Preparation method of tembotrione metabolite

Abstract

The present invention provides a method for preparing tembotrione metabolites. The method uses 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride, a key intermediate of tembotrione, as a raw material, and reacts with 1,3-cyclohexanedione compounds to prepare tembotrione metabolites M5 and M10 through three steps of condensation, transposition and hydrolysis. The method has a simple synthetic route and mild operating conditions, and can obtain high-purity tembotrione metabolites with a 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 tembotrione metabolites, in particular to a method for preparing tembotrione metabolites M5 and M10. 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 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.

[0005] The chemical name of cyclosulfone metabolite M5 is 4,6-dihydroxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione; the chemical name of cyclosulfone metabolite M10 is 4-hydroxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione. The document Reasoned opinion on the setting of new MRLs for tembotrione in kidney and liver of bovine and swine (EFSA Journal, 2012, 10, 10, 2932) reports that tembotrione is metabolized in plants, and the radioactivity intensity ratio of M5 is 12-44%, and the radioactivity intensity ratio of M10 is 27.7-30%; the document Tembotrion-Volume 3, Annex B.6 Toxicology and metabolism (June 2009) reports that tembotrione is metabolized in rats and animals (livestock and poultry) to produce a large amount of metabolite M10, and its radioactivity intensity ratio is 54-78%. According to the relevant provisions of the requirements for pesticide registration information (Announcement No. 2569 of the Ministry of Agriculture of the People's Republic of China), metabolites with a radioactivity intensity ratio greater than 10% are major metabolites, and corresponding toxicological test reports are required. A large number of samples need to be prepared to complete the corresponding toxicological tests, and there are no relevant reports on the chemical synthesis methods of metabolites M5 and M10. The document Development and establishment of a QuEChERS-based extraction method for determining tembotrione and its metabolite AE 1417268 in corn, corn oil and certain animal-origin foods by HPLC-MS / MS (Food additives & contaminants: Part A, 2020, 37, 10, 1678-1686) discloses a HPLC-MS / MS method for quantitatively determining the content of metabolite M5 in corn, corn oil, beef, pork, chicken and eggs, but does not involve chemical synthesis methods.

[0006] 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

[0007] In view of the deficiencies of the prior art, the purpose of the present invention is to provide a method for preparing tampron metabolites, in particular, to provide a method for preparing tampron metabolites M5 and M10. The present invention uses 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride, a key intermediate of tampron, as a raw material, and reacts with a 1,3-cyclohexanedione compound shown in formula I to prepare tampron metabolites M5 and M10 through three steps of condensation, transposition, and hydrolysis. The method involves a simple synthetic route, mild operating conditions, and can obtain high-purity tampron metabolites with a high yield, which fully meets the sample quantity requirements for tampron metabolites in pesticide registration.

[0008] To achieve this object, the present invention adopts the following technical solutions:

[0009] In one aspect, the present invention provides a method for preparing a tembotrione metabolite, the preparation method comprising the following steps:

[0010] Using 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride and the 1,3-cyclohexanedione compound shown in formula I as raw materials, condensation reaction, catalytic transposition reaction and hydrolysis reaction are carried out to obtain the cyclosulfone metabolite shown in formula IV. The reaction process is as follows:

[0011]

[0012] Where R 1 It is H, C 1 -C 4 Alkoxy, benzyloxy, acetoxy, benzoyloxy or alkylsilyloxy, R 2 It is H, C 1 -C 4 alkoxy, benzyloxy, acetoxy, benzoyloxy or alkylsilyloxy; and R 1 and R 2 H, R 3 and R 4 Same as hydroxyl or R 3 and R 4 One of them is hydroxyl and the other is H.

[0013] In the present invention, the key intermediate of tembotrione, 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride, is used as a raw material to react with a compound of formula I, and a tembotrione metabolite is prepared through three steps of condensation, transposition and hydrolysis. The synthetic route is simple, the operating conditions are mild, and a high-purity tembotrione metabolite can be obtained with a high yield.

[0014] Specifically, the method for preparing tembotrione metabolites provided by the present invention comprises the following steps:

[0015] (1) In the presence of an acid binding agent, 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride and the 1,3-cyclohexanedione compound represented by formula I are subjected to a condensation reaction to prepare a compound represented by formula II. The reaction formula is as follows:

[0016]

[0017] (2) The compound of formula II undergoes a transposition reaction under the action of a transposition catalyst to generate a compound of formula III. The reaction formula is as follows:

[0018]

[0019] (3) The compound of formula III undergoes a hydrolysis reaction under the action of a catalyst to generate a tembotrione metabolite represented by formula IV. The reaction formula is as follows:

[0020]

[0021] Where R 1 It is H, C 1 -C 4 Alkoxy, benzyloxy, acetoxy, benzoyloxy or alkylsilyloxy, R 2 It is H, C 1 -C 4 alkoxy, benzyloxy, acetoxy, benzoyloxy or alkylsilyloxy; and R 1 and R 2 H, R 3 and R 4 Same as hydroxyl or R 3 and R 4 One of them is hydroxyl and the other is H.

[0022] In the present invention, when R 1 and R 2 Independently selected from C 1 -C 4 When R is alkoxy, benzyloxy, acetoxy, benzoyloxy or alkylsilyloxy, the tembotrione metabolite of formula IV is M5; when R 1 and R 2 One of them is H and the other is C 1 -C 4 When the cyclohexane is alkoxy, benzyloxy, acetoxy, benzoyloxy or alkylsilyloxy, the cyclohexane metabolite of formula IV is M10.

[0023] Preferably, the alkylsilyl group is dimethyl tert-butylsilyl (OTBS) or triethylsilyl (OTES).

[0024] Preferably, the molar ratio of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride in step (1) to the 1,3-cyclohexanedione compound represented by formula I is 1:(1.0-1.5), for example, it can be 1:1.05, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.45, etc., and more preferably 1:1.05.

[0025] Preferably, the acid binding agent in step (1) is any one of triethylamine, pyridine or diisopropylethylamine or a combination of at least two thereof, more preferably triethylamine.

[0026] Preferably, the molar ratio of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride to the acid binding agent in step (1) is 1:(1.05-1.5), for example, it can be 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, and more preferably 1:1.1.

[0027] Preferably, the solvent for the condensation reaction in step (1) is selected from any one or a combination of at least two of dichloroethane, dichloromethane, chloroform, benzene, toluene and xylene, and dichloroethane is more preferably used.

[0028] Preferably, based on 1 mol of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride in step (1), the amount of the solvent is 900 to 2400 g, for example, 1200 g, 1500 g, 1800 g or 2100 g, as well as specific values ​​between the above 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.

[0029] Preferably, the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride in step (1) is added to the reaction system in a dropwise manner, which is beneficial to reaction control and avoids agglomeration.

[0030] Preferably, the dropping temperature of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is -15 to 60°C, for example, -5°C, 0°C, 15°C, 30°C, 45°C or 50°C, and 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 is further preferably 0 to 10°C.

[0031] Preferably, the dropping time of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is 0.5 to 3 h, for example, 1 h, 1.5 h, 2 h or 2.5 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 lists the specific point values ​​included in the range, and is further preferably 1 to 1.5 h.

[0032] Preferably, the temperature of the condensation reaction in step (1) is -15 to 60°C, for example, -5°C, 0°C, 15°C, 30°C, 45°C or 50°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 it is further preferably 0 to 10°C.

[0033] Preferably, the condensation reaction time of step (1) is 2 to 6 hours, for example, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours or 5.5 hours, as well as specific values ​​between the above 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 is further preferably 2.5 to 3 hours.

[0034] In the present invention, the reaction in step (1) does not require post-treatment, and the reaction solution is directly used to synthesize the compound of formula III.

