Preparation method of 1, 3-amino ether compound

Abstract

The invention relates to the technical field of medicinal chemistry and organic synthetic chemistry, in particular to a preparation method of a 1, 3-amino ether compound. The preparation method comprises the following steps: in an inert atmosphere, taking an azetidine derivative and a hydroxyl-containing compound as raw materials, taking aryl diazonium salt as a catalyst, and carrying out regioselective nucleophilic ring-opening reaction on the azetidine derivative and the hydroxyl-containing compound in the presence of an organic solvent, so as to obtain the 1, 3-amino ether compound. The aryl diazonium salt is used as the catalyst, so that the use of a traditional metal salt catalyst is avoided. Compared with a traditional method, the problem that metal salt residues are difficult to thoroughly remove is solved, and the dosage of the catalyst is remarkably reduced. Meanwhile, the preparation method disclosed by the invention realizes efficient and high-selectivity preparation of the 1, 3-amino ether compound.

Description

Technical Field

[0001] The present invention relates to the technical fields of medicinal chemistry and organic synthetic chemistry, and particularly relates to a preparation method of 1,3-amino ether compounds. Background Art

[0002] 1,3-Amino ether compounds are often used as intermediates in the fields of pharmaceuticals, agrochemicals, dyes and coatings, organic synthesis, and resin modifiers. In medicinal chemistry research, 1,3-amino ether compounds exist as the core skeleton in the structures of many molecules with important biological activities and medicinal values. For example, fluoxetine is one of the important derivatives of 1,3-amino ether and is a selective serotonin reuptake inhibitor type of antidepressant used to treat adult depression, obsessive-compulsive disorder, bulimia nervosa, and panic disorder with or without agoraphobia. Therefore, 1,3-amino ether compounds have good application values, and it is of great significance to find an efficient and stable synthesis method.

[0003] In recent years, the ring-opening reactions of azetidines with various carbon or heteroatom nucleophiles have attracted increasing attention from researchers. Among them, the ring-opening reaction of 2-aryl or heteroaryl azetidines activated by catalysts with alcohols or phenols provides a convenient method for the preparation of 1,3-amino ethers. However, in current synthesis technologies, most methods rely on metal salts as catalysts to promote the synthesis of such compounds, resulting in the problem that it is difficult to remove the metal salt residues. Although a few studies have attempted to use non-metal catalysts, these methods often require a large amount of catalysts. Summary of the Invention

[0004] Aiming at the deficiencies of the prior art, the present invention provides a preparation method of 1,3-amino ether compounds. The present invention uses azetidine derivatives and hydroxy-containing compounds as raw materials, and aryl diazonium salts as catalysts. In an inert atmosphere and in the presence of an organic solvent, the azetidine derivatives and the hydroxy-containing compounds undergo a regioselective nucleophilic ring-opening reaction to obtain 1,3-amino ether compounds. The present invention uses aryl diazonium salts as catalysts, avoiding the use of traditional metal salt catalysts and solving the problem that it is difficult to completely remove the metal salt residues. At the same time, the aryl diazonium salts used in the present invention have high activity when catalyzing the nucleophilic ring-opening reaction of azetidine derivatives, not only significantly reducing the amount of catalysts in the prior art, but also achieving the efficient and highly selective preparation of 1,3-amino ether compounds.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is as follows: The first object of the present invention is to provide the above-mentioned preparation method of 1,3-amino ether compounds, including the following steps: In an inert atmosphere, using an aziridine derivative and a hydroxyl-containing compound as raw materials, and an aryl diazonium salt as a catalyst, in the presence of an organic solvent, the aziridine derivative and the hydroxyl-containing compound undergo a regioselective nucleophilic ring-opening reaction. After quenching, extraction, drying, and evaporation of the solvent, a 1,3-amino ether compound is obtained.

