in a vacuum drying oven at 45 °C to obtain a slightly yellow oil, and the yield reaches 45%.

[0079] Example 9:

[0080] Perform standard Schlenk operation on the reaction flask to remove water and oxygen from the reaction system. Pump the reaction flask to vacuum, fill it with CO2 at 1 atm, and then repeat this operation three times to ensure that the reaction flask is filled with a carbon dioxide atmosphere. Add catalyst 1 (7.2 mg, 0.025 mmol, 0.05 equiv), N,N-dimethylformamide (0.5 mL), and finally add epoxyamine A (75 mg, 0.05 mmol, 1 equiv). React the reaction flask on a heating stirrer at a stirring rate of 400 revolutions per minute and 60 °C for 4 hours. After the reaction is completed, take out the reaction tube and let it cool naturally. After separation by column chromatography (petroleum ether:ethyl acetate = 1:1), a mixed solution is obtained. It is roughly dried on a rotary evaporator and dried to a constant weight in a vacuum drying oven at 45 °C to obtain a slightly yellow oil, and the yield reaches 99%.

[0081] Example 10:

[0082] Perform standard Schlenk operation on the reaction flask to remove water and oxygen from the reaction system. Pump the reaction flask to vacuum and fill it with CO2 at 1 atm, then repeat this operation three times to ensure that the reaction flask is filled with a carbon dioxide atmosphere. Add catalyst 1 (7.2 mg, 0.025 mmol, 0.05 equiv), toluene (0.5 mL), and finally add epoxyamine A (75 mg, 0.05 mmol, 1 equiv). React the reaction flask on a heating stirrer at a stirring rate of 400 rpm and 60 °C for 1 hour. After the reaction is completed, take out the reaction tube and let it cool naturally. After separation by column chromatography (petroleum ether: ethyl acetate = 1:1), a mixed solution is obtained. It is roughly dried on a rotary evaporator and dried to a constant weight in a vacuum drying oven at 45 °C to obtain a slightly yellow oil, and the yield reaches 77%.

[0083] Example 11:

[0084] Perform standard Schlenk operation on the reaction flask to remove water and oxygen from the reaction system. Pump the reaction flask to vacuum and fill it with CO2 at 1 atm, then repeat this operation three times to ensure that the reaction flask is filled with a carbon dioxide atmosphere. Add catalyst 1 (7.2 mg, 0.025 mmol, 0.05 equiv), 1,4-dioxane (0.5 mL), and finally add epoxyamine A (75 mg, 0.05 mmol, 1 equiv). React the reaction flask on a heating stirrer at a stirring rate of 400 rpm and 60 °C for 1 hour. After the reaction is completed, take out the reaction tube and let it cool naturally. After separation by column chromatography (petroleum ether: ethyl acetate = 1:1), a mixed solution is obtained. It is roughly dried on a rotary evaporator and dried to a constant weight in a vacuum drying oven at 45 °C to obtain a slightly yellow oil, and the yield reaches 50%.

[0085] Example 12:

[0086] Perform standard Schlenk operation on the reaction flask to remove water and oxygen from the reaction system. Pump the reaction flask to vacuum and fill it with CO2 at 1 atm, then repeat this operation three times to ensure that the reaction flask is filled with a carbon dioxide atmosphere. Add catalyst 1 (1.44 mg, 0.005 mmol, 0.01 equiv), N,N-dimethylformamide (0.5 mL), and finally add epoxyamine A (75 mg, 0.05 mmol, 1 equiv). React the reaction flask on a heating stirrer at a stirring rate of 400 rpm and 60 °C for 1 hour. After the reaction is completed, take out the reaction tube and let it cool naturally. After separation by column chromatography (petroleum ether: ethyl acetate = 1:1), a mixed solution is obtained. It is roughly dried on a rotary evaporator and dried to a constant weight in a vacuum drying oven at 45 °C to obtain a slightly yellow oil, and the yield reaches 46%.