[0035] Preferably, the transposition reaction in step (2) is carried out in the presence of an auxiliary agent, and the auxiliary agent is any one of triethylamine and diisopropylethylamine or a combination of the two, and triethylamine is more preferably used.

[0036] Preferably, the molar ratio of the auxiliary agent in step (2) to 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is (1.05-1.5):1, such as 1.05:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1 or 1.5:1, and more preferably 1.2:1;

[0037] Preferably, the transposition catalyst in step (2) is acetone cyanohydrin.

[0038] Preferably, based on the amount of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride used in step (1) as 1 mol, the amount of the transposition catalyst used is 1 to 50 g, for example, 2 g, 4 g, 6 g, 8 g, 10 g, 20 g, 30 g, 40 g or 45 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.

[0039] Preferably, the solvent for the metathesis reaction in step (2) is selected from any one or a combination of at least two of dichloroethane, dichloromethane, chloroform, benzene, toluene and xylene, and is further preferably the same as the solvent used for synthesizing compound II.

[0040] Preferably, based on 1 mol of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride used in step (1), the amount of the solvent used is 900 to 2400 g, for example, 1200 g, 1500 g, 1800 g or 2100 g, and is further preferably the same as the amount of solvent used in the synthesis of compound II.

[0041] Preferably, the temperature of the transposition reaction in step (2) is 5 to 60°C, for example, 10°C, 15°C, 30°C, 45°C or 50°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 is further preferably 20 to 30°C.

[0042] Preferably, the time of the transposition reaction in step (2) is 3 to 15 h, for example 5 h, 7 h, 9 h, 11 h or 13 h, as well as specific values ​​between the above 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 is further preferably 6 to 8 h.

[0043] Preferably, after the transposition reaction in step (2) is completed, post-treatment of the product is also included.

[0044] Preferably, the post-treatment includes acidification, layering, water washing and desolventizing.

[0045] Preferably, the acidification is to adjust the pH value of the system to 1-5, such as 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5, preferably 2-3.

[0046] In the present invention, the crude product obtained by desolventizing is directly used for the subsequent synthesis of the compound of formula IV without further treatment.

[0047] Preferably, the hydrolysis reaction in step (3) is carried out in the presence of an auxiliary agent.

[0048] Preferably, the auxiliary agent is water;

[0049] Preferably, the molar ratio of the auxiliary agent to 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride in step (3) is (1-10):1, for example, 1.1:1, 1.3:1, 1.7:1, 2:1, 4:1, 6:1, 8:1 or 9:1, and more preferably (1.2-1.6):1. If the auxiliary agent is too little in step (3), the reaction is incomplete, and if the auxiliary agent is too much, the triketone structure may be broken to generate 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoic acid as a byproduct, thereby reducing the overall reaction yield.

[0050] Preferably, the catalyst in step (3) is any one of HCl or HBr or a combination of both, more preferably HCl.

[0051] Preferably, the molar ratio of the catalyst to 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride in step (3) is (0.2-10):1, for example, it can be 3:1, 4:1, 6:1, 8:1 or 9:1, and more preferably (0.5-2):1.

[0052] Preferably, the reaction in step (3) is carried out in the presence of a solvent.

[0053] Preferably, the solvent is selected from any one or a combination of at least two of methanol, ethanol, tert-butanol, isopropanol, acetonitrile, benzonitrile or 1,4-dioxane, and more preferably methanol.

[0054] Preferably, based on the amount of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride used in step (3) as 1 mol, the amount of the solvent used is 600-3000 g, for example, 900 g, 1200 g, 1500 g, 2000 g or 2500 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.

[0055] Preferably, the temperature of the hydrolysis reaction in step (3) is 20-60°C, for example, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C or 55°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 it is further preferably 30-40°C.

[0056] Preferably, the hydrolysis reaction time in step (3) is 0.5 to 5 h, for example, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h or 4.5 h, as well as specific values ​​between the above 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 is further preferably 1 to 2 h.

[0057] Preferably, after the hydrolysis reaction in step (3) is completed, post-treatment of the product is also included.

[0058] Preferably, the post-treatment comprises recrystallization or desolvation followed by recrystallization.

[0059] Preferably, the recrystallization reagent includes methanol, ethanol and alcohol aqueous solution.

[0060] 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.

[0061] After the separation step, the content of the obtained tembotrione metabolites M5 and M10 is greater than 98.0%.

[0062] In the present invention, as a preferred technical solution, the preparation method specifically comprises the following steps:

[0063] (1) First, a solvent, an acid-binding agent and a compound of formula I are placed in a reaction kettle, 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is added dropwise to the reaction system at -15 to 60°C within 0.5 to 3 hours for a condensation reaction, and then the reaction is kept at -15 to 60°C for 2 to 6 hours to obtain a crude product, which is directly used for the synthesis of the compound of formula III without treatment; wherein the acid-binding agent and 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride are added dropwise to the reaction system for a condensation reaction within 0.5 to 3 hours. The molar ratio of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is (1.05-1.5):1; the molar ratio of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride to the 1,3-cyclohexanedione compound shown in formula I is 1:(1.0-1.5); based on the amount of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride being 1 mol, the amount of the solvent used is 900-2400 mL;

[0064] (2) placing a solvent, a compound of formula II, an auxiliary agent and a catalyst into a reaction kettle, and reacting at 5 to 60° C. for 3 to 15 hours to obtain a crude product of a compound of formula III, and acidifying, layering, washing with water and desolventizing to obtain a compound of formula III; the molar ratio of the auxiliary agent to 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is (1.05 to 1.5):1; based on the amount of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride being 1 mol, the amount of the transposition catalyst being 1 to 50 g; based on the amount of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride being 1 mol, the amount of the solvent being 900 to 2400 g;

[0065] (3) placing a solvent, a compound of formula III, an auxiliary agent and a catalyst into a reaction kettle, keeping the temperature at 20 to 60° C. for a reaction for 0.5 to 5 hours, and obtaining a compound of formula IV by crystallization or crystallization after desolvation; the molar ratio of the auxiliary agent to 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is (1 to 10):1; the molar ratio of the catalyst to 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is (0.2 to 10):1; based on the amount of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride being 1 mol, the amount of the solvent is 600 to 3000 g.

[0066] Compared with the prior art, the present invention has the following beneficial effects:

[0067] The present invention uses 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride and a compound of formula I as starting materials, undergoes a condensation reaction under the action of an acid-binding agent to prepare a compound of formula II, then undergoes intramolecular transposition under the action of an auxiliary agent and a transposition catalyst to prepare a compound of formula III, and then undergoes acid-catalyzed hydrolysis to prepare a compound of formula IV. When R 3 and R 4 When both are hydroxyl groups, it is M5. When one of them is H and the other is hydroxyl group, it is M10. The content of the obtained product is ≥98%, and the yield is as high as 73% or more. 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 cyclosulfuron metabolites is achieved, which can fully meet the sample amount requirements for cyclosulfuron metabolites in pesticide registration. DETAILED DESCRIPTION

[0068] 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.

[0069] 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.

[0070] Example 1

[0071] A method for preparing tembotrione metabolite M5, the specific steps are as follows:

[0072] Step 1: Preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid-3-oxo-4,6-diacetoxy-1-cyclohexenyl ester

[0073]

[0074] Add 120g of ethylene dichloride, 24.8g of 4,6-diacetoxy-1,3-cyclohexanedione (purity 96.5%, 0.105mol) and 11.2g of triethylamine (purity 99%, 0.11mol) to a three-necked flask, start stirring, and lower the system temperature to 5°C. After about 1h, drop 37.2g of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride (purity 98%, 0.1mol) into the reactor. After the dropwise addition, keep the reaction at 5°C for 3h. After the insulation is completed, stop the reaction by controlling 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride to less than 0.2%. The reaction solution does not need post-treatment and can be directly used for the next step.