[0006] In the prior art, the ring-opening reaction of aziridine generally occurs at the α-carbon atom of the aziridine ring, that is, at the C position adjacent to N on the aziridine ring. However, in the present invention, under the catalysis of an aryl diazonium salt, ring-opening can occur only at the C position adjacent to N on the aziridine ring and connected with a substituent, showing excellent regioselectivity.

[0007] Among them, the aziridine derivative is selected from 2-aryl-N-sulfonyl-protected aziridine or heteroaryl-N-sulfonic acid-protected aziridine.

[0008] Preferably, the hydroxyl-containing compound is selected from water, alcohols, phenols, or carboxylic acid compounds.

[0009] Preferably, the molar ratio of the aziridine derivative to the hydroxyl-containing compound is 1:1 to 3.

[0010] Preferably, the molar ratio of the aryl diazonium salt to the aziridine derivative is 1:20 to 100; among them, when the molar ratio of the aryl diazonium salt to the aziridine derivative is lower than 1:20, the reaction time will be prolonged and the yield will decrease significantly; when the molar ratio of the aryl diazonium salt to the aziridine derivative is higher than 1:20, there is no obvious change in the reaction time and yield.

[0011] Preferably, the conditions for the nucleophilic ring-opening reaction are: stirring and reacting at room temperature for 10 h to 56 h.

[0012] Preferably, the aryl diazonium salt is selected from phenyl diazonium borate, phenyl diazonium phosphate, substituted phenyl diazonium borate, or substituted phenyl diazonium phosphate.

[0013] Preferably, the substituent in the substituted phenyl is selected from p-methyl, tert-butyl, methoxy, p-trifluoromethyl, nitro, or halogen.

[0014] Preferably, the alcohol compound is selected from methanol, ethanol, isopropanol, tert-butanol, benzyl alcohol, naphthylmethyl alcohol, cycloalkanol, an alcohol containing a heteroatom or an unsaturated bond in the structure, wherein the heteroatom includes halogen, and the unsaturated bond includes a carbon-carbon double bond, a carbon-carbon triple bond, a carbon-nitrogen double bond, or a carbon-nitrogen triple bond.

[0015] Preferably, the phenol compound is selected from phenols having a single substituent or multiple substituents connected to the benzene ring, wherein the substituent includes an alkyl group, an alkoxy group, an aryloxy group, a trifluoromethyl group, an aryl group, a halogen, or a cyano group.

[0016] Preferably, the organic solvent is selected from toluene, dichloromethane, chloroform, ethyl acetate or N,N-dimethylformamide.

[0017] Preferably, the specific operation of the preparation method of the 1,3-amino ether compound is as follows: In an argon atmosphere, an azetidine derivative, a hydroxy-containing compound, an organic solvent and an aryldiazonium salt are mixed and stirred for reaction. After the azetidine derivative completely reacts, it is successively subjected to quenching, extraction, drying, solvent evaporation and purification to obtain a 1,3-amino ether compound.

[0018] Preferably, the 1,3-amino ether compound is also subjected to purification treatment, and the specific operation steps are as follows: Using a mixed solvent of ethyl acetate and petroleum ether as the eluent, the 1,3-amino ether compound is separated by column chromatography; wherein, in the mixed solvent, the volume ratio of petroleum ether to ethyl acetate is 6:1.

[0019] Preferably, extraction is carried out with ethyl acetate or dichloromethane; drying treatment is carried out with anhydrous sodium sulfate or anhydrous magnesium sulfate.

[0020] Preferably, the chromatography medium is a silica gel column with 300 to 400 mesh.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. The present invention provides a preparation method of a 1,3-amino ether compound. In an inert atmosphere, using an azetidine derivative and a hydroxy-containing compound as raw materials and an aryldiazonium salt as a catalyst, in the presence of an organic solvent, the azetidine derivative and the hydroxy-containing compound undergo a regioselective nucleophilic ring-opening reaction to obtain a 1,3-amino ether compound. The present invention uses an aryldiazonium salt as a catalyst, avoiding the use of traditional metal salt catalysts, not only solving the problem that metal salt residues are difficult to completely remove, but also significantly reducing the amount of catalyst used. At the same time, the preparation method of the present invention realizes the efficient and highly selective preparation of the 1,3-amino ether compound.

