A process for the preparation of (r)-5-chloromethyl-2-oxazolidinone

Abstract

The application relates to a preparation method of (R)-5-chloromethyl-2-oxanone and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: under a protective atmosphere, S1, azidotrimethylsilane and (R)-epichlorohydrin are added into a solvent at -10 DEG C to 10 DEG C, and 1-azido-3-chloro-2-propanol is obtained through reaction; S2, triphenylphosphine and the 1-azido-3-chloro-2-propanol of S1 are added into an organic solvent at -10 DEG C to 10 DEG C, and a mixture is obtained through reaction under a carbon dioxide atmosphere; S3, the mixture of S2 is subjected to recrystallization and cold filtration, and (R)-5-chloromethyl-2-oxanone is obtained. According to the preparation method, (R)-epichlorohydrin is used as a starting material, and (R)-5-chloromethyl-2-oxanone is synthesized through ring-opening reaction and ring-closing reaction, and the purity (98%-99%) and the yield (more than 70%) are high. The route is short, the raw material is cheap and easy to obtain, the reaction is mild, no toxic reagent is used, and the ee value of the obtained product is high (98%-99%).

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of (R)-5-chloromethyl-2-oxetanone. BACKGROUND

[0002] (R)-5-chloromethyl-2-oxetanone is an important pharmaceutical intermediate in the technical field of drug synthesis, and is widely used in the synthesis of antibacterial drugs, drugs for preventing or treating thromboembolic diseases and the like.

[0003] However, only a small amount of literature reports the synthesis of (R)-5-chloromethyl-2-oxetanone. Der Pharma Chemica 2012, 4(1), 266-271 provides a method for synthesizing (R)-5-chloromethyl-2-oxetanone, in which (R)-epichlorohydrin is used as a raw material, is reacted with ammonium hydroxide and benzaldehyde at 40 DEG C to obtain (R)-5-chloromethyl-2-phenyloxazolidine, is refluxed under the action of HCl to obtain (R)-1-amino-3-chloro-2-propanone hydrochloride, and is finally reacted with CDI at 0 DEG C to obtain (R)-5-chloromethyl-2-oxetanone. The method obtains (R)-5-chloromethyl-2-oxetanone through three steps of reaction, the yield of the route is moderate, but the ee value is low, and it is difficult to meet the demand. The synthesis route is as follows:

[0004]

[0005] European Journal of Organic Chemistry 2001, 13, 2425-2433 provides a method for synthesizing (R)-5-chloromethyl-2-oxetanone, in which (R)-epichlorohydrin is used as a raw material, is reacted with potassium cyanate at 100 DEG C to obtain (R)-5-chloromethyl-2-phenyloxazolidine. The method obtains (R)-5-chloromethyl-2-oxetanone through one step of reaction, the route uses water as a solvent, the water-solubility of the material is high, it is difficult to separate and extract, the yield is low, and the ee value is low, and it is difficult to meet the demand. The synthesis route is as follows:

[0006]

[0007] Therefore, it is very necessary to develop a preparation process of (R)-5-chloromethyl-2-oxetanone with high ee value and high yield. SUMMARY

[0008] The application aims to provide a preparation method of (R)-5-chloromethyl-2-oxetanone, comprising the following steps, under a protective atmosphere,

[0009] S1, at -10°C to 10°C, azidotrimethylsilane (TMSN3) and (R)-epichlorohydrin are added to a solvent to obtain 1-azido-3-chloro-2-propanol by reaction;

[0010] S2, at -10°C to 10°C, triphenylphosphine and 1-azido-3-chloro-2-propanol described in S1 are added to an organic solvent, and the reaction is carried out under a carbon dioxide atmosphere to obtain a mixture;

[0011] S3, the mixture described in S2 is recrystallized and cold filtered to obtain (R)-5-chloromethyl-2-oxetanone.

[0012] In an embodiment of the present application, in S1, the molar ratio of (R)-epichlorohydrin to azidotrimethylsilane is (1:2)-(1:5).

[0013] In an embodiment of the present application, in S1, the reaction is divided into two stages, the first stage is -10°C to 10°C for 15min-60min, and the second stage is 20°C-30°C for 4h-8h.

[0014] In an embodiment of the present application, in S1, the solvent is selected from dichloromethane and / or acetic acid.

