Preparation method of tembotrione metabolite M9

Abstract

The present invention provides a preparation method of tembotrione metabolite M9, wherein tembotrione is used as a raw material, and an aromatization reaction is carried out under the action of a catalyst and an oxidant to prepare tembotrione metabolite M9. The synthetic route of the present invention has easy-to-obtain raw materials, a simple synthetic route, mild conditions, and can obtain tembotrione metabolites with high purity and high yield, which fully meets the sample amount requirement for tembotrione metabolites in pesticide registration.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound preparation, and relates to a method for preparing a tembotrione metabolite, and in particular to a method for preparing a tembotrione metabolite M9. Background Art

[0002] Pesticides are important agricultural inputs. The use of pesticides is directly related to the quality and safety of agricultural products and the ecological environment. The new "Pesticide Management Regulations" put forward higher requirements for pesticide management. The difficulty of technical drug registration has increased, mainly reflected in the increase in test items. The requirements for technical drug metabolites are reflected in the environmental part and the residual part. The environmental part has added tests such as soil aerobic metabolism, soil anaerobic metabolism, and water-sediment system aerobic metabolism. The residual part has added tests such as metabolism in plants, metabolism in animals, metabolism in the environment, and pesticide metabolite residues in processed agricultural products. To complete the corresponding toxicological tests of metabolites (such as acute skin toxicity tests, subchronic oral toxicity tests, mutagenicity tests, etc.), at least 2 kilograms of samples need to be prepared. It is extremely difficult to separate such a large amount of samples from plants. At present, there is no report on obtaining enough samples to meet the needs of toxicological tests through separation. There are also few methods for synthesis by chemical means, and the synthesis process is complex and the synthesis efficiency is low. At the same time, the problem of pesticide residues has always been a livelihood issue that countries around the world have focused on. Countries around the world have set limits on various pesticide residues. Exceeding the limit will affect the export trade of agricultural products, and it is inevitable to prepare high-quality metabolite standards to detect the residues. Therefore, the research on the synthesis of pesticide metabolites is urgently needed in the fields of pesticide registration, pesticide residue quality inspection and scientific research, and has great social application value.

[0003] Tembotrione, with the chemical name of 2-(2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl)cyclohexane-1,3-dione and CAS number 335104-84-2, is a triketone HPPD inhibitor herbicide developed by Bayer in 2007. It is mainly used for the control of grass and broadleaf weeds in corn fields and rice fields. It has a killing effect on a variety of weeds, and also has a high control effect on cross-spectrum weeds (such as Setaria and Rhizoma Cyperi), as well as weeds resistant to glyphosate, acetolactate synthase inhibitors, and dicamba. Tembotrione has performed very well in the market in recent years and has attracted much attention. With the expiration of compound patents, the registration of pesticides is one of the important tasks of many companies. Therefore, a large number of tembotrione metabolites need to be prepared for toxicological tests.

[0004] The European Food Safety Authority has a large number of relevant reports on tembotrione metabolites. The literature Reasoned opinion on the setting of new MRLs for tembotrione in kidney and liver of bovine and swine (EFSA Journal, 2012, 10, 10, 2932), Conclusion on the peer review of the pesticide risk assessment of the active substance tembotrione (EFSA Journal, 2013, 11, 3, 3131), Review of the existing maximum residue levels for tembotrione according to Article 12 of Regulation (EC) No 396 / 2005 (EFSA Journal, 2018, 16, 9, 5417), Tembotrion-Volume 3, Annex B.7 Residue date (February 2007) discloses the production pathways and molecular structures of various metabolites of tembotrione; Shenyang Research Institute of Chemical Industry has also conducted a large number of studies on the metabolic pathways of tembotrione in plants, animals, rats, and the environment, confirming the existence of various metabolites of tembotrione in different pathways. The chemical name of metabolite M9 is 2,6-dihydroxy-2'-chloro-3'-(2,2,2-trifluoroethoxy)methyl-4'-methanesulfonylbenzophenone. The literature Tembotrion-Volume 3, Annex B.6 Toxicology and metabolism (June 2009) reported that tembotrione metabolized in rats and animals (livestock and poultry) to produce a large amount of metabolite M9, with a radioactivity ratio of 14.47%. According to the relevant provisions of the pesticide registration information requirements (Announcement No. 2569 of the Ministry of Agriculture of the People's Republic of China), metabolites with a radioactivity ratio greater than 10% are major metabolites, and corresponding toxicology test reports are required. A large number of samples need to be prepared to complete the corresponding toxicology test, and there is no relevant report on the chemical synthesis method of metabolite M9.