[0022] 2. The preparation method provided by the present invention has the significant advantage of simple reaction steps, clear reaction process, and no other by-products generated during the reaction, with high atom economy; at the same time, during the preparation process, the demand for the amount of catalyst used is relatively low. Compared with the situation in the prior art where the amount of catalyst used is at least 10%, the amount of catalyst used in the present invention is only 2.5% to 5%. Here, the amount refers to the molar ratio of the catalyst to the azetidine derivative, which significantly reduces the catalyst cost while ensuring the efficient progress of the reaction.

[0023] 3. The 1,3-amino ether compound of the present invention is the core skeleton of a drug with potential biological and pharmaceutical activities, and can be used to prepare antidepressant drugs, such as fluoxetine. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 It is a synthetic technical route diagram of an embodiment of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0025] Next, the technical solutions of the present invention will be clearly and completely described in conjunction with the data in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts belong to the scope of protection of the present invention.

[0026] It should be noted that the professional terms used in the present invention are only for the purpose of describing specific embodiments, and are not intended to limit the protection scope of the present invention. Unless otherwise specifically stated, various raw materials, reagents, instruments, and equipment used in the following embodiments of the present invention can be obtained through market purchase or prepared by existing methods.

[0027] In the prior art, the synthesis of 1,3-amino ether compounds mainly relies on metal salt catalysts, such as copper salts and iron salts, to promote the ring-opening reaction of azetidine with alcohols or phenols. However, when metal salts are used as catalysts, it will cause the problem that the metal salt residues are difficult to remove. Although a few studies have tried to use non-metal catalysts, these methods often require a large amount of catalyst.

[0028] In view of the problems existing in the above prior art, the present invention provides a method for preparing a 1,3-amino ether compound, which includes the following steps: in an inert atmosphere, using an azetidine derivative and a hydroxyl-containing compound as raw materials, and an aryl diazonium salt as a catalyst, in the presence of an organic solvent, the azetidine derivative and the hydroxyl-containing compound undergo a regioselective nucleophilic ring-opening reaction to obtain a 1,3-amino ether compound; wherein, the azetidine derivative is selected from 2-aryl-N-sulfonyl-protected azetidine.

[0029] The method for preparing a 1,3-amino ether compound provided by the present invention has a specific reaction equation as Figure 1 shown. In a specific embodiment, the azetidine derivative is 2-phenyl-N-p-toluenesulfonyl azetidine, and R is 4-methylphenyl; in a specific embodiment, when the hydroxyl-containing compound is phenol, R 1 is phenyl; when the hydroxyl-containing compound is p-trifluoromethylphenol, R 1 is 4-trifluoromethylphenyl; when the hydroxyl-containing compound is methanol, R 1is methyl; when the hydroxy - containing compound is propargyl alcohol, R 1 is propargyl.

[0030] Aiming at the problem that the metal salt catalyst in the prior art makes it difficult to remove the metal salt residue, the present invention uses an aryldiazonium salt as a catalyst, avoiding the use of metal salts, thus completely solving the problem of metal salt residue.

[0031] Aiming at the problems of large amount of non - metal salt catalyst used and high production cost in the prior art, the present invention optimizes the catalyst type and reaction conditions, achieving the efficient synthesis of 1,3 - amino ether compounds at an extremely low catalyst dosage, that is, 2.5% - 5%, and greatly reducing the catalyst cost.

