Preparation method of sulfentrazone intermediate

Abstract

The invention discloses a preparation method of a sulfentrazone intermediate, which comprises the following step: in a solvent, carrying out substitution ring closing reaction on a cis-trans isomer compound (nitrohydrazone) as shown in a formula II and cyanate to generate the sulfentrazone intermediate as shown in a formula III. According to the scheme provided by the invention, the problems that a large amount of solid waste is generated and the atom economy is low due to the fact that a large amount of inorganic reducing agents such as sodium sulfite are used in the production of the raw material phenylhydrazine in the process of preparing the triazolinone from the phenylhydrazine in the prior art are solved; the method solves the problem that a large amount of mixed salt is generated due to the fact that a large amount of sulfite reducing agent and sodium hypochlorite oxidizing agent are used in the production of the raw material phenylhydrazine in the process of preparing triazolinone from phenylhydrazine in the prior art, and also solves the problem of low chlorination selectivity of sulfentrazone prepared from phenylhydrazine as the raw material. The problems that diazonium salt is reduced into hydrazine and hydrazine is oxidized into hydrazine are solved; according to the method, intermediate-state hydrazine is directly utilized, and then cyanate is utilized for ring closing, so that compared with the prior art, three steps are shortened, and the energy consumption and the labor intensity are greatly reduced.

Description

Technical Field

[0001] The invention relates to the field of pesticides, and in particular to a method for preparing a sulfentrazone intermediate. Background Art

[0002] Sulfonamide, also known as sulfentrazone, was developed by FMC in 1985 and launched on the market in 1996. It is a triazolinone herbicide and a protoporphyrinogen oxidase inhibitor. It is mainly used in sugarcane, soybean and sunflower fields before sowing and before seedlings to control annual broadleaf weeds, grass weeds and sedges.

[0003] At present, the key intermediate III for synthesizing sulfentrazone is usually prepared by seven steps of reaction from aromatic amine I as the starting material. The existing process is as follows:

[0004] Taking 2,4-dichloroaniline as an example: CN106565532A reports a method for synthesizing 2,4-dichlorophenylhydrazine hydrochloride from 2,4-dichloroaniline, with a three-step yield of 90% (i.e., the first three steps of the following reaction route); the preparation of hydrazine requires 3eq of potassium bisulfite, which produces a large amount of cations (including potassium and sodium) and a large amount of anions (including chloride, nitrite, sulfite, sulfate, and bisulfate), forming a large amount of mixed salts, which makes it impossible to recycle solid waste; The Chemical Reaction Engineering and Technology, Vol. 25, No. 5, October 2012, P412-417, reported a method for preparing intermediate IIIa from 2,4-dichlorophenylhydrazine hydrochloride, with a yield of 88.43% (=99%×89.32%) in four steps (i.e., the last 4 steps of the following reaction route), but the defect of this method is that the diazonium salt needs to be excessively reduced to hydrazine, and then oxidized back with hypochlorous acid, resulting in mixed salts of sodium hypochlorite and sodium chloride. These multi-component waste salts are almost difficult to recycle. That is, the total yield of the seven-step reaction route of performing the first 3 steps according to CN106565532A and the first 4 steps according to Chemical Reaction Engineering and Technology is about 79.6%, and a large amount of mixed salts will be produced, making it difficult to recycle and greatly increasing the cost of post-processing. The reaction route is as follows:

[0005]

[0006] Similarly, 4-chloroaniline is used as a raw material to synthesize intermediate IIIb, see patents CN101928246A and CN107629015A. This method also produces a large amount of mixed inorganic salts, which are difficult to recycle, have high costs for three wastes treatment, and poor atom economy; on the other hand, this route is lengthy and inefficient.