[0015] In an embodiment of the present application, in S2, the molar ratio of 1-azido-3-chloro-2-propanol to triphenylphosphine is (1:1.1)-(1:1.3).

[0016] In an embodiment of the present application, in S2, the reaction is divided into two stages, the first stage is -10°C to 10°C for 15min-60min, and the second stage is 108°C-113°C for 8h-15h under normal pressure.

[0017] In an embodiment of the present application, in S2, the organic solvent is selected from one or more of toluene, benzene and 1,2-dichlorobenzene.

[0018] In an embodiment of the present application, in S3, the recrystallization solvent is selected from one or more of tetrahydrofuran, n-hexane, diethyl ether and ethyl acetate.

[0019] In an embodiment of the present application, in S3, the cold filtering temperature is -25°C to -15°C.

[0020] In an embodiment of the present application, the protective atmosphere is a nitrogen atmosphere.

[0021] In an embodiment of the present application, the synthesis route of (R)-5-chloromethyl-2-oxetanone is as follows:

[0022]

[0023] The technical scheme of the present application has the following advantages compared with the prior art:

[0024] (1) The preparation method described in the present application uses simple and easily available reagents, is easy to operate, and has stable yield, and can efficiently synthesize (R)-5-chloromethyl-2-oxanone that meets the requirements of drug synthesis. The present application solves the problems of the prior art, such as the need for reaction under alkaline conditions, low yield, low ee value, and strong water solubility that makes it difficult to separate.

[0025] (2) The preparation method described in the present application can synthesize chiral compounds with high purity and high ee value, reducing the chiral resolution operation in chiral drug synthesis, improving the synthesis yield and purity of chiral drugs, shortening the reaction steps, and thus realizing economic affordability.

[0026] (3) The preparation method described in the present application uses (R)-epichlorohydrin as the starting material, and synthesizes (R)-5-chloromethyl-2-oxanone with high purity (98%-99%) and high yield (more than 70%) through ring-opening and ring-closing reactions. This route is shorter and the raw materials are cheap and easy to obtain. At the same time, the reaction is mild, no toxic reagents are used, the ee value of the obtained product is high (98%-99%), and it has good prospects for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0027] In order to make the content of the present application more easily understood, the present application will be further described in detail below according to specific embodiments of the present application and in conjunction with the accompanying drawings, in which:

[0028] Figure 1 The HPLC chart of the compound (R)-5-chloromethyl-2-oxanone obtained in Example 5 of the present application;

[0029] Figure 2 The HPLC chart of the compound (R)-5-chloromethyl-2-oxanone obtained in Comparative Example 1 of the present application. DETAILED DESCRIPTION

[0030] Therefore, the technical problem to be solved by the present application is to overcome the problems of low ee value and low yield of the preparation process of (R)-5-chloromethyl-2-oxanone in the prior art, and the use of highly toxic raw materials.

[0031] To solve the above technical problems, the application provides a preparation method of (R)-5-chloromethyl-2-oxanone, which comprises the following steps: taking (R)-epichlorohydrin as a starting material, and performing ring-opening reaction and ring-closing reaction, so that (R)-5-chloromethyl-2-oxanone is synthesized in high purity and high yield, the route is short, raw materials are cheap and easy to obtain, the reaction is mild, no toxic reagent is used, the ee value of the obtained product is high, and the method has good prospects for industrial production.

[0032] The application aims to provide a preparation method of (R)-5-chloromethyl-2-oxanone, comprising the following steps: under a protective atmosphere,

[0033] S1, adding azidotrimethylsilane (TMSN3) and (R)-epichlorohydrin into a solvent at-10 to 10 DEG C, and performing reaction to obtain 1-azido-3-chloro-2-propanol;

[0034] S2, adding triphenylphosphine and the 1-azido-3-chloro-2-propanol in S1 into an organic solvent, and performing reaction under a carbon dioxide atmosphere to obtain a mixture;

[0035] S3, performing recrystallization and cold filtration on the mixture in S2 to obtain (R)-5-chloromethyl-2-oxanone.

[0036] In an embodiment of the application, in S1, the molar ratio of the (R)-epichlorohydrin and the azidotrimethylsilane is (1:2)-(1:5).

[0037] In an embodiment of the application, in S1, the reaction is divided into two stages, the first stage is reaction at-10 to 10 DEG C for 15 min-60 min, and the second stage is reaction at 20-30 DEG C for 4 h-8 h. If the temperature is too low, the reaction is insufficient, and if the temperature is too high, the generation of by-products is intensified.