[0075] Step 2: Preparation of 4,6-diacetoxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione

[0076]

[0077] Transfer the reaction solution prepared in the previous step to the three-necked flask, add 13.3g triethylamine (purity 99%, 0.13mol) and 1g acetone cyanohydrin, start stirring, raise the system temperature to 25°C, and keep warm for 6h. After the insulation is completed, the reaction is stopped by controlling 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoic acid-3-oxygen-4,6-diacetoxy-1-cyclohexenyl ester <0.2%. Add 14.2g concentrated hydrochloric acid (purity 36%, 0.14mol) to the reaction solution to adjust the pH value of the system to 1-2, then layer, wash the oil phase with 30g water, and desolventize the oil phase to obtain the crude product of 4,6-diacetoxy-2-[2-chloro-4-methylsulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3 dione, which is directly used in the next step without further purification.

[0078] Step 3: Preparation of 4,6-dihydroxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione (metabolite M5)

[0079] Add the crude 4,6-diacetoxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione obtained in the previous step, 180g methanol and 2.18g water (purity 99%, 0.12mol) into a three-necked flask, start stirring, pass 3.7g HCl gas (purity 99%, 0.1mol) at room temperature, then heat to 25°C and keep warm for 1.0h. After the insulation is completed, the reaction is stopped by controlling 4,6-diacetoxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione <0.2%. The solvent was evaporated under negative pressure in a water bath at 60°C, and then 60 g of methanol aqueous solution (methanol mass percentage content 90%) was added to the kettle residue and the temperature was raised to reflux for dissolution, and then the temperature was lowered to 0°C for low-temperature crystallization for 1 hour, and then filtered and dried to obtain 40.7 g of pure cyclosulfone metabolite M5 with a quantitative content of 98.2%. The three-step reaction yield was 84.7% based on 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride.

[0080] Structural testing:

[0081] Ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) (m / z, ESI - ): 471.01249 (MH) - ; Theoretical value: 471.01337 (negative ion).

[0082] 1 H-NMR (DMSO, 400MHz): δ: 1.219-1.249 (t, J=6Hz, 2H, CH 2 ), 2.071-2.101(t, J=6Hz, 2H, CH), 3.357(s, 3H, CH 3 ), 4.0235-4.304(q, J=9.2Hz, 2H, CH 2 ), 5.213(s, 2H, CH 2 ), 4.364 (s, 2H, OH), 7.611 (d, J=8.0Hz, 1H, ArH), 8.035 (d, J=8.0Hz, 1H, ArH), 16.702 (s, 1H, (CO) 3 CH).

[0083] The method of this example was used for scaled-up preparation, with an initial input of 1862.0 g of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride (purity 98%, 5.0 mol), and finally 2037.5 kg of tamponic metabolite M5 was prepared, with a quantitative content of 98.3%, and a three-step reaction yield of 84.9% based on 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride.

[0084] Example 2

[0085] A method for preparing tembotrione metabolite M5, the specific steps are as follows:

[0086] Step 1: Preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid-3-oxo-4,6-dimethoxy-1-cyclohexenyl ester

[0087]

[0088] Add 150g chloroform, 17.7g 4,6-dimethoxy-1,3-cyclohexanedione (purity 97.0%, 0.10mol) and 13.7g diisopropylethylamine (purity 99%, 0.105mol) to a three-necked flask, start stirring, lower the system temperature to 10°C, and then drip 37.2g 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride (purity 98%, 0.1mol) into the reactor about 1h after dripping, and keep the temperature at 10°C for 1h. After the insulation is completed, the reaction is stopped by controlling 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride <0.2%. The reaction solution does not need post-treatment and can be directly used for the next step.

[0089] Step 2: Preparation of 4,6-dimethoxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione

[0090]

[0091] Transfer the reaction solution prepared in the previous step to a three-necked flask, add 15.6 g of diisopropylethylamine (purity 99%, 0.12 mol) and 5 g of acetone cyanohydrin, start stirring, raise the system temperature to 20°C, and keep the temperature for 7 hours. After the temperature is kept, stop the reaction when the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoic acid-3-oxo-4,6-dimethoxy-1-cyclohexenyl ester is less than 0.2%. 13.2 g of concentrated hydrochloric acid (purity 36%, 0.13 mol) was added to the reaction solution to adjust the pH value of the system to 1-2, and then the crude product of 4,6-dimethoxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione was obtained by layering, washing the oil phase with 30 g of water, and desolvating the oil phase. The crude product was used directly in the next reaction without further purification.

[0092] Step 3: Preparation of 4,6-dihydroxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione (metabolite M5)

[0093]

[0094] Add the crude product of 4,6-dimethoxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione obtained in the previous step, 240g ethanol and 2.88g water (purity 99%, 0.16mol) to a three-necked flask, start stirring, pass 1.84g HCl gas (purity 99%, 0.05mol) at room temperature, then heat to 40°C and keep warm for 1.5h. After the insulation is completed, the reaction is stopped by controlling 4,6-dimethoxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione <0.2%. The solvent was evaporated under negative pressure in a water bath at 60°C, and then 60 g of ethanol aqueous solution (methanol content 90% by mass) was added to the kettle residue and the temperature was raised to reflux for dissolution, and then the temperature was lowered to 0°C for low-temperature crystallization for 0.5 h, and then filtered and dried to obtain 40.2 g of pure cyclosulfone metabolite M5 with a quantitative content of 98.4%. The three-step reaction yield was 83.8% based on 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride.

[0095] Structural detection: The tamponic acid metabolite M5 prepared in this example was subjected to the same detection as in Example 1 to verify the correctness of the structure.

[0096] Example 3

[0097] A method for preparing tembotrione metabolite M5, the specific steps are as follows:

[0098] Step 1: Preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid-3-oxo-4,6-dibenzyloxy-1-cyclohexenyl ester

[0099]

[0100] Add 240g toluene, 51.1g 4,6-dibenzyloxy-1,3-cyclohexanedione (purity 95.0%, 0.15mol) and 12.0g pyridine (purity 99%, 0.15mol) to a three-necked flask, start stirring, lower the system temperature to 0°C, and then drip 37.2g 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride (purity 98%, 0.1mol) into the reactor for about 0.5h. After dripping, keep the reaction at 0°C for 3h. After the insulation is completed, stop the reaction by controlling 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride <0.2%. The reaction solution does not need post-treatment and directly proceeds to the next step.

[0101] Step 2: Preparation of 4,6-dibenzyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione

[0102]

[0103] Transfer the reaction solution prepared in the previous step to a three-necked flask, add 10.7g triethylamine (purity 99%, 0.105mol) and 2g acetone cyanohydrin, start stirring, raise the system temperature to 30°C, and keep warm for 8h. After the insulation is completed, the reaction is stopped when the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoic acid-3-oxygen-4,6-dibenzyloxy-1-cyclohexenyl ester is less than 0.2%. Add 16.2g concentrated hydrochloric acid (purity 36%, 0.16mol) to the reaction solution to adjust the pH value of the system to 4-5, then layer, wash the oil phase with 30g water, and desolventize the oil phase to obtain the crude product of 4,6-dibenzyloxy-2-[2-chloro-4-methylsulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione, which is directly used in the next step without further purification.

[0104] Step 3: Preparation of 4,6-dihydroxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione (metabolite M5)

[0105]

[0106] Add the crude product of 4,6-dibenzyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione obtained in the previous step, 120g acetonitrile and 2.7g water (purity 99%, 0.15mol) into a three-necked flask, start stirring, pass 7.4g HCl gas (purity 99%, 0.2mol) at room temperature, then heat to 50°C and keep warm for 2h. After the insulation is completed, the reaction is stopped by controlling 4,6-dibenzyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione <0.2%. The solvent was evaporated under negative pressure in a water bath at 60°C, and then 65 g of methanol aqueous solution (methanol mass percentage content 95%) was added to the kettle residue and the temperature was raised to reflux for dissolution, and then the temperature was lowered to 0°C for low-temperature crystallization for 2 hours. After filtration and drying, 36.7 g of pure cyclosulfone metabolite M5 was obtained with a quantitative content of 94.7%. The three-step reaction yield was 73.6% based on 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride.