[0005] Therefore, developing a synthesis process for cyclosulfuron metabolites with simple steps and high preparation efficiency is an urgent problem to be solved in the field. Summary of the invention

[0006] In view of the deficiencies of the prior art, the object of the present invention is to provide a method for preparing a tembotrione metabolite, and specifically to provide a method for preparing a tembotrione metabolite M9. The synthetic route of the present invention has readily available raw materials, a simple synthetic route, mild conditions, and can obtain a tembotrione metabolite with high purity and high yield, which fully meets the sample quantity requirement for tembotrione metabolites in pesticide registration.

[0007] To achieve this object, the present invention adopts the following technical solutions:

[0008] In one aspect, the present invention provides a method for preparing a tembotrione metabolite M9, the method comprising: using tembotrione as a raw material, carrying out an aromatization reaction under the action of a catalyst and an oxidant to prepare the tembotrione metabolite M9, the reaction formula is as follows:

[0009]

[0010] In the present invention, tembotrione original drug is used as a raw material, and an aromatization reaction occurs under the action of a catalyst and an oxidant to prepare tembotrione metabolite M9. The method has high yield, high purity of the obtained product, simple synthesis route, mild conditions, and easy process implementation, thereby realizing the large-scale preparation of tembotrione metabolites and fully meeting the sample amount requirement for tembotrione metabolites in pesticide registration.

[0011] Preferably, the catalyst is any one of iodine or NIS (N-iodosuccinimide) or a combination of the two, and more preferably iodine.

[0012] Preferably, the molar ratio of tembotrione to the catalyst is 1:(0.001-0.1), for example, it can be 1:0.002, 1:0.004, 1:0.006, 1:0.008, 1:0.01, 1:0.02, 1:0.03, 1:0.05, 1:0.07 or 1:0.09, and more preferably 1:(0.005-0.01).

[0013] In the present invention, the oxidant is a sulfoxide derivative.

[0014] Preferably, the oxidizing agent is DMSO.

[0015] Preferably, the molar ratio of tembotrione to the oxidant is 1:(1.0-30), for example, it can be 1:1.1, 1:1.2, 1:1.3, 1:5, 1:8, 1:11, 1:16, 1:21, 1:26, 1:30, etc., and more preferably 1:(1.1-2.0).

[0016] Preferably, the reaction is carried out in the presence of a solvent.

[0017] Preferably, the solvent is selected from any one or a combination of at least two of dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMAC), acetonitrile, 1,4-dioxane, dichloroethane, dichloromethane, chloroform or nitromethane, and more preferably dimethyl sulfoxide (DMSO).

[0018] In the present invention, when DMSO is selected as a solvent, DMSO functions as both a solvent and an oxidizing agent.

[0019] Preferably, based on 1 mol of the tamponic acid ketone, the amount of the solvent is 400-2500 g, for example, 500 g, 800 g, 1000 g, 1200 g, 1400 g, 1600 g, 1800 g, 2000 g, 2200 g or 2400 g, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0020] Preferably, the reaction temperature is 50-110°C, for example 60°C, 70°C, 80°C, 90°C or 100°C, as well as specific values ​​between the above-mentioned points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range, and 70-80°C is further preferred.

[0021] Preferably, the reaction time is 5 to 30 h, for example 7 h, 9 h, 11 h, 13 h, 15 h, 17 h, 19 h, 21 h, 23 h, 25 h, 27 h or 29 h, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively enumerates the specific point values ​​included in the range, and 15 to 20 h is further preferred.

[0022] Preferably, the reaction further includes post-treatment of the product after completion.

[0023] Preferably, the post-treatment includes desolventizing, dissolving in water, solvent extraction and recrystallization.

[0024] Preferably, the extraction reagent includes any one or a combination of at least two of esters, aromatic hydrocarbons or halogenated hydrocarbons, preferably but not limited to any one or a combination of at least two of ethyl acetate, ethylene dichloride and toluene.

[0025] Preferably, the recrystallization reagent comprises methanol, ethanol or an alcohol aqueous solution.