[0038] In an embodiment of the application, in S1, the solvent is selected from dichloromethane and / or acetic acid.

[0039] In an embodiment of the application, in S2, the molar ratio of the 1-azido-3-chloro-2-propanol and the triphenylphosphine is (1:1.1)-(1:1.3).

[0040] In an embodiment of the application, in S2, the reaction is divided into two stages, the first stage is reaction at-10 to 10 DEG C for 15 min-60 min, and the second stage is normal pressure reflux reaction at 108-113 DEG C for 8 h-15 h. The reaction temperature is increased (the reflux state is the highest temperature of the reaction system), so that the reaction is sufficient.

[0041] In one embodiment of the present application, in S2, the organic solvent is selected from one or more of toluene, benzene and 1,2-dichlorobenzene.

[0042] In one embodiment of the present application, in S3, the solvent used in the recrystallization is selected from one or more of tetrahydrofuran, n-hexane, diethyl ether and ethyl acetate.

[0043] In one embodiment of the present application, in S3, the temperature of the cold filtration is -25°C to -15°C.

[0044] In one embodiment of the present application, the protective atmosphere is a nitrogen atmosphere, since the reaction raw materials and products are prone to react with water and oxygen, etc., the entire preparation process is carried out under a protective atmosphere, so as to protect the raw materials and target product from being destroyed by any water and oxygen in the reaction system.

[0045] In one embodiment of the present application, the synthesis route of (R)-5-chloromethyl-2-oxetanone is as follows:

[0046]

[0047] The present application will be further described below in conjunction with the accompanying drawings and specific embodiments, so that those skilled in the art can better understand the present application and implement it. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. It should be understood that the specific embodiments are only used to explain the present application, but the embodiments are not limiting to the present application.

[0048] In the present application, unless otherwise specified, the technical and scientific terms used in the present application have the same meanings as those commonly understood by the person skilled in the art to which the present application belongs.

[0049] In the present application, unless otherwise specified, the term "and / or" used in the embodiments of the present application includes any and all combinations of one or more of the related listed items.

[0050] In the present application, unless otherwise specified, the experimental methods used in the embodiments of the present application are conventional methods, and the materials, reagents, etc. used are commercially available, unless otherwise specified.

[0051] In the present application, unless otherwise specified, when the terms "comprising" and / or "including" are used in the specification of the present application, it means that the features, integers, steps, operations, materials or components exist, but does not exclude the presence or addition of one or more other features, integers, steps, operations, materials, components or combinations thereof.

[0052] Example 1

[0053] The preparation method of (R)-5-chloromethyl-2-oxetanone of the present application specifically comprises the following steps:

[0054] S1, synthesis of 1-azido-3-chloro-2-propanol: under nitrogen atmosphere, add glacial acetic acid (6.19 mL, 108.10 mmol) and DCM 100 mL into a 250 mL three-necked flask, cool to 0±5°C, slowly drop TMSN3 (14.22 mL, 108.10 mmol). After the drop is completed, continue stirring for 30 min at 0±5°C, add (R)-epichlorohydrin (5.00 g, 54.05 mmol). Stir for 6 h at room temperature, monitor the reaction process by thin layer chromatography. After the reaction is completed, filter the reaction liquid with silica gel, wash with 30% ethyl acetate / n-hexane, and concentrate the filtrate under reduced pressure to obtain 1-azido-3-chloro-2-propanol 8.56 g; yield 86%;

[0055] S2, synthesis of (R)-5-chloromethyl-2-oxetanone: under nitrogen atmosphere, add triphenylphosphine (10.64 g, 40.58 mmol) and toluene 130 mL into a 250 mL three-necked flask, replace the system with carbon dioxide atmosphere, cool the reaction system to 0±5°C, slowly drop 1-azido-3-chloro-2-propanol (5.00 g, 36.89 mmol). After the drop is completed, continue stirring for 15 min at 0±5°C, increase the temperature to about 110°C to reflux the reaction for 13 h, monitor the reaction process by thin layer chromatography;

[0056] S3, after the reaction is completed, reduce the temperature to room temperature, concentrate the reaction liquid under reduced pressure, dissolve the product with 2 times volume of DCM, add 6 times volume of n-hexane to precipitate the solid, perform suction filtration, cool the filtrate to-20°C to perform cold filtration to obtain high-purity (R)-5-chloromethyl-2-oxetanone 2.68 g; yield 73%, ee value 98.20%.