[0107] Structural detection: The tamponic acid metabolite M5 prepared in this example was subjected to the same detection as in Example 1 to verify the correctness of the structure.

[0108] Example 4

[0109] A method for preparing tembotrione metabolite M5, the specific steps are as follows:

[0110] Step 1: Preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid-3-oxo-4-(3-methylbutyloxy)-6-dimethyl-tert-butylsilyloxy-1-cyclohexenyl ester

[0111]

[0112] Add 180g chloroform, 36.3g 4-(3-methylbutyloxy)-6-dimethyl tert-butylsilyloxy-1,3-cyclohexanedione (purity 95.0%, 0.105mol) and 11.2g triethylamine (purity 99%, 0.11mol) to a three-necked flask, start stirring, lower the system temperature to 10°C, and then drip 37.2g 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride (purity 98%, 0.1mol) into the reactor about 1h after dripping, and keep the temperature at 10°C for 1h. After the insulation is completed, stop the reaction by controlling 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride <0.2%. The reaction solution does not need post-treatment and directly proceeds to the next step.

[0113] Step 2: Preparation of 4-(3-methylbutyloxy)-6-dimethyltert-butylsilyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione

[0114]

[0115] Transfer the reaction solution prepared in the previous step to a three-necked flask, add 12.2g triethylamine (purity 99%, 0.12mol) and 5g acetone cyanohydrin, start stirring, raise the system temperature to 20°C, and keep the temperature for 7 hours. After the insulation is completed, the reaction is stopped when the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid-3-oxy-4-(3-methylbutyloxy)-6-dimethyl-tert-butylsilyloxy-1-cyclohexenyl ester is less than 0.2%. 13.2 g of concentrated hydrochloric acid (purity 36%, 0.13 mol) was added to the reaction solution to adjust the pH value of the system to 1-2, and then the oil phase was washed with 30 g of water and the oil phase was desolvated to obtain a crude product of 4-(3-methylbutoxy)-6-dimethyl-tert-butylsilyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione, which was directly used in the next step without further purification.

[0116] Step 3: Preparation of 4,6-dihydroxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione (metabolite M5)

[0117]

[0118] Add the crude product of 4-(3-methylbutoxy)-6-dimethyl-tert-butylsilyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione obtained in the previous step, 240g ethanol and 2.88g water (purity 99%, 0.16mol) to a three-necked flask, start stirring, pass 1.84g HCl gas (purity 99%, 0.05mol) at room temperature, then heat to 40°C and keep warm for 1.5h. After the insulation is completed, the reaction is stopped by controlling 4-(3-methylbutoxy)-6-dimethyl-tert-butylsilyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione <0.2%. The solvent was evaporated under negative pressure in a water bath at 60°C, and then 60 g of ethanol aqueous solution (ethanol mass percentage content 90%) was added to the kettle residue and the temperature was raised to reflux for dissolution, and then the temperature was lowered to 0°C for low-temperature crystallization for 0.5 h, and then filtered and dried to obtain 39.6 g of pure cyclosulfone metabolite M5 with a quantitative content of 97.4%. The three-step reaction yield was 81.7% based on 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride.

[0119] Structural detection: The tamponic acid metabolite M5 prepared in this example was subjected to the same detection as in Example 1 to verify the correctness of the structure.

[0120] Example 5

[0121] A method for preparing tembotrione metabolite M5, the specific steps are as follows:

[0122] Step 1: Preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid-3-oxo-4-benzoyloxy-6-triethylsilyloxy-1-cyclohexenyl ester

[0123]

[0124] Add 180g chloroform, 39.6g 4-benzoyloxy-6-triethylsilyloxy-1,3-cyclohexanedione (purity 96.0%, 0.105mol) and 11.2g triethylamine (purity 99%, 0.11mol) to a three-necked flask, start stirring, lower the system temperature to 10°C, and then drip 37.2g 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride (purity 98%, 0.1mol) into the reactor about 1h after dripping, and keep the temperature at 10°C for 1h. After the insulation is completed, the reaction is stopped by controlling 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride <0.2%. The reaction solution does not need post-treatment and can be directly used for the next step.

[0125] Step 2: Preparation of 4-benzoyloxy-6-triethylsilyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione

[0126]

[0127] Transfer the reaction solution prepared in the previous step to a three-necked flask, add 12.2 g of triethylamine (purity 99%, 0.12 mol) and 5 g of acetone cyanohydrin, start stirring, raise the system temperature to 20°C, and keep the temperature for 7 hours. After the insulation is completed, the reaction is stopped by controlling the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid-3-oxy-4-benzoyloxy-6-triethylsilyloxy-1-cyclohexenyl ester to less than 0.2%. 13.2 g of concentrated hydrochloric acid (purity 36%, 0.13 mol) was added to the reaction solution to adjust the pH value of the system to 1-2, and then the oil phase was washed with 30 g of water and desolvated to obtain a crude product of 4-benzoyloxy-6-triethylsilyloxy-2-[2-chloro-4-methylsulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione, which was directly used in the next reaction without further purification.

[0128] Step 3: Preparation of 4,6-dihydroxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione (metabolite M5)

[0129]

[0130] Add the crude 4-benzoyloxy-6-triethylsilyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3 dione obtained in the previous step, 240g ethanol and 2.88g water (purity 99%, 0.16mol) to a three-necked flask, start stirring, pass 1.84g HCl gas (purity 99%, 0.05mol) at room temperature, then heat to 40°C and keep warm for 1.5h. After the insulation is completed, the reaction is stopped by controlling 4-benzoyloxy-6-triethylsilyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3 dione <0.2%. The solvent was evaporated under negative pressure in a water bath at 60°C, and then 60 g of ethanol aqueous solution (ethanol mass percentage content 90%) was added to the kettle residue and the temperature was raised to reflux for dissolution, and then the temperature was lowered to 0°C for low-temperature crystallization for 0.5 h, and then filtered and dried to obtain 39.8 g of pure cyclosulfone metabolite M5 with a quantitative content of 97.6%. The three-step reaction yield was 82.3% based on 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride.

[0131] Structural detection: The tamponic acid metabolite M5 prepared in this example was subjected to the same detection as in Example 1 to verify the correctness of the structure.

[0132] Example 6

[0133] A method for preparing tembotrione metabolite M10, the specific steps are as follows:

[0134] Step 1: Preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid-3-oxo-4-acetoxy-1-cyclohexenyl ester

[0135]

[0136] Add 180g of dichloromethane, 18.6g of 4-acetoxy-1,3-cyclohexanedione (purity 96.0%, 0.105mol) and 14.3g of diisopropylethylamine (purity 99%, 0.11mol) to a three-necked flask, start stirring, and lower the system temperature to 0°C. After about 1.5h, drop 37.2g of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride (purity 98%, 0.1mol) into the reactor. After the dropwise addition, keep the reaction at 0°C for 4h. After the insulation is completed, stop the reaction by controlling 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride to less than 0.2%. The reaction solution does not need post-treatment and can be directly used for the next step.