[0032] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the following will specifically describe the technical solution of the present invention with reference to specific embodiments: Example 1 A preparation method of a 1,3 - amino ether compound, comprising the following steps: Under an argon atmosphere, 0.1 mmol of 2 - phenyl - N - tosylazetidine, 0.2 mmol of phenol, 0.005 mmol of phenyl diazonium tetrafluoroborate, and 1 mL of dry dichloromethane were successively added to a dry Schlenk tube for mixing to obtain a mixture; then the mixture was stirred at 25 °C for 15 h, and the reaction was monitored by thin - layer chromatography until the disappearance of the 2 - phenyl - N - tosylazetidine raw material, and then the reaction was stopped; after the reaction was completed, 15 mL of water and 15 mL of ethyl acetate were added to the system to dilute the reaction mixture, then extracted with 10 mL of ethyl acetate, and the extraction operation was repeated three times, dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product; the crude product was separated by column chromatography, and the eluent was ethyl acetate and petroleum ether with a volume ratio of 1:6, and the yield was 60%.

[0033] 1 H NMR (500 MHz, Chloroform - d ) δ 7.72 – 7.67 (m, 2H), 7.27 – 7.20 (m,5H), 7.19 – 7.13 (m, 3H), 7.02 (td, J = 7.7, 1.7 Hz, 1H), 6.98 (dd, J = 7.7, 1.6Hz, 1H), 6.81 (td, J = 7.5, 1.2 Hz, 1H), 6.75 (dd, J = 8.0, 1.1 Hz, 1H), 4.38(dd,J = 8.9, 6.8 Hz, 1H), 3.03 (dt, J = 12.5, 6.0 Hz, 1H), 2.79 (ddd, J = 13.5, 8.0, 5.9 Hz, 1H), 2.38 (s, 3H), 2.25 – 2.06 (m, 2H).

[0034] 13 C NMR (126 MHz, Chloroform- d ) δ 153.12, 143.45, 143.26, 136.77, 130.04, 129.74, 128.50, 128.38, 128.01, 127.51, 127.09, 126.43, 121.14, 115.89, 41.47, 39.84, 34.39, 21.52.

[0035] Its structural formula is: .

[0036] Example 2 A method for preparing a 1,3-amino ether compound, comprising the following steps: Under an argon atmosphere, 0.1 mmol of 2-phenyl-N-p-toluenesulfonylazetidine, 0.2 mmol of p-trifluoromethylphenol, 0.005 mmol of phenyl diazonium tetrafluoroborate and 1 mL of dry dichloromethane were successively added to a dry Schlenk tube for mixing to obtain a mixture; then the mixture was stirred at 25 °C for 15 h, and monitored by thin layer chromatography until the disappearance of the 2-phenyl-N-p-toluenesulfonylazetidine raw material, and then the reaction was stopped; after the reaction was completed, 15 mL of water and 15 mL of ethyl acetate were added to the system to dilute the reaction mixture, and then extracted with 10 mL of ethyl acetate, and the extraction operation was repeated three times, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product; the crude product was separated by column chromatography, and the eluent was ethyl acetate and petroleum ether with a volume ratio of 1:6, and the yield was 80%.

[0037] 1 H NMR (500 MHz, Chloroform- d ) δ 7.72 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.31 – 7.19 (m, 7H), 6.80 (d, J= 8.5 Hz, 2H), 5.24 (dd, J = 8.9, 4.2 Hz, 2H), 3.23 – 3.13 (m, 1H), 3.09 (dq, J = 12.1, 5.8 Hz, 1H), 2.37 (s, 3H), 2.13 (ddt, J = 14.5, 8.7, 5.8 Hz, 1H), 2.01 (dddd, J = 14.3, 8.1, 5.7, 4.1 Hz, 1H).

[0038] 13 C NMR (126 MHz, Chloroform- d ) δ 160.00, 143.63, 140.05, 136.47, 129.78, 128.92, 128.09, 127.11, 126.80, 126.77, 126.74, 126.71, 125.70, 125.42, 123.36, 123.26, 123.10, 122.85, 115.75, 77.52, 39.87, 38.17, 21.51.