[0057] Example 2

[0058] The preparation method of (R)-5-chloromethyl-2-oxetanone of the present application specifically comprises the following steps:

[0059] S1, Synthesis of 1-azido-3-chloro-2-propanol: under nitrogen atmosphere, add glacial acetic acid (9.28 mL, 162.15 mmol) and DCM 250 mL into a 500 mL three-necked flask, cool to 0±3°C, slowly drop TMSN3 (21.33 mL, 162.15 mmol). After the drop is completed, continue to stir for 30 min at 0±5°C, add (R)-epichlorohydrin (5.00 g, 54.05 mmol). Stir for 4 h at room temperature, monitor the reaction process by thin layer chromatography. After the reaction is completed, filter the reaction solution with silica gel, wash with 30% ethyl acetate / n-hexane, and concentrate the filtrate under reduced pressure to obtain 1-azido-3-chloro-2-propanol 9.56 g; yield 96%;

[0060] S2, Synthesis of (R)-5-chloromethyl-2-oxetanone: under nitrogen atmosphere, add triphenylphosphine (11.61 g, 44.27 mmol) and toluene 150 mL into a 250 mL three-necked flask, replace the system with carbon dioxide atmosphere, cool the reaction system to 0±5°C, slowly drop 1-azido-3-chloro-2-propanol (5.00 g, 36.89 mmol). After the drop is completed, continue to react for 15 min at 0±5°C, increase the temperature to about 110°C, reflux the reaction for 11 h, monitor the reaction process by thin layer chromatography;

[0061] S3, After the reaction is completed, reduce the temperature to room temperature, concentrate the reaction solution under reduced pressure, dissolve the product in 2 volumes of DCM, add 6 volumes of n-hexane to precipitate the solid, perform suction filtration, and cool the filtrate to -20°C for cold filtration to obtain high-purity (R)-5-chloromethyl-2-oxetanone 2.87 g; yield 78.3%, ee value 98.28%.

[0062] Example 3

[0063] The preparation method of (R)-5-chloromethyl-2-oxetanone of the present application specifically comprises the following steps:

[0064] S1, Synthesis of 1-azido-3-chloro-2-propanol: under nitrogen atmosphere, add glacial acetic acid (12.38 mL, 216.20 mmol) and DCM 250 mL into a 500 mL three-necked flask, cool to 0±3°C, slowly drop TMSN3 (28.43 mL, 216.20 mmol). After the drop is completed, continue to stir for 30 min at 0±5°C, add (R)-epichlorohydrin (5.00 g, 54.05 mmol). Stir for 4 h at room temperature, monitor the reaction process by thin layer chromatography. After the reaction is completed, filter the reaction solution with silica gel, wash with 30% ethyl acetate / n-hexane, and concentrate the filtrate under reduced pressure to obtain 1-azido-3-chloro-2-propanol 9.50 g; yield 95.4%;

[0065] S2, Synthesis of (R)-5-chloromethyl-2-oxetanone: Under nitrogen atmosphere, a 250 mL three-necked flask was charged with triphenylphosphine (12.58 g, 47.96 mmol) and toluene 150 mL, the system was replaced with carbon dioxide atmosphere, the reaction system was cooled to 0±5°C, 1-azido-3-chloro-2-propanol (5.00 g, 36.89 mmol) was added dropwise slowly. After the dropwise addition was completed, 0±5°C was maintained to continue the reaction for 15 min, the temperature was increased to about 110°C to reflux the reaction for 11 h, the reaction process was monitored by thin layer chromatography;

[0066] S3, After the reaction was completed, the temperature was decreased to room temperature, the reaction liquid was concentrated under reduced pressure, 2 times volume of DCM was added to dissolve the product, 6 times volume of n-hexane was added to precipitate the solid, filtration was performed, the filtrate was cooled to -20°C to perform cold filtration to obtain high purity (R)-5-chloromethyl-2-oxetanone 2.67 g; yield 70%, ee value 98.44%.