[0026] Preferably, the recrystallization temperature is -5 to 10°C, for example, it can be -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C or 9°C, etc., preferably 0 to 5°C.

[0027] According to the preparation method of the present invention, after the reaction is completed and the post-treatment step is performed, the content of the tembotrione metabolite M9 obtained is greater than 98.0%.

[0028] Preferably, the preparation method specifically comprises the following steps: reacting tampronone, a catalyst and an oxidant in a solvent at 50-110° C. for 5-30 hours to obtain a crude product, and subjecting the crude product to desolventization, water dissolution, solvent extraction and recrystallization to obtain the tampronone metabolite M9; the molar ratio of the catalyst to tampronone is (0.001-0.01):1; the molar ratio of the oxidant to the tampronone original drug is (1.0-30):1.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] In the preparation method of the main metabolite M9 of tembotrione provided by the present invention, the tembotrione original drug is used as the starting material, and the high-purity tembotrione metabolite M9 can be obtained in high yield through direct aromatization through a one-step reaction in the presence of a catalyst and an oxidant, with a purity of ≥98.0% and a yield of more than 93%. The raw materials of the preparation method are easy to obtain, the steps are simple, the operation is convenient, the experimental process is controllable, no harsh reaction environment is required, the conditions are mild, the process is easy to implement, and a large amount of preparation of tembotrione metabolites is achieved, and the sample amount requirement for tembotrione metabolites in pesticide registration can be fully met, so that the toxicological test required for the main metabolite can be completed, and the corresponding toxicological test report can be obtained, and the necessary tembotrione metabolite M9 toxicological test report is provided for the successful registration of tembotrione products. DETAILED DESCRIPTION

[0031] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0032] The quantitative content (purity) in the following examples of the present invention was measured by high performance liquid chromatography (HPLC, LC-20AT, Shimadzu, Japan) external standard method.

[0033] Example 1

[0034] This embodiment provides a method for preparing tembotrione metabolite M9, and the specific steps are as follows:

[0035] Add 44.5g tampronone (purity 99%, 0.1mol), 90g DMF, 0.78g iodine (purity 99%, 3mmol) and 15.8g DMSO (purity 99%, 0.2mol) to a three-necked flask, start stirring, heat to 80℃ and keep warm for 12h, the reaction is complete, and the reaction is stopped after the tampronone is less than 0.5%. Remove the solvent under negative pressure, add 100g dichloroethane to the kettle residue and stir to dissolve, then add 100g water to wash away the residual impurities, then layer, wash the oil phase with 20g water, and desolventize the oil phase to obtain M9 crude product; add 50g methanol (purity 99%) to the M9 crude product, heat to dissolve, then cool to 0℃ and stir to crystallize for 1h, then filter and dry to obtain 41.4g product M9, quantitative content 98.6%, yield 93.2%.

[0036] Structural testing:

[0037] Tembotrione metabolite M9: UHPLC-MS (m / z, ESI + ): 439.02282 (M+H) + ; Theoretical value: 439.02245 (positive ion).

[0038] 1 H-NMR (CDCl3, 300MHz) δ: 3.22 (s, 3H, CH3), 3.98~4.04 (q, J=6.0Hz, 2H, CH2), 5.33 (s, 2H, CH2), 6.41 (d, J=6.0Hz, 2 H, ArH), 7.32~7.36 (t, J=6Hz, 1H, ArH), 7.42 (d, J=6.0Hz, 1H, ArH), 8.07 (d, J=6.0Hz, 1H, ArH), 9.44 (s, 2H, ArOH).

[0039] Example 2

[0040] This embodiment provides a method for preparing tembotrione metabolite M9, and the specific steps are as follows:

[0041] Add 44.5g tamponic acid ketone (purity 99%, 0.1mol), 150g DMSO and 0.45g NIS (purity 99%, 2mmol) to a three-necked flask, start stirring, heat to 80℃ and keep warm for 15h, the reaction is completed, and the reaction is stopped after the tamponic acid ketone is less than 0.5%. Remove the solvent under negative pressure, add 100g ethyl acetate to the kettle residue and stir to dissolve, then add 100g water to wash away the residual impurities, and then layer, wash the oil phase with 20g water, and desolventize the oil phase to obtain M9 crude product; add 50g ethanol (purity 99%) to the M9 crude product, heat to dissolve, then cool to 0℃ and stir to crystallize for 1h, then filter and dry to obtain 41.9g product M9, quantitative content 98.4%, yield 94.1%.