[0137] Step 2: Preparation of 4-acetoxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione

[0138]

[0139] Transfer the reaction solution prepared in the previous step to a three-necked flask, add 15.6g of diisopropylethylamine (purity 99%, 0.12mol) and 1g of acetone cyanohydrin, start stirring, raise the system temperature to 30-35°C, and keep warm for 8h. After the insulation is completed, the reaction is stopped when the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoic acid-3-oxygen-4-acetoxy-1-cyclohexenyl ester is less than 0.2%. Add 13.2g of concentrated hydrochloric acid (purity 36%, 0.13mol) to the reaction solution to adjust the pH value of the system to 1-2, then separate, wash the oil phase with 30g of water, and desolventize the oil phase to obtain the crude product of 4-acetoxy-2-[2-chloro-4-methylsulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3 dione, which is directly used in the next step without further purification.

[0140] Step 3: Preparation of 4-hydroxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione (metabolite M10)

[0141]

[0142] Add the crude 4-acetoxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione obtained in the previous step, 300g methanol and 2.18g water (purity 99%, 0.12mol) into a three-necked flask, start stirring, pass 3.7g HCl gas (purity 99%, 0.1mol) at room temperature, then heat to 30°C and keep warm for 2h. After the insulation is completed, the reaction is stopped when the 4-acetoxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione is less than 0.2%. The solvent was evaporated under negative pressure in a water bath at 60°C, and then 75 g of ethanol aqueous solution (ethanol mass percentage content 90%) was added to the kettle residue and the temperature was raised to reflux for dissolution, and then the temperature was lowered to 0°C for low-temperature crystallization for 0.5 h, and then filtered and dried to obtain 39.5 g of pure cyclosulfone metabolite M10 with a quantitative content of 98.2%. The three-step reaction yield was 85.1% based on 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride.

[0143] Structural testing:

[0144] Ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) (m / z, ESI - ): 455.01286 (MH) - ; Theoretical value: 455.01846 (negative ion).

[0145] 1 H-NMR (CDCl 3 , 400MHz) δ: 1.892~1.937 (q, J=6.0Hz, 2H, CH 2 ), 2.428~2.447 (t, J=3.8Hz, 1H, CH), 2.935~2.949 (t, J=2.6Hz, 2H, CH 2 ), 3.255(s, 3H, CH 3 ), 3.993~4.059 (q, J=8.8Hz, 2H, CH 2 ), 4.157(s, 1H, OH), 5.365(s, 2H, CH 2 ), 7.373 (d, J=8.0Hz, 1H, ArH), 8.176 (d, J=8.0Hz, 1H, ArH), 16.687 (s, 1H, (CO)3 CH).

[0146] The method of this example was used for scaled-up preparation, with an initial input of 2234.4 g of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride (purity 98%, 6.0 mol), and finally 2339.2 kg of tamponic acid metabolite M10 was prepared, with a quantitative content of 98.6%, and a three-step reaction yield of 84.3% based on 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride.

[0147] Example 7

[0148] A method for preparing tembotrione metabolite M10, the specific steps are as follows:

[0149] Step 1: Preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid-3-oxo-4-methoxy-1-cyclohexenyl ester

[0150]

[0151] Add 90g of ethylene dichloride, 15.4g of 4-methoxy-1,3-cyclohexanedione (purity 97.0%, 0.105mol) and 16.9g of diisopropylethylamine (purity 99%, 0.13mol) to a three-necked flask, start stirring, lower the system temperature to 10°C, and then drip 37.2g of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride (purity 98%, 0.1mol) into the reactor about 1.5h later. After dripping, keep the reaction at 10°C for 2h. After the insulation is completed, stop the reaction by controlling 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride to less than 0.2%. The reaction solution does not need post-treatment and can be directly used for the next step.

[0152] Step 2: Preparation of 4-methoxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione

[0153]

[0154] Transfer the reaction solution prepared in the previous step to the three-necked flask, add 15.6g of diisopropylethylamine (purity 99%, 0.12mol) and 10g of acetone cyanohydrin, start stirring, raise the system temperature to 20°C, and keep warm for 7h. After the insulation is completed, the reaction is stopped when the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoic acid-3-oxygen-4-methoxy-1-cyclohexenyl ester is less than 0.2%. Add 15.2g of concentrated hydrochloric acid (purity 36%, 0.15mol) to the reaction solution to adjust the pH value of the system to 3-4, then layer, wash the oil phase with 30g of water, and desolventize the oil phase to obtain the crude product of 4-methoxy-2-[2-chloro-4-methylsulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione, which is directly used in the next step without further purification.

[0155] Step 3: Preparation of 4-hydroxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione (metabolite M10)

[0156]

[0157] Add the crude product of 4-methoxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione obtained in the previous step, 90g isopropanol and 2.36g water (purity 99%, 0.13mol) to a three-necked flask, start stirring, pass 7.4g HCl gas (purity 99%, 0.2mol) at room temperature, then heat to 40°C and keep warm for 1.5h. After the insulation is completed, the reaction is stopped by controlling 4-methoxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione <0.2%. The solvent was evaporated under negative pressure in a water bath at 60°C, and then 60 g of methanol aqueous solution (methanol mass percentage content 90%) was added to the kettle residue and the temperature was raised to reflux for dissolution, and then the temperature was lowered to 0°C for low-temperature crystallization for 1 hour, and then filtered and dried to obtain 39.3 g of pure cyclosulfone metabolite M10 with a quantitative content of 98.5%. The three-step reaction yield was 84.8% based on 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride.

[0158] Structural detection: The tampoxone metabolite M10 prepared in this example was subjected to the same detection as in Example 6 to verify the correctness of the structure.

[0159] Example 8

[0160] A method for preparing tembotrione metabolite M10, the specific steps are as follows:

[0161] Step 1: Preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid-3-oxo-4-benzyloxy-1-cyclohexenyl ester

[0162]

[0163] Add 240g xylene, 24.1g 4-benzyloxy-1,3-cyclohexanedione (purity 95.0%, 0.105mol) and 11.2g triethylamine (purity 99%, 0.11mol) to a three-necked flask, start stirring, lower the system temperature to 0°C, and then drip 37.2g 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride (purity 98%, 0.1mol) into the reactor about 1h later. After dripping, keep the reaction at 0°C for 3h. After the insulation is completed, stop the reaction by controlling 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride to less than 0.2%. The reaction solution does not need post-treatment and can be directly used for the next step.

[0164] Step 2: Preparation of 4-benzyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione

[0165]

[0166] Transfer the reaction solution prepared in the previous step to a three-necked flask, add 15.2g triethylamine (purity 99%, 0.15mol) and 3g acetone cyanohydrin, start stirring, raise the system temperature to 30°C, and keep the temperature for 10h. After the insulation is completed, the reaction is stopped by controlling 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoic acid-3-oxygen-4-benzyloxy-1-cyclohexenyl ester <0.2%. Add 16.2g concentrated hydrochloric acid (purity 36%, 0.16mol) to the reaction solution to adjust the pH value of the system to 2-3, then layer, wash the oil phase with 30g water, and desolventize the oil phase to obtain the crude product of 4-benzyloxy-2-[2-chloro-4-methylsulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3 dione, which does not need further purification and is directly used in the next step.

[0167] Step 3: Preparation of 4,6-dihydroxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione (metabolite M10)

[0168]

[0169] Add the crude product of 4-benzyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione obtained in the previous step, 150g of tert-butyl alcohol and 2.55g of water (purity 99%, 0.14mol) to a three-necked flask, start stirring, pass 5.5g of HCl gas (purity 99%, 0.15mol) at room temperature, then heat to 40°C and keep warm for 1.5h. After the insulation is completed, the reaction is stopped when 4-benzyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione is less than 0.2%. The solvent was evaporated under negative pressure in a water bath at 60°C, and then 60 g of methanol was added to the kettle residue and the temperature was raised to reflux for dissolution, and then the temperature was lowered to 0°C for low-temperature crystallization for 0.5 h. After filtration and drying, 37.9 g of pure cyclosulfone metabolite M10 was obtained with a quantitative content of 98.8%. The three-step reaction yield was 82.2% based on 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride.