[0087] Example 13:

[0088] Perform standard Schlenk operation on the reaction flask to remove water and oxygen from the reaction system. Pump the reaction flask to vacuum, fill it with CO2 at 1 atm, and then repeat this operation three times to ensure that the reaction flask is filled with a carbon dioxide atmosphere. Add catalyst 1 (14.4 mg, 0.05 mmol, 0.1 equiv), N,N-dimethylformamide (0.5 mL), and finally add epoxyamine A (75 mg, 0.05 mmol, 1 equiv). React the reaction flask on a heating stirrer at a stirring rate of 400 rpm and 60 °C for 1 hour. After the reaction is completed, take out the reaction tube and let it cool naturally. After separation by column chromatography (petroleum ether:ethyl acetate = 1:1), a mixed solution is obtained. It is roughly dried on a rotary evaporator and dried to a constant weight at 45 °C in a vacuum drying oven to obtain a slightly yellow oil, with a yield of 97%.

[0089] Example 14:

[0090] Perform standard Schlenk operation on the reaction flask to remove water and oxygen from the reaction system. Pump the reaction flask to vacuum, fill it with CO2 at 1 atm, and then repeat this operation three times to ensure that the reaction flask is filled with a carbon dioxide atmosphere. Add catalyst 1 (7.2 mg, 0.05 mmol, 0.1 equiv), N,N-dimethylformamide (0.5 mL), and finally add epoxyamine B (82 mg, 0.05 mmol, 1 equiv). React the reaction flask on a heating stirrer at a stirring rate of 400 rpm and 60 °C for 1 hour. After the reaction is completed, take out the reaction tube and let it cool naturally. After separation by column chromatography (petroleum ether:ethyl acetate = 1:1), a mixed solution is obtained. It is roughly dried on a rotary evaporator and dried to a constant weight at 45 °C in a vacuum drying oven to obtain a slightly yellow oil, with a yield of 95%. The 1H NMR spectrum of the product is as Figure 2 shown (1H NMR, 400 MHz, CDCl3). The 1H NMR spectrum of the product is as attached Figure 3 shown, and the 13C NMR spectrum is as attached Figure 4 shown. The spectral data are: δ 7.24–7.15 (m, 4H), 4.71 (ddt, J = 9.6, 6.7, 3.4 Hz, 1H), 3.95–3.78 (m, 3H), 3.66 (d, J = 12.4 Hz, 1H), 2.55 (s, 1H), 2.24 (s, 3H).

[0091] Example 15:

[0092] Perform standard Schlenk operation on the reaction flask to remove water and oxygen from the reaction system. Pump the reaction flask to vacuum and fill it with CO2 at 1 atm, then repeat this operation three times to ensure that the reaction flask is filled with a carbon dioxide atmosphere. Add catalyst 1 (7.2 mg, 0.05 mmol, 0.1 equiv), N,N-dimethylformamide (0.5 mL), and finally add epoxyamine C (82 mg, 0.05 mmol, 1 equiv). React the reaction flask on a heating stirrer at a stirring rate of 400 rpm and 60 °C for 1 hour. After the reaction is completed, take out the reaction tube and let it cool naturally. After separation by column chromatography (petroleum ether:ethyl acetate = 1:1), a mixed solution is obtained. It is roughly dried on a rotary evaporator and dried to a constant weight in a vacuum drying oven at 45 °C to obtain a slightly yellow oil, and the yield reaches 86%. The 1H NMR spectrum of the product is as shown in Figure 3 shown (1H NMR, 400 MHz, CDCl3). The 1H NMR spectrum of the product is as attached Figure 5 shown, and the 13C NMR spectrum is as attached Figure 6 shown. The spectral data are: δ 7.39–7.29 (m, 2H), 7.11 (d, J = 8.2 Hz, 2H), 4.67 (ddt, J = 9.0, 7.2, 3.7 Hz, 1H), 4.01–3.85 (m, 3H), 3.70 (dd, J = 12.5, 4.3 Hz, 1H), 2.26 (s, 3H), 1.57 (s, 1H).