[0042] The method of this example was used for scaled-up preparation, and 2224.7 g of tembotrione (purity 99%, 5.0 mol) was added for reaction, and finally 2109.8 g of tembotrione metabolite M9 was obtained, with a quantitative content of 98.3% and a yield of 94.7%.

[0043] Example 3

[0044] This embodiment provides a method for preparing tembotrione metabolite M9, and the specific steps are as follows:

[0045] Add 44.5g tampronone (purity 99%, 0.1mol), 180g acetonitrile, 0.13g iodine (purity 99%, 0.5mmol) and 11.8g DMSO (purity 99%, 0.15mol) to a three-necked flask, start stirring, heat to 70℃ and keep warm for 25h, the reaction is complete, and the reaction is stopped after the tampronone is less than 0.5%. Remove the solvent under negative pressure, add 100g toluene to the kettle residue and stir to dissolve, then add 100g water to wash away the residual impurities, then layer, wash the oil phase with 20g water, and desolventize the oil phase to obtain M9 crude product; add 60g methanol aqueous solution (90%) to the M9 crude product, heat to dissolve, then cool to 0℃ and stir to crystallize for 1h, then filter and dry to obtain 42.1g product M9, quantitative content 98.2%, yield 94.4%.

[0046] Example 4

[0047] This embodiment provides a method for preparing tembotrione metabolite M9, and the specific steps are as follows:

[0048] Add 44.5g tampronone (purity 99%, 0.1mol), 100g acetonitrile, 0.45g NIS (purity 99%, 2mmol) and 8.7g DMSO (purity 99%, 0.11mol) to a three-necked flask, start stirring, heat to 80℃ and keep warm for 24h, the reaction is complete, and the reaction is stopped after the tampronone is controlled to be less than 0.5%. Remove the solvent under negative pressure, add 100g toluene to the kettle residue and stir to dissolve, then add 100g water to wash away the residual impurities, then layer, wash the oil phase with 20g water, and desolventize the oil phase to obtain M9 crude product; add 60g methanol aqueous solution (90%) to the M9 crude product, heat to dissolve, then cool to 0℃ and stir to crystallize for 1h, then filter and dry to obtain 41.9g product M9, quantitative content 98.3%, yield 94.0%.

[0049] Example 5

[0050] This embodiment provides a method for preparing tembotrione metabolite M9, and the specific steps are as follows:

[0051] Add 44.5g tampronone (purity 99%, 0.1mol), 50g DMF, 2.6g iodine (purity 99%, 10mmol) and 7.9g DMSO (purity 99%, 0.1mol) to a three-necked flask, start stirring, heat to 70℃ and keep warm for 26h, the reaction is complete, and the reaction is stopped after the tampronone is less than 0.5%. Remove the solvent under negative pressure, add 100g dichloroethane to the kettle residue and stir to dissolve, then add 100g water to wash away the residual impurities, then layer, wash the oil phase with 20g water, and desolventize the oil phase to obtain M9 crude product; add 50g methanol aqueous solution (90%) to the M9 crude product, heat to dissolve, then cool to 0℃ and stir to crystallize for 1h, then filter and dry to obtain 40.6g product M9, quantitative content 98.6%, yield 91.4%. When the amount of oxidant DMSO is 1.0 equivalent, the yield is slightly affected.

[0052] Example 6

[0053] This embodiment provides a method for preparing tembotrione metabolite M9, and the specific steps are as follows:

[0054] Add 44.5g tampronone (purity 99%, 0.1mol), 200g 1,4-dioxane, 0.262.05g iodine (purity 99%, 8mmol) and 79g DMSO (purity 99%, 1mol) to a three-necked flask, start stirring, heat to 100℃ and keep warm for 5h, the reaction is complete, and the reaction is stopped after the tampronone is less than 0.5%. Remove the solvent under negative pressure, add 100g dichloroethane to the kettle residue and stir to dissolve, then add 100g water to wash away the residual impurities, then layer, wash the oil phase with 20g water, and desolventize the oil phase to obtain M9 crude product; add 50g methanol aqueous solution (90%) to the M9 crude product, heat to dissolve, then cool to 0℃ and stir to crystallize for 1h, then filter and dry to obtain 41.6g product M9, quantitative content 98.6%, yield 93.6%.