[0170] Structural detection: The tampoxone metabolite M10 prepared in this example was subjected to the same detection as in Example 6 to verify the correctness of the structure.

[0171] Example 9

[0172] A method for preparing tembotrione metabolite M10, the specific steps are as follows:

[0173] Step 1: Preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid-3-oxo-4-(3-methylbutyloxy)-1-cyclohexenyl ester

[0174]

[0175] Add 180g chloroform, 21.7g 4-(3-methylbutoxy)-1,3-cyclohexanedione (purity 96.0%, 0.105mol) and 11.2g triethylamine (purity 99%, 0.11mol) to a three-necked flask, start stirring, lower the system temperature to 10°C, and then drip 37.2g 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride (purity 98%, 0.1mol) into the reactor about 1h after dripping. After dripping, keep the temperature at 10°C for 1h. After the insulation is completed, stop the reaction by controlling 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride <0.2%. The reaction solution does not need post-treatment and can be directly used for the next step.

[0176] Step 2: Preparation of 4-(3-methylbutoxy)-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione

[0177]

[0178] Transfer the reaction solution prepared in the previous step to a three-necked flask, add 12.2 g of triethylamine (purity 99%, 0.12 mol) and 5 g of acetone cyanohydrin, start stirring, raise the system temperature to 20°C, and keep the temperature for 7 hours. After the temperature is kept, the reaction is stopped when the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoic acid-3-oxo-4-(3-methylbutyloxy)-1-cyclohexenyl ester is less than 0.2%. 13.2 g of concentrated hydrochloric acid (purity 36%, 0.13 mol) was added to the reaction solution to adjust the pH value of the system to 1-2, and then the oil phase was washed with 30 g of water and the oil phase was desolvated to obtain a crude product of 4-(3-methylbutoxy)-6-dimethyl-tert-butylsilyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione, which was directly used in the next reaction without further purification.

[0179] Step 3: Preparation of 4,6-dihydroxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione (metabolite M10)

[0180]

[0181] Add the crude product of 4-(3-methylbutoxy)-6-dimethyl-tert-butylsilyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione obtained in the previous step, 240g ethanol and 2.88g water (purity 99%, 0.16mol) to a three-necked flask, start stirring, pass 1.84g HCl gas (purity 99%, 0.05mol) at room temperature, then heat to 40°C and keep warm for 1.5h. After the insulation is completed, the reaction is stopped by controlling 4-(3-methylbutoxy)-6-dimethyl-tert-butylsilyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione <0.2%. The solvent was evaporated under negative pressure in a water bath at 60°C, and then 60 g of ethanol aqueous solution (ethanol mass percentage content 90%) was added to the kettle residue and the temperature was raised to reflux for dissolution, and then the temperature was lowered to 0°C for low-temperature crystallization for 0.5 h, and then filtered and dried to obtain 39.1 g of pure cyclosulfone metabolite M10 with a quantitative content of 97.6%. The three-step reaction yield was 83.7% based on 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride.

[0182] Structural detection: The tampoxone metabolite M10 prepared in this example was subjected to the same detection as in Example 6 to verify the correctness of the structure.

[0183] Example 10

[0184] A method for preparing tembotrione metabolite M10, the specific steps are as follows:

[0185] Step 1: Preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid-3-oxo-4-benzoyloxy-1-cyclohexenyl ester

[0186]

[0187] Add 180g of ethylene dichloride, 25.4g of 4-benzoyloxy-1,3-cyclohexanedione (purity 96.0%, 0.105mol) and 11.2g of triethylamine (purity 99%, 0.11mol) to a three-necked flask, start stirring, lower the system temperature to 10°C, and then drip 37.2g of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride (purity 98%, 0.1mol) into the reactor about 1h after dripping. After dripping, keep the temperature at 10°C for 1h. After the insulation is completed, stop the reaction by controlling 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride <0.2%. The reaction solution does not need post-treatment and directly proceeds to the next step.

[0188] Step 2: Preparation of 4-benzoyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione

[0189]

[0190] Transfer the reaction solution prepared in the previous step to a three-necked flask, add 12.2g triethylamine (purity 99%, 0.12mol) and 5g acetone cyanohydrin, start stirring, raise the system temperature to 20°C, and keep warm for 7h. After the insulation is completed, the reaction is stopped when the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoic acid-3-oxygen-4-benzoyloxy-1-cyclohexenyl ester is less than 0.2%. Add 13.2g concentrated hydrochloric acid (purity 36%, 0.13mol) to the reaction solution to adjust the pH value of the system to 1-2, then layer, wash the oil phase with 30g water, and desolventize the oil phase to obtain the crude product of 4-benzoyloxy-2-[2-chloro-4-methylsulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3 dione, which is directly used in the next step without further purification.

[0191] Step 3: Preparation of 4,6-dihydroxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione (metabolite M10)

[0192]

[0193] Add the crude product of 4-benzoyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione obtained in the previous step, 240g ethanol and 2.88g water (purity 99%, 0.16mol) to a three-necked flask, start stirring, pass 1.84g HCl gas (purity 99%, 0.05mol) at room temperature, then heat to 40°C and keep warm for 1.5h. After the insulation is completed, the reaction is stopped when 4-benzoyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione is less than 0.2%. The solvent was evaporated under negative pressure in a water bath at 60°C, and then 60 g of ethanol aqueous solution (ethanol mass percentage content 90%) was added to the kettle residue and the temperature was raised to reflux for dissolution, and then the temperature was lowered to 0°C for low-temperature crystallization for 0.5 h, and then filtered and dried to obtain 39.3 g of pure cyclosulfone metabolite M10 with a quantitative content of 97.7%. The three-step reaction yield was 84.2% based on 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride.

[0194] Structural detection: The tampoxone metabolite M10 prepared in this example was subjected to the same detection as in Example 6 to verify the correctness of the structure.

[0195] Embodiment 11

[0196] A method for preparing tembotrione metabolite M10, the specific steps are as follows:

[0197] Step 1: Preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid-3-oxo-4-dimethyl-tert-butylsilyloxy-1-cyclohexenyl ester

[0198] Add 180g chloroform, 28.0g 4-dimethyl tert-butylsilyloxy-1,3-cyclohexanedione (purity 95.0%, 0.11mol) and 11.2g triethylamine (purity 99%, 0.11mol) to a three-necked flask, start stirring, lower the system temperature to 10°C, and then drip 37.2g 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride (purity 98%, 0.1mol) into the reactor about 1h after dripping. After dripping, keep the temperature at 10°C for 1h. After the insulation is completed, stop the reaction by controlling 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride <0.2%. The reaction solution does not need post-treatment and directly proceeds to the next step.

[0199] Step 2: Preparation of 4-dimethyl-tert-butylsilyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione

[0200]

[0201] Transfer the reaction solution prepared in the previous step to a three-necked flask, add 12.2 g of triethylamine (purity 99%, 0.12 mol) and 5 g of acetone cyanohydrin, start stirring, raise the system temperature to 20°C, and keep the temperature for 7 hours. After the insulation is completed, the reaction is stopped by controlling the concentration of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid-3-oxy-4-dimethyl-tert-butylsilyloxy-1-cyclohexenyl ester to less than 0.2%. 13.2 g of concentrated hydrochloric acid (purity 36%, 0.13 mol) was added to the reaction solution to adjust the pH value of the system to 1-2, and then the oil phase was washed with 30 g of water and the oil phase was desolvated to obtain a crude product of 4-dimethyl-tert-butylsilyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione, which was directly used in the next reaction without further purification.