[0093] Example 16:

[0094] Perform standard Schlenk operation on the reaction flask to remove water and oxygen from the reaction system. Pump the reaction flask to vacuum and fill it with CO2 at 1 atm, then repeat this operation three times to ensure that the reaction flask is filled with a carbon dioxide atmosphere. Add catalyst 1 (7.2 mg, 0.05 mmol, 0.1 equiv), N,N-dimethylformamide (0.5 mL), and finally add epoxyamine D (92 mg, 0.05 mmol, 1 equiv). React the reaction flask on a heating stirrer at a stirring rate of 400 rpm and 60 °C for 1 hour. After the reaction is completed, take out the reaction tube and let it cool naturally. After separation by column chromatography (petroleum ether:ethyl acetate = 1:1), a mixed solution is obtained. It is roughly dried on a rotary evaporator and dried to a constant weight in a vacuum drying oven at 45 °C to obtain a slightly yellow oil, and the yield reaches 92%. The 1H NMR spectrum of the product is as shown in Figure 4 shown (1H NMR, 400 MHz, CDCl3). The 1H NMR spectrum of the product is as attached Figure 7 shown, and the 13C NMR spectrum is as attached Figure 8As shown. The spectral data are as follows: δ 7.18–7.08 (m, 2H), 6.63–6.52 (m, 2H), 3.93–3.88 (s, 1H), 3.57–3.48 (m, 1H), 3.23–3.13 (m, 2H), 2.82 (dd, J = 5.6, 3.1 Hz, 1H), 2.67 (dd, J = 4.8, 2.3 Hz, 1H).

[0095] Example 17:

[0096] Perform standard Schlenk operation on the reaction flask to remove water and oxygen from the reaction system. Evacuate the reaction flask to vacuum and fill it with CO2 at 1 atm, then repeat this operation three times to ensure that the reaction flask is filled with a carbon dioxide atmosphere. Add catalyst 1 (7.2 mg, 0.05 mmol, 0.1 equiv), N,N-dimethylformamide (0.5 mL), and finally add epoxyamine E (92 mg, 0.05 mmol, 1 equiv). React the reaction flask on a heating stirrer at a stirring rate of 400 rpm and 60 °C for 1 hour. After the reaction is completed, take out the reaction tube and let it cool naturally. After separation by column chromatography (petroleum ether:ethyl acetate = 1:1), a mixed solution is obtained. It is roughly dried on a rotary evaporator and dried to a constant weight in a vacuum drying oven at 45 °C to obtain a slightly yellow oil, and the yield reaches 89%. The 1H NMR spectrum of the product is as Figure 5 shown (1H NMR, 400 MHz, CDCl3). The 1H NMR spectrum of the product is as attached Figure 9 shown, and the 13C NMR spectrum is as attached Figure 10 shown. The spectral data are as follows: δ 7.53–7.45 (m, 2H), 7.37–7.29 (m, 2H), 4.75 (ddt, J = 8.8, 7.0, 3.5 Hz, 1H), 4.06–3.94 (m, 3H), 3.76 (dd, J = 12.7, 3.9 Hz, 1H), 2.09 (s, 1H).

[0097] Example 18:

[0098] Perform standard Schlenk operation on the reaction flask to remove water and oxygen from the reaction system. Pump the reaction flask to vacuum and fill it with CO2 at 1 atm, then repeat this operation three times to ensure that the reaction flask is filled with a carbon dioxide atmosphere. Add catalyst 1 (7.2 mg, 0.05 mmol, 0.1 equiv), N,N-dimethylformamide (0.5 mL), and finally add epoxyamine F (114 mg, 0.05 mmol, 1 equiv). React the reaction flask on a heating stirrer at a stirring rate of 400 revolutions per minute and 60 °C for 1 hour. After the reaction is completed, take out the reaction tube and let it cool naturally. After separation by column chromatography (petroleum ether:ethyl acetate = 1:1), a mixed solution is obtained. It is roughly dried on a rotary evaporator and dried to a constant weight in a vacuum drying oven at 45 °C to obtain a slightly yellow oil, and the yield reaches 86%. The 1H NMR spectrum of the product is as shown in Figure 6 shown (1H NMR, 400 MHz, CDCl3). The 1H NMR spectrum of the product is as attached Figure 11 shown, and the 13C NMR spectrum is as attached Figure 12 shown. The spectral data are: δ 7.23–7.09 (m, 2H), 6.54–6.37 (m, 2H), 3.84 (s, 1H), 3.51–3.41 (m, 1H), 3.22–3.07 (m, 2H), 2.75 (t, J = 4.3 Hz, 1H), 2.61 (dd, J = 4.8, 2.3 Hz, 1H).