[0055] Example 7

[0056] This embodiment provides a method for preparing tembotrione metabolite M9, and the specific steps are as follows:

[0057] Add 44.5g tampronone (purity 99%, 0.1mol), 40g DMF, 0.026g iodine (purity 99%, 0.1mmol) and 15.8g DMSO (purity 99%, 0.2mol) to a three-necked flask, start stirring, heat to 80℃ and keep warm for 30h, the reaction is complete, and the reaction is stopped after the tampronone is less than 0.5%. Remove the solvent under negative pressure, add 100g dichloroethane to the kettle residue and stir to dissolve, then add 100g water to wash away the residual impurities, then layer, wash the oil phase with 20g water, and desolventize the oil phase to obtain M9 crude product; add 50g methanol aqueous solution (90%) to the M9 crude product, heat to dissolve, then cool to 0℃ and stir to crystallize for 1h, then filter and dry to obtain 38.5g product M9, quantitative content 98.2%, yield 86.3%.

[0058] Example 8

[0059] This embodiment provides a method for preparing tembotrione metabolite M9, and the specific steps are as follows:

[0060] 44.5g tampronone (purity 99%, 0.1mol), 250g DMF, 2.6g iodine (purity 99%, 10mmol) and 221g DMSO (purity 99%, 2.8mol) were added to a three-necked flask, stirred, heated to 80°C for 6h, and the reaction was completed. The reaction was stopped after the tampronone was controlled to be less than 0.5%. The solvent was completely removed under negative pressure, 100g dichloroethane was added to the kettle residue and stirred to dissolve, then 100g water was added to wash away the residual impurities, and then the crude M9 product was obtained by layering, washing the oil phase with 20g water, and desolventizing the oil phase; 50g methanol aqueous solution (90%) was added to the crude M9 product, heated to dissolve, and then cooled to 0°C for stirring and crystallization for 1h, then filtered and dried to obtain 42.2g product M9, with a quantitative content of 98.1% and a yield of 94.5%.

[0061] Example 9

[0062] This embodiment provides a method for preparing tembotrione metabolite M9, and the specific steps are as follows:

[0063] Add 44.5g tampronone (purity 99%, 0.1mol), 80g 1,4-dioxane, 2.05g iodine (purity 99%, 8mmol) and 11.8g DMSO (purity 99%, 0.15mol) to a three-necked flask, start stirring, heat to 50℃ and keep warm for 30h, the reaction is complete, and the reaction is stopped after the tampronone is less than 0.5%. Remove the solvent under negative pressure, add 100g dichloroethane to the kettle residue and stir to dissolve, then add 100g water to wash away the residual impurities, then layer, wash the oil phase with 20g water, and desolventize the oil phase to obtain M9 crude product; add 50g methanol aqueous solution (90%) to the M9 crude product, heat to dissolve, then cool to 0℃ and stir to crystallize for 1h, then filter and dry to obtain 40.8g product M9, quantitative content 98.1%, yield 91.4%.

[0064] The products obtained in Example 2-9 were also subjected to ultra-high performance liquid chromatography-mass spectrometry and nuclear magnetic resonance hydrogen spectrum detection to verify the correctness of the structure.

[0065] Comparative Example 1

[0066] Add 44.5 g of cyclosulfone (purity 99%, 0.1 mol), 260 g of xylene and 96.7 g of MnO2 (purity 90%, 1.0 mol) into a three-necked flask, start stirring, raise the temperature to 140°C and keep the reaction for 3 hours. After the reaction is completed, the reaction is controlled and the target product M9 is not found.

[0067] Comparative Example 2

[0068] Add 44.5 g of cyclosulfone (purity 99%, 0.1 mol), 180 g of ethylene dichloride and 54.5 g of potassium persulfate (purity 99%, 0.2 mol) into a three-necked flask, start stirring, raise the temperature to 80°C and keep the reaction for 6 hours. After the reaction is completed, the reaction is controlled and no target product M9 is found.

[0069] Comparative Example 3

[0070] Add 44.5 g of cyclosulfone (purity 99%, 0.1 mol), 360 g of acetonitrile and 96.4 g of mercuric acetate (purity 99%, 0.3 mol) into a three-necked flask, start stirring, and keep the reaction at 30°C for 12 hours. After the reaction is completed, the reaction is centrally controlled. HPLC detection of the target product M9 area normalization shows that its content is 21.4%. A large amount of impurities are produced as by-products. The yield of this scheme is extremely low.