[0007] However, the above process route uses a large amount of inorganic reducing agents such as sodium sulfite, which will produce a large amount of mixed inorganic salts (such as mixed salts of sulfite, sulfate, bisulfate, etc., and mixed salts of sodium hypochlorite and sodium chloride). Since the mixed inorganic salts are difficult to separate and recycle, the cost of three wastes treatment is high and the atom economy is poor; on the other hand, the reduction of the diazonium salt in this route needs to be reduced to hydrazine, and hydrazine is further reduced to hydrazine, and finally oxidized back to hydrazine, which means that the route is lengthy and inefficient. Summary of the invention

[0008] Purpose of the Invention

[0009] In order to overcome the above-mentioned shortcomings, the purpose of the present invention is to provide a method for preparing a sulfentrazone intermediate which reduces solid waste emissions and is green and environmentally friendly. The present invention adopts a method of converting a diazonium salt into a hydrazone intermediate state, avoiding the scheme of excessive reduction and then oxidation, and further utilizing cyanate ring closure, which not only reduces the number of operating steps, but also reduces solid waste emissions (a large reduction in inorganic salts), making the production process of sulfentrazone intermediate III simple and efficient, and easy to produce sulfentrazone intermediate III on a large scale.

[0010] Solution

[0011] To achieve the purpose of the present invention, the technical solution adopted by the present invention is as follows:

[0012] In a first aspect, the present invention provides a method for preparing a sulfentrazone intermediate represented by formula III, comprising:

[0013] Step 1: Under acidic conditions, the aromatic amine shown in formula I reacts with nitrite to generate a diazonium salt product; the diazonium salt product is added to an alkaline system containing nitroethane to generate a sulfentrazone intermediate shown in formula II;

[0014] Step 2: In a solvent, the cis-trans isomer compound (nitrohydrazone) shown in formula II undergoes a substitution ring-closing reaction with cyanate to generate the sulfentrazone intermediate shown in formula III. The reaction route is as follows:

[0015]

[0016] Wherein, X is Cl or H; M is Na or K.

[0017] In a second aspect, a method for preparing a sulfentrazone intermediate represented by formula III is provided, comprising the following steps:

[0018] 1) Under acidic conditions, the substituted aromatic amine shown in formula I reacts with nitrite to form a diazonium salt;

[0019] 2) Adding a diazonium salt to an alkaline system containing nitroethane to generate a nitrohydrazone;

[0020] 3) Nitrohydrazone and cyanate undergo substitution ring-closing reaction to generate the sulfentrazone intermediate shown in formula III;

[0021]

[0022] Wherein, X is Cl or H; M is Na or K.

[0023] In the first aspect or the second aspect, in the ring-closure reaction, the cyanate is sodium cyanate and / or potassium cyanate.

[0024] In the first aspect or the second aspect, in the ring-closing reaction, the molar ratio of the cis-trans isomer compound shown in formula II to the cyanate is 1:(1-2), optionally 1:(1-1.2), optionally 1:(1.05-1.1). Too high a molar ratio will produce side reactions.

[0025] In the first aspect or the second aspect above, in the ring-closing reaction, the solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, alcohols, and acetonitrile; optionally, the alcohols are selected from C1 to C6 low-carbon alcohols.

[0026] In the first aspect or the second aspect above, in the ring-closing reaction, when X is Cl (the compound of formula II is 2,4-dichloronitrohydrazone), the solvent is alcohols, DMF, acetonitrile, and optionally, the alcohol includes one or more of methanol, ethanol, propanol, n-butanol, isopropanol, sec-butanol, tert-butanol, and pentanol; preferably, the solvent is n-butanol; 2,4-dichloronitrohydrazone has relatively good stability and can withstand higher reaction temperatures. The selectable solvents are alcohols, DMF, and acetonitrile, but alcohols are preferred, preferably butanol.

[0027] In the first aspect or the second aspect, in the ring-closing reaction, when X is H (the compound of formula II is 4-chlorophenyl nitrohydrazone), the solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and acetonitrile; optionally, the solvent is N,N-dimethylformamide and / or acetonitrile. 4-Chlorophenyl nitrohydrazone has good stability and reaction selectivity in acetonitrile.

[0028] Furthermore, in the ring-closure reaction, the ring-closure reaction temperature is 20 to 80°C.

[0029] In the first aspect or the second aspect above, in the ring-closing reaction, when X is Cl, the compound of formula I is 2,4-dichloroaniline; the compound of formula II generated is recorded as IIa, which has two isomers, Z and E. For IIa, due to the steric hindrance effect of the adjacent chlorine atom, the E-isomer is mainly present, and the molar ratio of Z-isomer:E-isomer is about 1:5.