[0067] Example 4

[0068] The preparation method of (R)-5-chloromethyl-2-oxetanone of the present application specifically comprises the following steps:

[0069] S1, Synthesis of 1-azido-3-chloro-2-propanol: Under nitrogen atmosphere, a 500 mL three-necked flask was charged with glacial acetic acid (15.47 mL, 270.25 mmol) and DCM 250 mL, the temperature was decreased to 0±3°C, TMSN3 (35.54 mL, 270.25 mmol) was added dropwise slowly. After the dropwise addition was completed, 0±5°C was maintained to continue stirring for 30 min, (R)-epichlorohydrin (5.00 g, 54.05 mmol) was added. The stirring was resumed at room temperature for 4 h, the reaction process was monitored by thin layer chromatography. After the reaction was completed, the reaction liquid was subjected to silica gel filtration, washed with 30% ethyl acetate / n-hexane, and the filtrate was concentrated under reduced pressure to obtain 1-azido-3-chloro-2-propanol 6.77 g; yield 68%;

[0070] S2, Synthesis of (R)-5-chloromethyl-2-oxetanone: Under nitrogen atmosphere, a 250 mL three-necked flask was charged with triphenylphosphine (12.58 g, 47.96 mmol) and toluene 150 mL, the system was replaced with carbon dioxide atmosphere, the reaction system was cooled to 0±5°C, 1-azido-3-chloro-2-propanol (5.00 g, 36.89 mmol) was added dropwise slowly. After the dropwise addition was completed, 0±5°C was maintained to continue the reaction for 15 min, the temperature was increased to about 110°C to reflux the reaction for 11 h, the reaction process was monitored by thin layer chromatography;

[0071] S3, after the reaction is completed, the temperature is lowered to room temperature, the reaction liquid is concentrated under reduced pressure, 2 volumes of DCM are added to dissolve the product, 6 volumes of n-hexane are added to precipitate the solid, and filtration is performed; the filtrate is cooled to -20°C and cold filtration is performed to obtain high-purity (R)-5-chloromethyl-2-oxetanone 2.86 g; yield 78%, ee value 98.42%.

[0072] Example 5

[0073] The preparation method of (R)-5-chloromethyl-2-oxetanone of the present application specifically comprises the following steps:

[0074] S1, synthesis of 1-azido-3-chloro-2-propanol: under a nitrogen atmosphere, 5L reaction kettle is added glacial acetic acid (171.74mL, 3mol) and DCM 1500mL, cooled to -10°C, slowly added TMSN3 (394.55mL, 3mol). After the addition is completed, -10°C is maintained for 1h, (R)-epichlorohydrin 92.52g, 1.00mol) is added. The temperature is restored to room temperature and stirred for 7h, and the reaction process is monitored by thin layer chromatography. After the reaction is completed, the reaction liquid is filtered with silica gel, washed with 30% ethyl acetate / n-hexane, and the filtrate is concentrated under reduced pressure to obtain 1-azido-3-chloro-2-propanol 178.85g; yield 98%;

[0075] S2, synthesis of (R)-5-chloromethyl-2-oxetanone: under a nitrogen atmosphere, 5L reaction kettle is added triphenylphosphine (314.75g, 1.2mol) and toluene 2L, the system is replaced with a carbon dioxide atmosphere, the reaction system is cooled to -10°C, and 1-azido-3-chloro-2-propanol (135.55g, 1mol) is slowly added. After the addition is completed, -10°C is maintained for 1h, the temperature is raised to about 110°C and refluxed for 15h, and the reaction process is monitored by thin layer chromatography;

[0076] S3, after the reaction is completed, the temperature is lowered to room temperature, the reaction liquid is concentrated under reduced pressure, 2 volumes of DCM are added to dissolve the product, 6 volumes of n-hexane are added to precipitate the solid, and filtration is performed; the filtrate is cooled to -20°C and cold filtration is performed to obtain high-purity (R)-5-chloromethyl-2-oxetanone 2.86 g; yield 78%, ee value 98.42%.

[0077] The HPLC chromatogram is shown in Figure 1 .

[0078] Comparative Example 1

[0079] Synthesis of (R)-5-chloromethyl-2-oxanone: To a 250 mL flask was added (R)-l-amino-3-chloro-2-propanone hydrochloride (10.00 g, 60 mmol) and 100 mL DCM under nitrogen atmosphere. The solution was cooled to 0 °C and carbonyldiimidazole (11.68 g, 72 mmol) was added portionwise. The reaction was stirred at room temperature for 3 h, monitored by TLC. After completion of the reaction, the reaction mixture was diluted with 20 mL DCM and washed with water (2 x 40 mL). The organic layer was dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by column chromatography (ethyl acetate / n-hexane, 30:70) to give (R)-5-chloromethyl-2-oxanone, 4.7 g; yield 50%, ee 91.4%.

