A method for preparing a topramezone metabolite T319

Abstract

The present application relates to a preparation method of a metabolite T319 of carfentrazone-ethyl, and belongs to the technical field of pesticides. The preparation method comprises the following steps: reacting a compound of formula I with liquid alkali to generate a compound of formula II, and then after separation and purification, the compound of formula II is reacted with a compound of formula III to generate a compound of formula IV. The raw material of the preparation method is easy to obtain, and no toxic raw material is needed. The steps are simple, the operation is convenient, the experimental process is controllable, no harsh reaction environment is needed, the conditions are mild, the process is easy to realize, the preparation of the metabolite of carfentrazone-ethyl is realized in large quantities, and the sample quantity demand of pesticide registration can be fully met.

Description

Technical Field

[0001] This invention relates to the technical field of pesticides, specifically to a method for preparing the benzoxazine metabolite T319. Background Technology

[0002] Topramezone is a novel pyrazoline ketone post-emergence foliar herbicide developed by the European company BASF. It has many trade names, including Convey, Impact, Clio, and Baowei. Topramezone is primarily used to control weeds in corn fields, such as broadleaf and grass weeds. As a broad-spectrum biologically active compound, topramezone exhibits excellent control effects against a variety of weeds, including Cyperus difformis, Setaria viridis, Barnyardgrass, Cyperus rotundus, Eleusine indica, Ragweed, Matricaria champaca, and Chenopodium album. The mechanism of action of topramezone involves forming a complex with the iron ion at the active center of HPPD (Hyperhydropyruvic acid), thus neutralizing its catalytic activity. This effectively inhibits the biosynthesis of hydroxyphenylpyruvic acid (HPP) to homogentisic acid (HGA), thereby inhibiting the synthesis of plastoquinones and tocopherols, and indirectly hindering carotenoid synthesis and chloroplast photosynthesis, ultimately leading to weed bleaching and death. Benzoflubenzuron exhibits high safety for corn and low toxicity to mammals. It degrades into non-toxic products under high temperature and ultraviolet light, eliminating concerns about pesticide residues in the environment after application. It possesses promising market prospects. Currently, pesticide registration is a crucial task for pesticide companies, representing the foundation for their development and the most effective way to gain core competitiveness. Therefore, the preparation of large quantities of benzoflubenzuron metabolites for toxicological studies has become a top priority for many researchers.

[0003] The chemical name of benzoxazine metabolite T319 is 4-[2-methyl-3-cyano-4-methylsulfonyl]-1-methyl-5-hydroxy-1H-pyrazole. Because it requires the introduction of a cyano group, the current mainstream route uses cyanide as a raw material to undergo a substitution reaction on the benzene ring. The synthetic route is complex, and the reagents used are dangerous and highly toxic, making it unsuitable for large-scale preparation. Summary of the Invention

[0004] To address the problems of high toxicity of raw materials and the inability to produce large quantities in existing methods for synthesizing benzoxazine metabolite T319, this invention provides a method for preparing benzoxazine metabolite T319 to solve these problems. This invention uses oxime compounds as starting materials, avoiding the use of highly toxic cyanides, and the process is easy to implement.

[0005] The technical solution of this invention is as follows: A method for preparing the benzoxazine metabolite T319, the reaction formula is as follows: ; Compound I reacts with liquid alkali to produce compound II, which, after separation and purification, reacts with compound III to produce compound IV. The specific method is as follows: (1) Dissolve the compound of formula I in organic solvent I, add alkali, heat to 20~70℃ and keep the temperature for 1~8h; after the reaction is completed, separate the liquid and extract the aqueous phase once with organic solvent, and combine the organic phases; wash the organic phase with hydrochloric acid and water in sequence, then evaporate the solvent and add methanol to crystallize; filter and use methanol to purify to obtain the compound of formula II. (2) Take the compound of formula II and compound of formula III prepared in step (1), add organic solvent II and acid binder, stir evenly, add condensing agent, heat to 10~80℃, keep warm; after the reaction is completed, add water to wash, concentrate the organic phase and add methanol to crystallize, to obtain compound of formula IV.

[0006] Furthermore, in step (1), the organic solvent is at least one of 1,2-dichloroethane, toluene, or benzene.

[0007] Furthermore, based on the compound of formula I, the amount of organic solvent I is 2~5 g / g.

[0008] Furthermore, in step (1), the base is at least one of sodium methoxide, sodium ethoxide, potassium carbonate, triethylamine, pyridine, and sodium hydroxide.

[0009] Furthermore, in step (1), the amount of base used is 0.5~3 mol / mol, preferably 0.5~2 mol / mol, based on the compound of formula I.

[0010] Furthermore, in step (2), the amount of compound III is 1.1~1.5 mol / mol, based on compound II.