[0030]

[0031] In the first aspect or the second aspect above, when X is H, the compound of formula I is 4-chloroaniline; the compound of formula II generated is recorded as IIb, which also has two isomers, Z and E. For IIb, due to the low hydrogen bond energy within the molecule, the Z-isomer is mainly formed, and the molar ratio of Z-isomer: E-isomer is about 3:1. The different configurations have an important influence on the subsequent ring-closing reaction.

[0032] The ring-closing reaction of sodium cyanide on nitrohydrazone is relatively complicated, and the steric hindrance of the 2-position substituent has a greater impact. Under the same room temperature conditions, Ⅱb is much easier than Ⅱa, so the ring-closing of Ⅱa requires a higher reaction temperature than Ⅱb; on the other hand, the configuration of intermediate Ⅱ may have a greater impact on the reaction. For nitrohydrazone, the ratio of Z-form to E-form of Ⅱa is about 1:5, and the ratio of Z-form to E-form of Ⅱb is about 3:1. For the Z-form structure, a reaction similar to SN1 may occur to generate intermediate M, and then the intramolecular ring closure obtains Ⅲb; however, for the E-form isomer, N is generated, which obviously requires a higher reaction activation energy, that is, heating is required to flip the configuration to complete the ring-closing reaction, and during the reaction, we detected the presence of intermediate isocyanate by liquid chromatography-mass spectrometry, and it is speculated that it should be trans-N.

[0033]

[0034] According to Examples 14 to 16, the reaction results are better at room temperature (generally 25°C), but 4-chloronitrohydrazone is also unstable at room temperature and is easy to decompose and release nitrogen and is sensitive to water vapor and temperature. At higher temperatures, the raw materials decompose faster and the selectivity of the reaction becomes worse. The main reason is that nitrite is generated during the reaction, and nitrohydrazone is a reducing agent. The generated by-product nitrite oxidizes the raw material II; if the reaction time is prolonged, sodium nitrite will also oxidize the ring-closed product, causing the product to become complicated.

[0035] Optionally, in the ring-closing reaction, when X is Cl, the ring-closing reaction temperature is 40 to 80°C, optionally 55 to 65°C, optionally 60 to 65°C;

[0036] Optionally, in the ring-closing reaction, when X is H, 4-chlorophenyl nitrohydrazone is highly sensitive to the reaction temperature. The decomposition of the raw material is accelerated at high temperature, and the reaction rate is slow at low temperature. Prolonging the reaction time will cause the product to be oxidized due to the presence of nitrite, thereby reducing the yield. Therefore, the ring-closing reaction temperature is 20 to 60°C, optionally 20 to 40°C, optionally 20 to 30°C, and optionally 25 to 30°C.

[0037] In terms of substrate selection, 4-chlorophenylnitrohydrazone (Ⅱb) is better than 2,4-dichloronitrohydrazone (Ⅱa). The main reason is that the presence of 2-chloro in 2,4-dichloronitrohydrazone has a significant steric hindrance effect, making the ring-closure reaction and subsequent fluoromethylation reaction more difficult.

[0038] Considering that the nitrohydrazone and the intermediates M and N can be stabilized by the coordination of metal ions, and the decomposition of nitrohydrazone can be alleviated, a coordination metal salt is also added to the reaction system during the ring-closing reaction. Optionally, the coordination metal salt is a halogenated salt. Optionally, the coordination metal salt is selected from lithium chloride and / or zinc chloride. Adding a small amount of coordination metal salt has a certain inhibitory effect on the decomposition of the substrate. Taking lithium chloride as an example, see the following formula:

[0039]

[0040] In the first aspect or the second aspect, in the alkaline system containing nitroethane, the pH value at the reaction end point is controlled to be 7 to 9, and optionally 7 to 8.

[0041] Optionally, in the alkaline system containing nitroethane, the amount of alkaline substance added is such that the pH value of the reaction system at the end point is maintained at 6 to 9; preferably 7 to 8.

[0042] If the pH value is less than 7, the generated nitroethane anion is easily quenched, so the yield is low; if the pH value is greater than 8, the diazonium salt is unstable, which will also cause a low yield. As the diazonium salt is continuously added to the reaction system, a sodium bicarbonate-carbonic acid buffer system is formed. It has been found that when the end point pH value is controlled between 7 and 8, the reaction is best and a very high yield can be achieved.