[0202] Step 3: Preparation of 4,6-dihydroxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione (metabolite M10)

[0203]

[0204] Add the crude product of 4-dimethyl-tert-butylsilyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione obtained in the previous step, 240g of ethanol and 2.88g of water (purity 99%, 0.16mol) to a three-necked flask, start stirring, pass 1.84g of HCl gas (purity 99%, 0.05mol) at room temperature, then heat to 40°C and keep warm for 1.5h. After the insulation is completed, the reaction is stopped when 4-dimethyl-tert-butylsilyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione is less than 0.2%. The solvent was evaporated under negative pressure in a water bath at 60°C, and then 60 g of ethanol aqueous solution (ethanol mass percentage content 90%) was added to the kettle residue and the temperature was raised to reflux for dissolution, and then the temperature was lowered to 0°C for low-temperature crystallization for 0.5 h, and then filtered and dried to obtain 39.4 g of pure cyclosulfone metabolite M10 with a quantitative content of 97.6%. The three-step reaction yield was 84.3% based on 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride.

[0205] Structural detection: The tampoxone metabolite M10 prepared in this example was subjected to the same detection as in Example 6 to verify the correctness of the structure.

[0206] Example 12

[0207] A method for preparing tembotrione metabolite M10, the specific steps are as follows:

[0208] Step 1: Preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid-3-oxo-4-triethylsilyloxy-1-cyclohexenyl ester

[0209]

[0210] Add 180g chloroform, 26.5g 4-triethylsilyloxy-1,3-cyclohexanedione (purity 96.0%, 0.105mol) and 11.2g triethylamine (purity 99%, 0.11mol) to a three-necked flask, start stirring, lower the system temperature to 10°C, and then drip 37.2g 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride (purity 98%, 0.1mol) into the reactor about 1h after dripping, and keep the temperature at 10°C for 1h. After the insulation is completed, the reaction is stopped by controlling 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride <0.2%. The reaction solution does not need post-treatment and can be directly used for the next step.

[0211] Step 2: Preparation of 4-triethylsilyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione

[0212]

[0213] Transfer the reaction solution prepared in the previous step to the three-necked flask, add 12.2g triethylamine (purity 99%, 0.12mol) and 5g acetone cyanohydrin, start stirring, raise the system temperature to 20°C, and keep warm for 7h. After the insulation is completed, the reaction is stopped by controlling 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid-3-oxygen-4-triethylsilyloxy-1-cyclohexene ester <0.2%. Add 13.2g concentrated hydrochloric acid (purity 36%, 0.13mol) to the reaction solution to adjust the pH value of the system to 1-2, then layer, wash the oil phase with 30g water, and desolventize the oil phase to obtain the crude product of 4-triethylsilyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3 dione, which does not need further purification and is directly used in the next step.

[0214] Step 3: Preparation of 4,6-dihydroxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione (metabolite M10)

[0215]

[0216] Add the crude product of 4-triethylsilyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione obtained in the previous step, 240g ethanol and 2.88g water (purity 99%, 0.16mol) to a three-necked flask, start stirring, pass 1.84g HCl gas (purity 99%, 0.05mol) at room temperature, then heat to 40°C and keep warm for 1.5h. After the insulation is completed, the reaction is stopped when 4-triethylsilyloxy-2-[2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoroethoxy)methylbenzoyl]cyclohexane-1,3-dione is less than 0.2%. The solvent was evaporated under negative pressure in a water bath at 60°C, and then 60 g of ethanol aqueous solution (ethanol mass percentage content 90%) was added to the kettle residue and the temperature was raised to reflux for dissolution, and then the temperature was lowered to 0°C for low-temperature crystallization for 0.5 h, and then filtered and dried to obtain 39.1 g of pure cyclosulfone metabolite M10 with a quantitative content of 97.7%. The three-step reaction yield was 83.8% based on 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride.

[0217] Structural detection: The tampoxone metabolite M10 prepared in this example was subjected to the same detection as in Example 6 to verify the correctness of the structure.

[0218] The applicant declares that the present invention illustrates the preparation process of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments 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 a tembotrione metabolite, characterized in that: The preparation method uses 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride and a 1,3-cyclohexanedione compound shown in formula I as raw materials, and undergoes condensation reaction, catalytic transposition reaction and hydrolysis reaction to obtain a cyclosulfone metabolite shown in formula IV. The reaction process is as follows: Where R 1 is H, C1-C4 alkoxy, benzyloxy, acetoxy, benzoyloxy or alkylsilyloxy, R 2 is H, C1-C4 alkoxy, benzyloxy, acetoxy, benzoyloxy or alkylsilyloxy; and R 1 and R 2 H, R 3 and R 4 Same as hydroxyl or R 3 and R 4 One of them is hydroxyl and the other is H.

2. The preparation method according to claim 1, characterized in that: The preparation method comprises the following steps: (1) In the presence of an acid binding agent, 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride and the 1,3-cyclohexanedione compound represented by formula I are subjected to a condensation reaction to prepare a compound represented by formula II. The reaction formula is as follows: (2) The compound of formula II undergoes a transposition reaction under the action of a transposition catalyst to generate a compound of formula III. The reaction formula is as follows: (3) The compound of formula III undergoes a hydrolysis reaction under the action of a catalyst to generate a tembotrione metabolite represented by formula IV. The reaction formula is as follows: Where R 1 is H, C1-C4 alkoxy, benzyloxy, acetoxy, benzoyloxy or alkylsilyloxy, R 2 is H, C1-C4 alkoxy, benzyloxy, acetoxy, benzoyloxy or alkylsilyloxy; and R 1 and R 2 H, R 3 and R 4 Same as hydroxyl or R 3 and R 4 One of them is hydroxyl and the other is H.

3. The preparation method according to claim 1 or 2, characterized in that: When R 1 and R 2 When independently selected from C1-C4 alkoxy, benzyloxy, acetoxy, benzoyloxy or alkylsilyloxy, the tembotrione metabolite of formula IV is M5; when R 1 and R 2 When one of them is H and the other is C1-C4 alkoxy, benzyloxy, acetoxy, benzoyloxy or alkylsilyloxy, the tembotrione metabolite of formula IV is M10.

4. The preparation method according to claim 3, characterized in that: The alkylsilyl group is a dimethyl tert-butylsilyl group or a triethylsilyl group.

5. The preparation method according to claim 2, characterized in that: The molar ratio of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride in step (1) to the 1,3-cyclohexanedione compound shown in formula I is 1:(1.0-1.5).

6. The preparation method according to claim 5, characterized in that: The molar ratio of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride in step (1) to the 1,3-cyclohexanedione compound shown in formula I is 1:1.

05.

7. The preparation method according to claim 2, characterized in that: The acid binding agent in step (1) is any one of triethylamine, pyridine or diisopropylethylamine or a combination of at least two thereof.

8. The preparation method according to claim 7, characterized in that: The acid binding agent in step (1) is triethylamine.

9. The preparation method according to claim 2, characterized in that: The molar ratio of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride to the acid binding agent in step (1) is 1:(1.05-1.5).

10. The preparation method according to claim 9, characterized in that: The molar ratio of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride to the acid binding agent in step (1) is 1:1.

1.

11. The preparation method according to claim 2, characterized in that: The solvent for the condensation reaction in step (1) is selected from any one of dichloroethane, dichloromethane, chloroform, benzene, toluene and xylene, or a combination of at least two thereof.

12. The preparation method according to claim 11, characterized in that: The solvent for the condensation reaction in step (1) is ethylene dichloride.

13. The preparation method according to claim 2, characterized in that: Based on the usage of 1 mol of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride in step (1), the usage of the solvent is 900 to 2400 g.

14. The preparation method according to claim 2, characterized in that: The 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride in step (1) is added dropwise into the reaction system.

15. The preparation method according to claim 14, characterized in that: The dropping temperature of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is -15 to 60°C.

16. The preparation method according to claim 15, characterized in that: The dropping temperature of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is 0-10°C.