[0039] Its structural formula is: .

[0040] Example 3 A method for preparing a 1,3-amino ether compound, comprising the following steps: Under an argon atmosphere, 0.1 mmol of 2-phenyl-N-p-toluenesulfonylazetidine, 0.2 mmol of methanol, 0.005 mmol of phenyl diazonium tetrafluoroborate, and 1 mL of dry dichloromethane were successively added to a dry Schlenk tube and mixed to obtain a mixture; then the mixture was stirred at 25 °C for 10 h, and monitored by thin-layer chromatography until the disappearance of the 2-phenyl-N-p-toluenesulfonylazetidine raw material, and then the reaction was stopped; after the reaction was completed, 15 mL of water and 15 mL of ethyl acetate were added to the system to dilute the reaction mixture, then extracted with 10 mL of ethyl acetate, and the extraction operation was repeated three times, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product; the crude product was separated by column chromatography, and the eluent was ethyl acetate and petroleum ether with a volume ratio of 1:6, and the yield was 94%.

[0041] 1 H NMR (500 MHz, Chloroform- d) δ 7.82 – 7.72 (m, 2H), 7.34 – 7.20 (m,5H), 7.17 – 7.11 (m, 2H), 5.36 (dd, J J = 6.7, 4.8 Hz, 1H), 4.19 (dd, J J = 8.1, 4.5Hz, 1H), 3.14 (s, 3H), 3.10 (ddd, J J = 13.9, 6.9, 5.0 Hz, 1H), 3.00 (ddt, J J =12.2, 7.1, 4.9 Hz, 1H), 2.43 (s, 3H), 1.88 – 1.73 (m, 2H).

[0042] 13 C NMR (126 MHz, Chloroform- d ) δ 143.29, 140.93, 137.01, 129.71,128.56, 127.85, 127.18, 126.35, 82.84, 56.69, 40.94, 37.04, 21.55.

[0043] Its structural formula is: .

[0044] Example 4 A method for preparing a 1,3 - amino ether compound, comprising the following steps: Under an argon atmosphere, 0.1 mmol of 2 - phenyl - N - p - toluenesulfonylazetidine, 0.2 mmol of propargyl alcohol, 0.005 mmol of phenyl diazonium tetrafluoroborate, and 1 mL of dry dichloromethane were successively added to a dry Schlenk tube and mixed to obtain a mixture; then the mixture was stirred at 25 °C for 15 h, and the reaction was monitored by thin - layer chromatography until the disappearance of the 2 - phenyl - N - p - toluenesulfonylazetidine raw material, and then the reaction was stopped; after the reaction was completed, 15 mL of water and 15 mL of ethyl acetate were added to the system to dilute the reaction mixture, and then it was extracted with 10 mL of ethyl acetate, and the extraction operation was repeated three times, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product; the crude product was separated by column chromatography, and the eluent was ethyl acetate and petroleum ether with a volume ratio of 1:6, and the yield was 90%.

[0045] 1 H NMR (500 MHz, Chloroform- d) δ 7.81 – 7.76 (m, 2H), 7.34 – 7.21 (m,5H), 7.18 – 7.12 (m, 2H), 5.54 (dd, J J = 7.2, 4.7 Hz, 1H), 4.35 (dd, J J = 8.6, 4.1Hz, 1H), 3.40 (dt, J J = 9.1, 6.0 Hz, 1H), 3.29 (ddd, J J = 9.2, 7.4, 6.0 Hz, 1H),3.19 (dtd, J J = 11.9, 7.3, 4.5 Hz, 1H), 3.06 (ddt, J J = 12.2, 7.1, 4.6 Hz, 1H),2.44 (s, 3H), 2.42 – 2.38 (m, 1H), 2.38 – 2.31 (m, 1H), 1.88 – 1.73 (m, 2H).