[0099] Example 19:

[0100] Perform standard Schlenk operation on the reaction flask to remove water and oxygen from the reaction system. Pump the reaction flask to vacuum and fill it with CO2 at 1 atm, then repeat this operation three times to ensure that the reaction flask is filled with a carbon dioxide atmosphere. Add catalyst 1 (7.2 mg, 0.05 mmol, 0.1 equiv), N,N-dimethylformamide (0.5 mL), and finally add epoxyamine G (108 mg, 0.05 mmol, 1 equiv). React the reaction flask on a heating stirrer at a stirring rate of 400 revolutions per minute and 60 °C for 1 hour. After the reaction is completed, take out the reaction tube and let it cool naturally. After separation by column chromatography (petroleum ether:ethyl acetate = 1:1), a mixed solution is obtained. It is roughly dried on a rotary evaporator and dried to a constant weight in a vacuum drying oven at 45 °C to obtain a brown oil, and the yield reaches 92%. The 1H NMR spectrum of the product is as attached Figure 13 shown, and the 13C NMR spectrum is as attached Figure 14 shown. The spectral data are: δ 7.50 (d, J = 1.8 Hz, 2H), 7.12 (t, J = 1.8 Hz, 1H), 4.76 (dq, J = 8.6, 3.5 Hz, 1H), 4.06–3.94 (m, 3H), 3.75 (dd, J = 12.7, 3.6 Hz, 1H).

Claims

1. A method for synthesizing 5-hydroxymethyloxazolidinone, characterized in that: in Under the protection of inert gas or nitrogen, the catalyst shown in Formulas 1-7 and the epoxyamine shown in Formula II are added to the reactor at a molar feeding ratio of 1:(10-100), 1 atm of CO2 is charged, and the reactor is placed at 25-60 °C for reaction for 1-4 hours. After the reaction solution is cooled and subjected to column chromatography, it is dried to obtain the product; ； Among them, R 7 ~R 11 is selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, isopropyl. When R 7 ~R 11 wherein one of the substituents is selected from fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, the other substituents are selected from hydrogen; when R 8 and R 10 are both selected from chlorine at the same time, the other substituents are selected from hydrogen; when R 7 and R 11 are both isopropyl at the same time, the other substituents are selected from hydrogen; when R 7 , R 9 and R 11 are selected from methyl, the other substituents are selected from hydrogen.

2. The method according to claim 1, wherein The said R 7 ~R 11 is selected from hydrogen, fluorine, chlorine, bromine, methyl. When R 7 ~R 11 one of them is selected from fluorine, chlorine, bromine, methyl, the other substituents are selected from hydrogen; when R 8 and R 10 are both selected from chlorine at the same time, the other substituents are selected from hydrogen.

3. The method according to claim 1, wherein The epoxyamine shown in Formula II is selected from the following structures: 。 4. The method according to claim 1, wherein The synthesis method of 5-hydroxymethyloxazolidinone is as follows: 。 5. The method according to any one of claims 1 to 4, characterized in that, Under the protection of inert gas or nitrogen, the reaction temperature is 25-60 °C, the reaction time is 1-4 hours, the molar feeding ratio of the catalyst and the epoxyamine shown in Formula II is 1:(10-100), and the reaction is carried out in an organic solvent medium.

6. The method according to claim 5, wherein The reaction temperature is 60 °C, the reaction time is 1 hour, the molar feeding ratio of the catalyst and the epoxyamine shown in Formula II is 1:100, and the organic solvent is selected from one of toluene, N,N-dimethylformamide, and 1,4-dioxane.

7. The method according to claim 2 or 3, characterized in that, The synthesis method of the epoxyamine shown in Formula II is as follows: 。

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