[0043] Therefore, a high yield can be obtained when the amount and type of alkaline substance added can make the pH value of the reaction end point between 7 and 8. It should be noted that the pH value of the acetic acid-acetate system is about 5 regardless of the amount of acetate (sodium acetate or potassium acetate) used in the literature, which makes the nitroethane anion return to the free state, resulting in a low yield.

[0044] In the alkaline system containing nitroethane, the alkaline substance includes an inorganic strong base and a weak acid strong base salt. The inorganic strong base is used to make nitroethane form negative ions (the main function of the strong base is to extract hydrogen), and the weak acid strong base salt is used to form an alkaline buffer system, which is used to control the pH in the reaction at a relatively stable level and make the end point pH between 7 and 8.

[0045] Optionally, the weak acid and strong base salt is an alkali metal weak acid salt; Optionally, the alkali metal weak acid salt is one or both of carbonate and bicarbonate; Optionally, the alkali metal weak acid salt is one or both of alkali metal carbonate and alkali metal bicarbonate; Optionally, the inorganic strong base includes an alkali metal hydroxide, and the alkali metal hydroxide is optionally selected from sodium hydroxide and / or potassium hydroxide; Optionally, the alkali metal weak acid salt is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate;

[0046] Optionally, the molar ratio of the inorganic strong base to nitroethane is (1.1-1.5):1, optionally (1.2-1.5):1;

[0047] Optionally, the molar ratio of the substituted aromatic amine shown in Formula I to nitroethane is 1:(1-2), preferably 1:(1-1.5), and more preferably 1:(1.1-1.2);

[0048] Alternatively, when the alkali metal weak acid salt is an alkali metal carbonate, the OH - The molar ratio of the alkali metal carbonate is 1:(0.6-1.01), optionally 1:(0.8-1.01), optionally 1:(0.9-1.01);

[0049] Optionally, when the alkali metal acid salt is an alkali metal bicarbonate, the OH - The molar ratio of X to alkali metal bicarbonate is 1:(1-2.02); optionally, when X is Cl, OH in the inorganic strong base - The molar ratio of the inorganic strong base to the alkali metal bicarbonate is 1:(1.2-2.02), optionally 1:(1.8-2.02); optionally, when X is H, the OH in the inorganic strong base is - The molar ratio with alkali metal bicarbonate is 1:1:(1-2.02);

[0050] And / or, the substituted aromatic amine shown in formula I reacts with OH in an inorganic strong base - The molar ratio is 1:(1.1-2), optionally 1:

[0051] (1.3~1.8), optionally 1:(1.3~1.5).

[0052] Further, in the diazonium salt reaction, the substituted aromatic amine shown in Formula I, the H + , the molar ratio of nitrite is 1:

[0053] (3-5):(1-2), preferably 1:(3.5-4.5):(1-1.2), optionally 1:(3-4):1.05, more preferably 1:4:1.05; optionally, the substituted aromatic amine represented by formula I is a free amine;

[0054] Alternatively, in the diazonium salt reaction, the substituted aromatic amine shown in Formula I, the H + , the molar ratio of nitrite is 1:

[0055] (2-4):(1-2), preferably 1:(2.5-3.5):1:1.2, more preferably 1:3:1.05; Optionally, the substituted aromatic amine represented by formula I is an ammonium salt;

[0056] Optionally, in the diazonium salt reaction, the nitrite is selected from sodium nitrite and potassium nitrite;

[0057] Optionally, in the diazonium salt reaction, the acid used in the diazotization reaction is a protonic acid, and the protonic acid is optionally selected from an inorganic strong acid, and preferably the inorganic strong acid is selected from HCl, H 2 SO 4 .

[0058] Furthermore, the reaction temperature of the diazonium salt and nitroethane is 0-40°C.

[0059] Optionally, when X is Cl, the reaction temperature of the diazonium salt and nitroethane is 0 to 40°C, optionally 20 to 35°C; 2,4-dichlorophenyl diazonium salt has relatively high stability and better tolerance to temperature. For aromatic diazonium salts, the more electron-withdrawing groups on the benzene ring, the more stable the diazonium salt.