[0046] 13 C NMR (126 MHz, Chloroform- d ) δ 143.23, 141.60, 137.04, 129.68,128.49, 127.67, 127.19, 126.21, 80.98, 66.22, 41.17, 36.95, 21.56, 18.56, -1.36.

[0047] Its structural formula is: .

[0048] Example 5 A method for preparing a 1,3-amino ether compound is the same as the preparation steps in Example 1, except that the amount of phenyl diazonium tetrafluoroborate is replaced from 0.005 mmol to 0.001 mmol, and it includes the following steps: Under an argon atmosphere, 0.1 mmol of 2-phenyl-N-p-toluenesulfonylazetidine, 0.2 mmol of p-trifluoromethylphenol, 0.001 mmol of phenyl diazonium tetrafluoroborate, and 1 mL of dry dichloromethane were successively added to a dry Schlenk tube and mixed to obtain a mixture. Subsequently, the mixture was stirred at 25 °C for 56 h, and the reaction was monitored by thin-layer chromatography until the disappearance of the 2-phenyl-N-p-toluenesulfonylazetidine raw material. After the reaction was completed, 15 mL of water and 15 mL of ethyl acetate were added to the system to dilute the reaction mixture, and then it was extracted with 10 mL of ethyl acetate. After repeating the extraction operation three times, it was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated by column chromatography, and the eluent was ethyl acetate and petroleum ether with a volume ratio of 1:6, and the yield was 45%.

[0049] Example 6 A method for preparing a 1,3-amino ether compound is the same as the preparation steps in Example 1, except that the amount of phenyl diazonium tetrafluoroborate is replaced from 0.005 mmol to 0.0025 mmol, and it includes the following steps: Under an argon atmosphere, 0.1 mmol of 2-phenyl-N-p-toluenesulfonylazetidine, 0.2 mmol of p-trifluoromethylphenol, 0.0025 mmol of phenyl diazonium tetrafluoroborate, and 1 mL of dry dichloromethane were successively added to a dry Schlenk tube and mixed to obtain a mixture. Subsequently, the mixture was stirred at 25 °C for 22.5 h, and the reaction was monitored by thin-layer chromatography until the disappearance of the 2-phenyl-N-p-toluenesulfonylazetidine raw material. After the reaction was completed, 15 mL of water and 15 mL of ethyl acetate were added to the system to dilute the reaction mixture, and then it was extracted with 10 mL of ethyl acetate. After repeating the extraction operation three times, it was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated by column chromatography, and the eluent was ethyl acetate and petroleum ether with a volume ratio of 1:6, and the yield was 55%.

[0050] Taking the 1,3-amino ether compound of Example 2 of the present invention as an example, its application in the preparation of fluoxetine is as follows: S1. Under an argon-protected atmosphere and under ice-water bath conditions, add dimethylformamide and 0.10 mmol of N-[3-phenyl-3-[4-(trifluoromethyl)phenoxy]propyl]-4-methylbenzenesulfonamide to a reactor. After stirring for 5 min, add 0.30 mmol of sodium hydride in batches. After the addition is complete, restore to room temperature and stir for 0.5 h. Subsequently, add 0.15 mmol of methyl iodide under ice-water bath conditions, and then transfer the reactor to room temperature and continue the reaction for 1 h. Monitor the reaction progress by thin-layer chromatography. When it is observed that N-[3-phenyl-3-[4-(trifluoromethyl)phenoxy]propyl]-4-methylbenzenesulfonamide has completely disappeared, stop the reaction.

[0051] Under ice-water bath conditions, add 5.0 mL of deionized water to the reactor for quenching, and then perform extraction with 10 mL of ethyl acetate. This process is repeated 3 times. Combine the extracted organic phases and dry them with anhydrous sodium sulfate. Remove the solvent by vacuum distillation to obtain the crude product of Product II, denoted as N,4-dimethyl-N-(3-phenyl-3-(4-(trifluoromethyl)phenoxy)propyl)benzenesulfonamide. Finally, separate and purify the crude product by column chromatography, using a mixture of ethyl acetate and petroleum ether as the eluent, and the final yield is 94%.