[0071] Comparative Example 4

[0072] To a three-necked flask, 44.5 g of cyclosulfone (purity 99%, 0.1 mol), 160 g of acetonitrile and 0.045 g of palladium chloride (purity 99%, 0.25 mmol) were added, stirring was started, and the mixture was kept at 70°C for 12 h. After the reaction was completed, the reaction was centrally controlled. The target product M9 was detected by HPLC and its content was normalized to 9.3%. A large amount of impurities were produced as by-products. The yield of this solution was extremely low.

[0073] The applicant declares that the present invention illustrates the preparation method of the tembotrione metabolite M9 of the present invention through the above-mentioned embodiment, but the present invention is not limited to the above-mentioned embodiment, that is, it does not mean that the present invention must rely on the above-mentioned embodiment to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing tembotrione metabolite M9, characterized in that: The preparation method comprises: using tembotrione as a raw material, carrying out an aromatization reaction under the action of a catalyst and an oxidant to prepare tembotrione metabolite M9, and the reaction formula is as follows: The catalyst is any one of iodine or N-iodosuccinimide or a combination of the two; The oxidant is DMSO.

2. The preparation method according to claim 1, characterized in that: The catalyst is iodine.

3. The preparation method according to claim 1, characterized in that: The molar ratio of tamponic acid ketone to the catalyst is 1:(0.001-0.1).

4. The preparation method according to claim 3, characterized in that: The molar ratio of cyclosulfone to the catalyst is 1:(0.005-0.01).

5. The preparation method according to claim 1, characterized in that: The molar ratio of tamponic acid ketone to the oxidant is 1:(1.0-30).

6. The preparation method according to claim 5, characterized in that: The molar ratio of tamponic acid ketone to the oxidant is 1:(1.1-2.0).

7. The preparation method according to claim 1, characterized in that: The reaction is carried out in the presence of a solvent.

8. The preparation method according to claim 7, characterized in that: The solvent is selected from any one of dimethyl sulfoxide, dimethylformamide, dimethylacetamide, acetonitrile, 1,4-dioxane, dichloroethane, dichloromethane, chloroform or nitromethane, or a combination of at least two thereof.

9. The preparation method according to claim 8, characterized in that: The solvent is dimethyl sulfoxide.

10. The preparation method according to claim 7, characterized in that: Based on 1 mol of the tamponic acid ketone, the amount of the solvent used is 400 to 2500 g.

11. The preparation method according to claim 1, characterized in that: The reaction temperature is 50-110°C.

12. The preparation method according to claim 11, characterized in that: The reaction temperature is 70-80°C.

13. The preparation method according to claim 1, characterized in that: The reaction time is 5 to 30 hours.

14. The preparation method according to claim 1, characterized in that: After the reaction is completed, the product may be post-processed.

15. The preparation method according to claim 14, characterized in that: The post-treatment includes desolventizing, dissolving in water, solvent extraction and recrystallization.

16. The preparation method according to claim 15, characterized in that: The extraction reagent includes any one of esters, aromatic hydrocarbons or halogenated hydrocarbons, or a combination of at least two of them.

17. The preparation method according to claim 16, characterized in that: The extraction reagent includes any one of ethyl acetate, ethylene dichloride and toluene, or a combination of at least two of them.

18. The preparation method according to claim 15, characterized in that: The recrystallization reagent includes methanol, ethanol or an alcohol aqueous solution.

19. The preparation method according to claim 15, characterized in that: The recrystallization temperature is -5 to 10°C.

20. The preparation method according to claim 19, characterized in that: The recrystallization temperature is 0-5°C.

21. The preparation method according to claim 1, characterized in that: The preparation method comprises the following steps: The cyclosulfone, catalyst and oxidant are reacted in a solvent at 50-110° C. for 5-30 hours to obtain a crude product, and the crude product is subjected to desolventizing, water dissolution, solvent extraction and recrystallization to obtain the cyclosulfone metabolite M9; wherein the molar ratio of the catalyst to the cyclosulfone is (0.001-0.1):1; the molar ratio of the oxidant to the cyclosulfone original drug is (1.0-30):1.

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