[0060] Optionally, when X is H, the reaction temperature of the diazonium salt and nitroethane is 0 to 15°C, and optionally 5 to 15°C. When 4-chloroaniline is used to prepare IIb, the diazonium salt may be unstable and easy to decompose under higher temperature conditions; but if the temperature is too low, the reaction rate is slow, and the diazonium salt is unstable and easy to decompose into free radicals to further react with nitrohydrazone. When the temperature is 0 to 15°C, the yield is higher, especially when the temperature is controlled at 5 to 10°C. The possible reason is that 4-chlorophenyl diazonium salt is both stable and has a higher reaction rate in this temperature range.

[0061] The reaction route for preparing the sulfentrazone intermediate of formula III using the substituted aromatic amine of formula I is as follows:

[0062]

[0063] Beneficial Effects

[0064] The solution provided by the present invention solves the problem that a large amount of inorganic reducing agents such as sodium sulfite is used in the production of raw material phenylhydrazine in the preparation of triazolinone by phenylhydrazine in the prior art (generally, 3 to 4 equivalents of sodium sulfite are required for the generation of diazonium salt in the prior art), a large amount of solid waste is generated, and the atom economy is low; the problem that a large amount of mixed salts are generated in the production of raw material phenylhydrazine in the preparation of triazolinone by phenylhydrazine in the prior art using a large amount of sulfite reducing agent and sodium hypochlorite oxidant is used; in the process of forming hydrazone from diazonium salt, the inorganic salts generated by the present invention are mainly sodium chloride, sodium carbonate and sodium bicarbonate, which can be converted into single sodium chloride by hydrochloric acid treatment, and can be easily recycled, and the excess of sodium nitrite is very small and can be almost ignored, that is, the inorganic salts in the reaction route of the present invention can be recycled, which is superior to the traditional technology; at the same time, the problem of low chlorination selectivity of sulfentrazone prepared by using phenylhydrazine as raw material is solved, and the problem of reducing diazonium salt to hydrazine and oxidizing hydrazine to hydrazine is solved; the present invention directly utilizes intermediate hydrazine and then utilizes cyanate to close the ring, which shortens 3 steps compared with the prior art, greatly reduces energy consumption and labor intensity, and has a good application prospect. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] One or more embodiments are exemplarily described by the pictures in the accompanying drawings, and these exemplary descriptions do not constitute limitations on the embodiments. The special word "exemplary" here means "used as an example, embodiment or illustrative". Any embodiment described as "exemplary" here is not necessarily interpreted as being superior or better than other embodiments.

[0066] Figure 1 This is the H NMR spectrum of (E)-1-(2,4-dichlorophenyl)-2-(1-nitroethylidene)hydrazine of Example 3 of the present invention.

[0067] Figure 2 for Figure 1 A magnified portion of the H NMR spectrum.

[0068] Figure 3 This is the hydrogen NMR spectrum of (Z)-1-(2,4-dichlorophenyl)-2-(1-nitroethylidene)hydrazine of Example 3 of the present invention.

[0069] Figure 4 This is the hydrogen NMR spectrum of 1,1-bis(4-chlorophenyl)-2-(1-nitroethylidene)hydrazine of Example 6 of the present invention.

[0070] Figure 5 This is the H NMR spectrum of (E)-1-(4-chlorophenyl)-2-(1-nitroethylidene)hydrazine of Example 8 of the present invention.

[0071] Figure 6 This is the hydrogen NMR spectrum of (Z)-1-(4-chlorophenyl)-2-(1-nitroethylidene)hydrazine of Example 8 of the present invention.

[0072] Figure 7 This is the relationship between the dropping temperature of the 4-chlorophenyldiazonium salt of the present invention and the temperature.

[0073] Figure 8 This is the hydrogen NMR spectrum of 2-(4-chlorophenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one of Example 17 of the present invention. DETAILED DESCRIPTION

[0074] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0075] In addition, in order to better illustrate the present invention, numerous specific details are provided in the specific embodiments below. It should be understood by those skilled in the art that the present invention can be implemented without certain specific details. In some embodiments, raw materials, schemes, methods, means, etc. well known to those skilled in the art are not described in detail, so as to highlight the main purpose of the present invention.

[0076] Unless explicitly stated otherwise, throughout the specification and claims, the term “comprise” or variations such as “include” or “comprising”, etc., will be understood to include the stated elements or components but not to exclude other elements or components.

[0077] The product contents in the following examples were confirmed by liquid or gas chromatography, the reaction process was tracked by the area normalization method, and the selectivity of some reactions was determined by the reaction system area normalization method.