[0011] Furthermore, in step (2), the condensing agent is at least one of sulfonyl chloride, methanesulfonyl chloride, thionyl chloride, and N,N'-carbonyldiimidazole.

[0012] Furthermore, in step (2), the organic solvent is at least one of benzene, toluene, acetonitrile, tetrahydrofuran, 1,2-dichloroethane, and 1,2-dioxane.

[0013] Furthermore, in step (2), the amount of organic solvent II used is 2~4 g / g, based on compound II.

[0014] Furthermore, in step (2), the acid-binding agent is at least one of sodium methoxide, sodium ethoxide, potassium carbonate, triethylamine, and pyridine.

[0015] Furthermore, in step (2), the amount of condensing agent used is 1~3 mol / mol, based on compound II.

[0016] The beneficial effects of this invention are as follows: The method for preparing benzoxazine metabolite T319 provided by this invention can ultimately obtain a product with a purity ≥97.5%. The raw materials used in this preparation method are readily available and do not require the use of highly toxic materials. The steps are simple, the operation is convenient, the experimental process is controllable, no harsh reaction environment is required, the conditions are mild, and the process is easy to implement, enabling the large-scale preparation of benzoxazine metabolites, which can fully meet the sample quantity requirements for pesticide registration. Attached Figure Description

[0017] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0018] Figure 1 It is the compound of formula IV in Example 1 of this invention. 1 HNMR spectrum.

[0019] Figure 2 It is the compound of formula IV in Example 1 of this invention. 13 CNMR spectrum.

[0020] Figure 3 This is the HPLC chromatogram of compound IV from Example 1 of the present invention. Detailed Implementation

[0021] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions of the embodiments of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this invention.

[0022] Example 1 A method for preparing the benzoxazine metabolite T319 is as follows: (1) Dissolve 50g (0.19mol) of compound I in 100g of 1,2-dichloroethane, add 15g (0.11mol) of 30% alkali solution, heat to 65℃, and keep warm for 4h; after the reaction is completed, separate the liquids, and the upper layer is the organic phase. According to the observation of the experimental phenomena and the TLC analysis results, the sodium carboxylate product generated by the reaction is mainly soluble in the organic phase. The main reasons are as follows: 1. The amount of water in the reaction system is small, which reduces the solubility of sodium carboxylate; 2. The amount of alkali in the water is large, which further reduces the solubility of sodium carboxylate; 3. The sodium carboxylate prepared in this invention is different from sodium benzoate, and the benzene ring contains other hydrophobic groups, which affects the water solubility of the entire structure. The organic phase was washed once with 70g of water, and the aqueous phase was washed once with 50g of 1,2-dichloroethane. The organic phases were combined. The organic phase was washed twice with 100g of 10% hydrochloric acid solution and twice with 100g of water. The organic phase was then concentrated under reduced pressure until no distillate was obtained. A small amount of methanol was added to disperse the solid, and the solid was allowed to precipitate overnight. The solid was filtered, washed with a small amount of methanol, and dried to obtain 42.55g of pink solid (compound of formula II) with a purity of 97.2% and a yield of 90.8%.

[0023] (2) Take 40g (0.16mol) of compound II and 17.9g (0.18mol) of compound III prepared in step (1), add 100g of 1,2-dichloroethane and 55.3g (0.40mol) of potassium carbonate, stir evenly, and then add 22.0g (0.19mol) of methanesulfonyl chloride dropwise. Control the temperature at 50℃ and keep warm for 1h after the addition is complete. After the reaction is complete, add 100g of water to wash three times, then concentrate under negative pressure to near dryness, add 100g of methanol to cool and precipitate, filter, wash with a small amount of methanol to obtain 45.9g of yellow solid (compound IV), with a content of 97.8% and a yield of 88.2%.

[0024] For detailed HNMR, CNMR and HPLC spectra of compound IV, please refer to [link to relevant documentation]. Figures 1-3 .

[0025] 1 H NMR (500 MHz, Chloroform-d) δ 8.05 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 3.54 (s, 3H), 3.42 (s, 3H), 2.51 (s, 3H).

[0026] 13C NMR (500 MHz, Chloroform-d) δ 186.42, 155.07, 145.24, 142.81, 141.90, 139.90, 131.20, 126.91, 114.43, 111.15, 104.89, 42.78, 32.96, 17.99.

[0027] The HPLC detection data are shown in Table 1 below.

[0028] Table 1. HPLC detection results of compound IV Example 2 A method for preparing the benzoxazine metabolite T319 is as follows: (1) Dissolve 50g (0.19mol) of compound I in 150g of toluene, add 65.8g (0.14mol) of 30% potassium carbonate aqueous solution, heat to 70℃ and keep warm for 6h; after the reaction is completed, separate the liquid and liquid. The upper layer is the organic phase. Wash the organic phase once with 100g of water. Wash the organic phase twice with 100g of 10% hydrochloric acid aqueous solution and twice with 100g of water. Then concentrate the organic phase under reduced pressure to remove about 1 / 3 of the solvent. Let it stand overnight to precipitate solid. Filter, wash with a small amount of methanol, and dry to obtain 43.61g of pink solid (compound II) with a content of 96.1% and a yield of 92.0%.