17. The preparation method according to claim 14, characterized in that: The dropwise addition time of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is 0.5 to 3 hours.

18. The preparation method according to claim 17, characterized in that: The dropwise addition time of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is 1 to 1.5 hours.

19. The preparation method according to claim 2, characterized in that: The temperature of the condensation reaction in step (1) is -15 to 60°C.

20. The preparation method according to claim 19, characterized in that: The temperature of the condensation reaction in step (1) is 0 to 10°C.

21. The preparation method according to claim 2, characterized in that: The condensation reaction time of step (1) is 2 to 6 hours.

22. The preparation method according to claim 21, characterized in that: The condensation reaction time of step (1) is 2.5 to 3 hours.

23. The preparation method according to claim 2, characterized in that: The reaction in step (1) does not require post-treatment, and the reaction solution is directly used to synthesize the compound of formula III.

24. The preparation method according to claim 2, characterized in that: The transposition reaction in step (2) is carried out in the presence of an auxiliary agent, wherein the auxiliary agent is any one of triethylamine and diisopropylethylamine or a combination of the two.

25. The preparation method according to claim 24, characterized in that: The auxiliary agent is triethylamine.

26. The preparation method according to claim 2, characterized in that: The molar ratio of the auxiliary agent in step (2) to 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is (1.05-1.5):

1.

27. The preparation method according to claim 26, characterized in that: The molar ratio of the auxiliary agent in step (2) to 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is 1.2:

1.

28. The preparation method according to claim 2, characterized in that: The transposition catalyst in step (2) is acetone cyanohydrin.

29. The preparation method according to claim 2, characterized in that: Based on the amount of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride used in step (1) as 1 mol, the amount of the transposition catalyst used is 1 to 50 g.

30. The preparation method according to claim 2, characterized in that: The solvent for the metathesis reaction in step (2) is selected from any one of dichloroethane, dichloromethane, chloroform, benzene, toluene and xylene, or a combination of at least two thereof.

31. The preparation method according to claim 2, characterized in that: The solvent used in the reaction of step (1) is the same as that used in the transposition reaction of step (2).

32. The preparation method according to claim 2, characterized in that: Based on the usage of 1 mol of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride in step (1), the usage of the solvent in step (2) is 900 to 2400 g.

33. The preparation method according to claim 2, characterized in that: The temperature of the transposition reaction in step (2) is 5 to 60°C.

34. The preparation method according to claim 33, characterized in that: The temperature of the transposition reaction in step (2) is 20-30°C.

35. The preparation method according to claim 2, characterized in that: The time of the transposition reaction in step (2) is 3 to 15 hours.

36. The preparation method according to claim 35, characterized in that: The time of the transposition reaction in step (2) is 6 to 8 hours.

37. The preparation method according to claim 2, characterized in that: After the transposition reaction in step (2) is completed, the product is further treated.

38. The preparation method according to claim 37, characterized in that: The post-treatment includes acidification, layering, water washing and desolventizing.

39. The preparation method according to claim 38, characterized in that: The acidification is to adjust the pH value of the system to 1-5.

40. The preparation method according to claim 39, characterized in that: The acidification is to adjust the pH value of the system to 2-3.

41. The preparation method according to claim 38, characterized in that: The crude product obtained by the desolventizing is directly used for the subsequent synthesis of the cyclosulfone metabolite shown in formula IV without further treatment.

42. The preparation method according to claim 2, characterized in that: The hydrolysis reaction in step (3) is carried out in the presence of an auxiliary agent.

43. The preparation method according to claim 42, characterized in that: The auxiliary agent is water.

44. The preparation method according to claim 2, characterized in that The molar ratio of the auxiliary agent in step (3) to 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is (1-10):

1.

45. The preparation method according to claim 44, characterized in that: The molar ratio of the auxiliary agent in step (3) to 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is (1.2-1.6):

1.

46. ​​The preparation method according to claim 2, characterized in that: The catalyst in step (3) is any one of HCl or HBr or a combination of the two.

47. The preparation method according to claim 46, characterized in that The catalyst in step (3) is HCl.

48. The preparation method according to claim 2, characterized in that: Based on the amount of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride used in step (1) as 1 mol, the amount of the catalyst used is 0.2 to 10 mol.

49. The preparation method according to claim 48, characterized in that Based on the amount of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride used in step (1) as 1 mol, the amount of the catalyst used is 0.5 to 2 mol.

50. The preparation method according to claim 2, characterized in that: The reaction in step (3) is carried out in the presence of a solvent.

51. The preparation method according to claim 50, characterized in that: The solvent is selected from any one of methanol, ethanol, tert-butyl alcohol, isopropanol, acetonitrile, benzonitrile or 1,4-dioxane, or a combination of at least two thereof.

52. The preparation method according to claim 51, characterized in that The solvent is methanol.

53. The preparation method according to claim 2, characterized in that: Based on the usage of 1 mol of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride in step (1), the usage of the solvent is 600 to 3000 g.

54. The preparation method according to claim 2, characterized in that: The temperature of the hydrolysis reaction in step (3) is 20 to 60°C.

55. The preparation method according to claim 54, characterized in that: The temperature of the hydrolysis reaction in step (3) is 30-40°C.

56. The preparation method according to claim 2, characterized in that: The hydrolysis reaction time in step (3) is 0.5 to 5 hours.

57. The preparation method according to claim 56, characterized in that The hydrolysis reaction time in step (3) is 1 to 2 hours.

58. The preparation method according to claim 2, characterized in that: After the hydrolysis reaction in step (3) is completed, the product is further treated.

59. The preparation method according to claim 58, characterized in that The post-treatment includes recrystallization or desolvation followed by recrystallization.

60. The preparation method according to claim 59, characterized in that: The recrystallization reagents include methanol, ethanol and alcohol aqueous solution.

61. The preparation method according to claim 59, characterized in that: The recrystallization temperature is -5 to 10°C.

62. The preparation method according to claim 61, characterized in that The recrystallization temperature is 0-5°C.

63. The preparation method according to claim 2, characterized in that: The preparation method specifically comprises the following steps: (1) First, a solvent, an acid-binding agent and a compound of formula I are placed in a reaction kettle, 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is added dropwise to the reaction system at -15 to 60°C within 0.5 to 3 hours for a condensation reaction, and then the reaction is kept at -15 to 60°C for 2 to 6 hours to obtain a crude product, which is directly used for the synthesis of the compound of formula III without treatment; wherein the acid-binding agent and 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride are added dropwise to the reaction system for a condensation reaction within 0.5 to 3 hours. The molar ratio of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is (1.05-1.5):1; the molar ratio of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride to the 1,3-cyclohexanedione compound shown in formula I is 1:(1.0-1.5); based on the amount of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride being 1 mol, the amount of the solvent used is 900-2400 mL; (2) placing a solvent, a compound of formula II, an auxiliary agent and a catalyst into a reaction kettle, and reacting at 5 to 60° C. for 3 to 15 hours to obtain a crude product of a compound of formula III, and acidifying, layering, washing with water and desolventizing to obtain a compound of formula III; the molar ratio of the auxiliary agent to 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is (1.05 to 1.5):1; based on the amount of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride being 1 mol, the amount of the transposition catalyst being 1 to 50 g; based on the amount of the 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride being 1 mol, the amount of the solvent being 900 to 2400 g; (3) placing a solvent, a compound of formula III, an auxiliary agent and a catalyst into a reaction kettle, keeping the temperature at 20 to 60° C. for a reaction for 0.5 to 5 hours, and obtaining a compound of formula IV by crystallization or crystallization after desolvation; the molar ratio of the auxiliary agent to 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is (1 to 10):1; the molar ratio of the catalyst to 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride is (0.2 to 10):1; based on the amount of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoyl chloride being 1 mol, the amount of the solvent is 600 to 3000 g.

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