[0078] LCMS: Liquid chromatography mass spectrometry, liquid quality.

[0079] GCMS: Gas chromatography mass spectrometry, temperament.

[0080] HPLC: High Performance Liquid Chromatography, high pressure liquid chromatography.

[0081] GC: Gas chromatography.

[0082] NMR: Nuclear magnetic resonance spectrometry.

[0083] 2,4-dichloroaniline, 4-chloroaniline and other reagents in the following examples are commercially available; if not otherwise specified, the reaction process and results were detected by high performance liquid chromatography (HPLC), and the purity and selectivity were determined by normalization.

[0084] The preparation method of the sulfentrazone intermediate 2-(2,4-dichlorophenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (IIIa) and 2-(4-chlorophenyl)-5-methyl-2,4-dihydro-3H-1,2,4-oxazol-3-one (IIIb) shown in formula III of the present invention has the following reaction scheme:

[0085]

[0086] 1. Preparation of (E)-1-(2,4-dichlorophenyl)-2-(1-nitroethylidene)hydrazine and (Z)-1-(2,4-dichlorophenyl)-2-(1-nitroethylidene)hydrazine (Intermediate IIa) (i.e., 2,4-dichlorophenyl nitrohydrazone)

[0087] The Japp-Klingemann reaction is a hydrazone synthesis reaction, in which an aromatic diazonium salt is coupled with an enol isomer of an active methylene compound under the catalysis of an alkaline medium to generate an aromatic hydrazone compound. Among them, sodium acetate / sodium hydroxide as an alkaline medium catalyst is considered to be a preferred combination. However, when the inventors used sodium acetate / sodium hydroxide as an alkaline medium for verification, they found that there were more side reactions, resulting in low yield, purity and yield, as shown in Example 1.

[0088] Example 1

[0089] Preparation of (E)-1-(2,4-dichlorophenyl)-2-(1-nitroethylidene)hydrazine and (Z)-1-(2,4-dichlorophenyl)-2-(1-nitroethylidene)hydrazine (Intermediate IIa), specifically:

[0090] 1) 2,4-dichloroaniline (5.0 g, 30.86 mmol) was suspended in 29.08 g of a hydrochloric acid aqueous solution (wherein the hydrochloric acid aqueous solution was prepared by mixing hydrochloric acid (14.54 g, HCl molar amount of about 123.5 mmol, 4.0 eq) with water (14.54 g)), the temperature was raised to 80°C and stirred for 1 hour until the raw material was dissolved, then the temperature was slowly lowered to room temperature and stirred for 0.5 hour, then cooled to 0°C, a 30% aqueous solution prepared by sodium nitrite (2.24 g, 32.4 mol, 1.05 eq) and water (5.23 g) was slowly added dropwise, the reaction temperature was controlled (0-5°C), the reaction progress was tracked by HPLC, the reaction was kept warm for 0.5 hour, the raw material was completely converted, and 2,4-dichlorophenyl diazonium salt was obtained, and the diazonium salt solution normalization value was 99.6%.

[0091] 2) Add NaOH (1.85g, 46.3mmol, 1.5eq) to water (9.25g), stir at room temperature for 20 minutes, then add nitroethane (2.78g, 37mmol, 1.2eq), stir at room temperature for 0.5 hour, then add sodium acetate (7.6g, 92.6mmol, 3.0eq) and water (31g), stir at room temperature for 10 minutes. Then slowly drop the 2,4-dichlorophenyldiazonium salt solution prepared in step 1) at room temperature (internal temperature 28-30°C), control the internal temperature at 30-35°C, after the addition, pH = 5-6, then stir at room temperature for 0.5 hour, the system is brown, HPLC tracking diazonium salt conversion is complete. Filter, there is brown oil in the filtrate, the filter cake wet weight is 6.6g. Dry the filter cake at room temperature for 16 hours to obtain a light hydrazone solid weighing 3.55g, with a yield of 46.4%.

[0092] The brown oil produced in the filtrate of Example 1 was separated and analyzed by LC-MS and GC-MS, and it was found that the main by-products were 2,4-dichlorophenol and its azo compounds. The structure is as follows:

[0093]

[0094] Example 2

[0095] 1) 2,4-Dichloroaniline diazonium salt was prepared according to step 1) of Example 1.