[0080] HPLC chromatogram is shown in Figure 1. Figure 2

[0081] Comparative Example 2

[0082] Synthesis of (R)-5-chloromethyl-2-oxanone: To a 250 mL flask was added (R)-l-amino-3-chloro-2-propanone hydrochloride (10.00 g, 60 mmol) and 100 mL DCM under nitrogen atmosphere. The solution was cooled to 0 °C and carbonyldiimidazole (11.68 g, 72 mmol) was added portionwise. The reaction was stirred at room temperature for 3 h, monitored by TLC. After completion of the reaction, the reaction mixture was diluted with 20 mL DCM and washed with water (2 x 40 mL). The organic layer was dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by column chromatography (ethyl acetate / n-hexane, 30:70) to give (R)-5-chloromethyl-2-oxanone, 4.7 g; yield 50%, ee 91.4%.

[0083] From the results of Examples 1-5, it can be seen that the preparation method of the present application has mild reaction, does not use toxic reagents, and the obtained product has high ee value (98%-99%), and has good prospects for industrial production.

[0084] From the results of Comparative Example 1, it can be seen that the route has moderate yield and low ee value, which is difficult to meet the demand.

[0085] From the results of Comparative Example 2, it can be seen that the material has high water solubility, which is difficult to separate and extract, and has low yield and ee value, which is difficult to meet the demand.

[0086] Obviously, the above examples are merely examples for clarity and are not limitations on the embodiments. Based on the above description, other different forms of changes or variations can be made by those of ordinary skill in the art. Here, it is not necessary and impossible to exhaust all embodiments. The obvious changes or variations derived therefrom are still within the protection scope of the present application.​

Claims

1. A method for preparing (R)-5-chloromethyl-2-oxanone, characterized in that, Includes the following steps, under a protective atmosphere, S1. At -10℃ to 10℃, azidotrimethylsilane and (R)-epoxychloropropane are added to a solvent to react and obtain 1-azido-3-chloro-2-propanol; the molar ratio of (R)-epoxychloropropane to azidotrimethylsilane is (1:2) to (1:5); the reaction is divided into two stages, the first stage is a reaction at -10℃ to 10℃ for 15 min to 60 min, and the second stage is a reaction at 20℃ to 30℃ for 4 h to 8 h; the solvent is selected from dichloromethane and acetic acid; S2. At -10°C to 10°C, triphenylphosphine and the 1-azido-3-chloro-2-propanol described in S1 are added to an organic solvent, and the reaction is carried out under a carbon dioxide atmosphere to obtain a mixture. S3. The mixture described in S2 is recrystallized and cold filtered to obtain (R)-5-chloromethyl-2-oxanone.

2. The method for preparing (R)-5-chloromethyl-2-oxanone according to claim 1, characterized in that, In S2, the molar ratio of 1-azido-3-chloro-2-propanol to triphenylphosphine is (1:1.1)-(1:1.3).

3. The method for preparing (R)-5-chloromethyl-2-oxanone according to claim 1, characterized in that, In S2, the reaction is divided into two stages: the first stage is a reaction at -10℃ to 10℃ for 15 min to 60 min, and the second stage is a reflux reaction at 108℃ to 113℃ under normal pressure for 8 h to 15 h.

4. The method for preparing (R)-5-chloromethyl-2-oxanone according to claim 1, characterized in that, In S2, the organic solvent is selected from one or more of toluene, benzene, and 1,2-dichlorobenzene.

5. The method for preparing (R)-5-chloromethyl-2-oxanone according to claim 1, characterized in that, In S3, the solvent used for recrystallization is selected from one or more of tetrahydrofuran, n-hexane, diethyl ether, and ethyl acetate.

6. The method for preparing (R)-5-chloromethyl-2-oxanone according to claim 1, characterized in that, In S3, the temperature of the cold filter is -25°C to -15°C.

7. The method for preparing (R)-5-chloromethyl-2-oxanone according to claim 1, characterized in that, The protective atmosphere is a nitrogen atmosphere.

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