[0052] 。

[0053] S2. Under argon protection, sequentially add 0.1 mmol of II and 1.0 mL of tetrahydrofuran solution to a dry reaction flask, stir at -78 °C, and then add 1.0 mL of 1.0 mol / L sodium / naphthalene tetrahydrofuran solution. After the reaction proceeds for 1 h, monitor by thin-layer chromatography and find that the raw materials have been completely consumed, then stop the reaction. Next, add 20.0 mL of ethyl acetate and 20.0 mL of water to the reactor for quenching the reaction. Extract the organic phase with 10 mL of dichloromethane, and repeat this operation 3 times. Combine the extracted organic phases and dry them with anhydrous magnesium sulfate for 0.5 h. Remove the solvent by vacuum distillation to obtain the crude product, and separate and purify the crude product by column chromatography, with a yield of 73%.

[0054] 。

[0055] It should be noted that when the present invention involves numerical ranges, it should be understood that both endpoints of each numerical range and any value between the two endpoints can be selected. Since the step methods adopted are the same as those in the embodiments, in order to prevent redundancy, the present invention describes preferred embodiments. Although the preferred embodiments of the present invention have been described, those skilled in the art can make additional changes and modifications to these embodiments once they know the basic creative concept. Therefore, the appended claims are intended to be construed as including the preferred embodiments and all changes and modifications falling within the scope of the present invention.

Claims

1. A method for preparing a 1,3-amino ether compound, characterized in that, It includes the following steps: In an inert atmosphere, using an azetidine derivative and a hydroxyl-containing compound as raw materials, and an aryl diazonium salt as a catalyst, in the presence of an organic solvent, the azetidine derivative and the hydroxyl-containing compound undergo a regioselective nucleophilic ring-opening reaction to obtain a 1,3-amino ether compound; Among them, the azetidine derivative is 2-aryl-N-sulfonyl-protected azetidine.

2. The method for preparing the 1,3-amino ether compound according to claim 1, wherein The hydroxyl-containing compound is selected from water, alcohols, phenols or carboxylic acid compounds.

3. The method for preparing the 1,3-amino ether compound according to claim 1, wherein The molar ratio of the azetidine derivative to the hydroxyl-containing compound is 1:1 to 3.

4. The method for preparing the 1,3-amino ether compound according to claim 1, wherein The molar ratio of the aryl diazonium salt to the azetidine derivative is 1:20 to 100.

5. The method for preparing the 1,3-amino ether compound according to claim 1, characterized in that, The aryl diazonium salt is selected from phenyl diazonium borate, phenyl diazonium phosphate, substituted phenyl diazonium borate or substituted phenyl diazonium phosphate.

6. The method for preparing the 1,3-amino ether compound according to claim 1, wherein The conditions for the nucleophilic ring-opening reaction are: stirring and reacting at room temperature for 10 h to 56 h.

7. The method for preparing the 1,3-amino ether compound according to claim 1, characterized in that, Purification treatment is also carried out on the 1,3-amino ether compound. The specific operation steps are: Using a mixed solvent of ethyl acetate and petroleum ether as the eluent, the 1,3-amino ether compound is separated by column chromatography.

8. The method for preparing the 1,3-amino ether compound according to claim 1, characterized in that, The specific operation of the preparation method of the 1,3-amino ether compound is: In an argon atmosphere, the azetidine derivative, the hydroxyl-containing compound, the organic solvent and the aryl diazonium salt are mixed and stirred for reaction. After the azetidine derivative completely reacts, it is successively quenched, extracted, dried, the solvent is evaporated and purified to obtain a 1,3-amino ether compound.

9. The method for preparing the 1,3-amino ether compound according to claim 8, characterized in that, The drying treatment is carried out using anhydrous sodium sulfate or anhydrous magnesium sulfate for drying.

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