[0096] 2) NaOH (1.85 g, 46.3 mmol, 1.5 eq) was dissolved in water (9.25 g), stirred at room temperature for 20 minutes, then nitroethane (2.78 g, 37 mmol, 1.2 eq) was added, stirred at room temperature for 0.5 hours, then sodium carbonate (9.81 g, 92.6 mmol, 3.0 eq) and water (31 g) were added, and stirred at room temperature for 10 minutes. Then, the 2,4-dichlorophenyl diazonium salt prepared in step 1) was slowly added dropwise at room temperature (internal temperature 28-30° C.), and the internal temperature was controlled at 30-35° C. After the addition, the pH was 9-10, and then stirred at room temperature for 0.5 hours. The system was brown, and HPLC tracking showed that the diazonium salt was completely converted. Filter, the filter cake wet weight was 11.3 g. The filter cake was dried at room temperature for 16 hours to obtain a light hydrazone-colored solid, weighing 5.99 g, with a yield of 78.3%.

[0097] Example 3

[0098] 1) 2,4-Dichloroaniline diazonium salt was prepared by referring to step 1) of Example 1, with the amount of raw materials increased by 10 times.

[0099] 2) NaOH (18.5 g, 460 mmol, 1.5 eq) was dissolved in water (92.6 g), stirred at room temperature for 20 minutes, then nitroethane (27.8 g, 370 mmol, 1.2 eq) was added, stirred at room temperature for 0.5 hours, then sodium bicarbonate (77.78 g, 926 mmol, 3.0 eq) and water (311.1 g) were added, and stirred at room temperature for 0.5 hours. Then, the 2,4-dichlorophenyl diazonium salt prepared in step 1) was slowly added dropwise at room temperature (internal temperature 28-30° C.), and the internal temperature was controlled at 30-35° C. After the addition, pH=7-8, and then stirred at room temperature for 0.5 hours. The system was light yellow, and the liquid phase detected that the diazonium salt was completely converted. Filter, the filter cake wet weight was 112 g. The filter cake was dried at room temperature for 16 hours to obtain 75 g of light brown solid, wherein the water content was 2.95% as determined by Karl Fischer method, and the yield was 95.4%.

[0100] The product contains two isomers, and the results of mass spectrometry and nuclear magnetic resonance hydrogen spectrum are as follows Figure 1 , 2 , 3. The relevant data are as follows:

[0101] LC-MS: [M+H] + =248

[0102] 1 H NMR (DMSO-d6, 500 MHz), (E-isomer) δ (ppm): 9.54 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.520 (d, J = 10.0 Hz, 1H), 7.45 (dd, J1 = 5.0 Hz, 1H, J2 = 10.0 Hz, 1H), 2.53 (s, 3H) (see Figure 1 and Figure 2 )

[0103] LC-MS: [M+H] + =248

[0104] 1 H NMR (DMSO-d6, 500 MHz), (Z-isomer) δ (ppm): 12.17 (s, 1H), 7.68 (d, 1H, J = 5.0 Hz), 7.63 (d, 1H, J = 10.0 Hz), 7.48 (d, 1H, J = 5.0 Hz), 2.51-2.52 (m, 3H) (see Appendix Figure 3 )

[0105] The target product IIa has two isomers, Z and E, but the E-isomer is the main one, and the molar ratio of Z-isomer:E-isomer is about 1:5.

[0106]

[0107] Example 4

[0108] The difference from Example 3 is that sodium bicarbonate is replaced by sodium carbonate, the added amount of sodium carbonate is 49 g (463 mmol, 1.5 eq), after the diazonium salt is added dropwise, pH=7-8, and the yield is 96.3%.

[0109] The pH and yield at the end of the reaction of Examples 1 to 4 are shown in Table 1:

[0110] Table 1. Effect of pH value at the end point on the reaction:

[0111] Example pH at the end point Yield (%) Example 1 5～6 46.4 Example 2 9～10 78.3 Example 3 7～8 95.4 Example 4 7～8 96.3

[0112] The results show that when sodium acetate is used in Example 1, the pH at the end point is less than 7, and the reaction yield is only 46.8%. The inventors speculate that this may be because if the pH value is less than 7, the generated nitroethane anion is easily quenched, so the yield is low.