[0029] (2) Take 40g (0.16mol) of compound II and 24.0g (0.24mol) of compound III prepared in step (1), add 112g of toluene and 35.6g (0.35mol) of triethylamine, stir evenly, and then add 29.1g (0.24mol) of thionyl chloride dropwise. Control the temperature at 30℃ and keep warm for 1.5h after the addition is complete. After the reaction is complete, add 100g of water to wash three times, then concentrate under negative pressure to near dryness, add 100g of methanol to cool and precipitate, filter, wash with a small amount of methanol to obtain 44.2g of yellow solid (compound IV), with a content of 97.7% and a yield of 84.5%.

[0030] Example 3 A method for preparing the benzoxazine metabolite T319 is as follows: (1) Dissolve 50g (0.19mol) of compound I in 100g of 1,2-dichloroethane, add 22.7g (0.17mol) of 30% alkali solution, heat to 40℃ and keep warm for 4h; after the reaction is completed, separate the liquids, the upper layer is the organic phase, wash the organic phase once with 70g of water and the aqueous phase once with 50g of 1,2-dichloroethane, and combine the organic phases; wash the organic phase twice with 100g of 10% hydrochloric acid aqueous solution and twice with 100g of water, then concentrate the organic phase under reduced pressure until no distillate is produced, add a small amount of methanol to disperse, let stand overnight to precipitate solid, filter, wash with a small amount of methanol, dry to obtain 43.90g of pink solid (compound II), with a content of 98.1% and a yield of 94.7%.

[0031] (2) Take 40g (0.16mol) of compound II, 120g of acetonitrile, 47.0g (0.29mol) of N,N'-carbonyldiimidazole and 16.6g (0.21mol) of pyridine prepared in step (1), stir evenly, dissolve 22.02g (0.22mol) of compound III in 40g of acetonitrile and add it dropwise, control the temperature at 20℃, and keep it at the temperature for 4h after the addition is completed; concentrate under negative pressure to near dryness, add 50g of methanol and 50g of water respectively, then add a small amount of hydrochloric acid to adjust pH <2, cool down to crystallize and precipitate, and obtain 40.5g of yellow solid (compound IV) with a content of 97.0% and a yield of 76.9%.

[0032] Although the present invention has been described in detail with reference to the accompanying drawings and preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made to the embodiments of the present invention by those skilled in the art without departing from the spirit and essence of the invention, and such modifications or substitutions should all be within the scope of the present invention. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should also be covered within the protection scope of the present invention.

Claims

1. A method for preparing the benzoxazine metabolite T319, characterized in that, The reaction formula is as follows: ； The specific method is as follows: (1) Dissolve the compound of formula I in organic solvent I, add alkali, heat to 20~70℃ and keep the temperature for 1~8h; after the reaction is completed, separate the liquid and extract the aqueous phase once with organic solvent, and combine the organic phases; wash the organic phase with hydrochloric acid and water in sequence, then evaporate the solvent and add methanol to crystallize; filter and use methanol to purify to obtain the compound of formula II. (2) Take the compound of formula II and compound of formula III prepared in step (1), add organic solvent II and acid-binding agent, stir evenly, add condensing agent, heat to 10~80℃ and keep warm; after the reaction is completed, add water to wash, concentrate the organic phase and add methanol to crystallize, to obtain compound of formula IV. In step (1), the base is at least one of potassium carbonate or sodium hydroxide; In step (2), the acid-binding agent is at least one of potassium carbonate, triethylamine or pyridine; the condensing agent is at least one of methanesulfonyl chloride, thionyl chloride or N,N'-carbonyldiimidazole.

2. The preparation method according to claim 1, characterized in that, In step (1), the organic solvent is at least one of 1,2-dichloroethane, toluene, or benzene.

3. The preparation method according to claim 1, characterized in that, In step (1), the amount of base used is 0.5~3 mol / mol, based on the compound of formula I.

4. The preparation method according to claim 1, characterized in that, In step (2), the amount of compound III is 1.1~1.5 mol / mol, based on compound II.

5. The preparation method according to claim 1, characterized in that, In step (2), the organic solvent is at least one of benzene, toluene, acetonitrile, tetrahydrofuran, 1,2-dichloroethane, and 1,2-dioxane.

6. The preparation method according to claim 1, characterized in that, In step (2), the amount of organic solvent II is 2~4 g / g, calculated based on compound II.

7. The preparation method according to claim 1, characterized in that, In step (2), the amount of condensing agent used is 1~3 mol / mol, based on compound II.

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