[0113] The inventor unexpectedly discovered that when sodium acetate was replaced with sodium carbonate or sodium bicarbonate, the yield was unexpectedly improved, such as in Examples 2 to 4, but the yield of Example 2 was slightly lower. The inventor believed that the pH value at the end point of Example 2 was greater than 8, which caused the diazonium salt to be unstable and also caused the low yield. The yields of Examples 3 and 4 were as high as 95%, which was probably because as the diazonium salt was continuously added dropwise into the reaction system, a sodium bicarbonate-carbonic acid buffer system was formed, and the pH value at this time was just between 7 and 8, and the reaction yield was higher.

[0114] In step 2), sodium hydroxide can remove hydrogen from the nitroethane anion, and other strong bases can also be used, which can be alkali metal hydroxides, preferably sodium hydroxide or potassium hydroxide.

[0115] In step 2), sodium carbonate or sodium bicarbonate is mainly used as a buffer system, and other alkali metal carbonates and alkali metal bicarbonates can also be used. Preferably, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; when sodium carbonate or potassium carbonate is used as a buffer system, the amount added can be appropriately reduced to avoid excessively high pH at the end of the reaction, and can be 1 to 3 eq, preferably 1 to 1.8 eq, and more preferably 1.3 to 1.8 eq.

[0116] Preferably, MOH, M 2 The molar ratio of CO3 (sodium hydroxide-sodium carbonate) is 1:0.6-1.0, MOH, MHCO 3 The molar ratio of (sodium hydroxide-sodium bicarbonate) is 1:1.2-2.0, wherein M is sodium or potassium.

[0117] In step 2), the equivalent of the base is slightly larger than the total equivalent of the acid in the reaction system, so that the pH value of the reaction system at the end point is maintained at 6 to 9; preferably 7 to 8.

[0118] It should be noted that the inorganic salts produced by the reaction in the whole process of the present invention are mainly sodium chloride, sodium carbonate and sodium bicarbonate, which can be converted into single sodium chloride by treating with hydrochloric acid. Waste salt can be recycled and easily treated, which is why this technology has greater advantages than previous literature methods in the treatment of three wastes.

[0119] II. Preparation of (E)-1-(4-chlorophenyl)-2-(1-nitroethylidene)hydrazine and (Z)-1-(4-chlorophenyl)-2-(1-nitroethylidene)hydrazine (Intermediate IIb) (4-chlorophenyl nitrohydrazone)

[0120] Example 5

[0121] The substrate was replaced with 4-chloroaniline, specifically:

[0122] 1) 4-Chloroaniline (65 g, 509.5 mmol) was suspended in a hydrochloric acid aqueous solution (the preparation method of the hydrochloric acid aqueous solution was: concentrated hydrochloric acid (31.8%, 233.9 g, 2038 mmol, 4.0 eq) was mixed with 233.9 g of water), heated to 80°C and stirred for 1 hour, then slowly cooled to room temperature, stirred for 0.5 hour and then cooled to 0°C, and a 30% aqueous solution prepared by sodium nitrite (36.9 g, 535 mol, 1.05 eq) and 86.2 g of water was slowly added dropwise, the reaction temperature was controlled (0-5°C), the reaction progress was monitored by the liquid phase, and the reaction was kept warm for 0.5 hour. The raw material conversion was complete, and the diazo liquid normalization value was 98.3%.

[0123] 2) Add NaOH (23.5g, 588mmol, 1.5eq) to another reaction bottle and add it to 120g water, stir at room temperature for 20 minutes, then add nitroethane (35.3g, 466mmol, 1.2eq), stir at room temperature for 0.5 hour, then add sodium carbonate (62.3g, 588mmol, 1.5eq) and water (32g), stir at room temperature for 0.5 hour. Then (internal temperature 25-30℃) slowly drip the prepared diazo solution, control the internal temperature 25-30℃, after the addition, pH = 7-8, then naturally heat and stir for 0.5 hour, liquid phase detection diazonium salt conversion is complete. Filter, filter cake wet weight 136g. Dry at room temperature for 16 hours and weigh 96g, external standard content 66.6%, equivalent to dry weight 63.9g, yield 58.6%.

[0124] The substrates of Example 5 and Example 4 are slightly different, and the yields are quite different. The inventors have found through continuous research that 4-chlorophenyl diazonium salt may be unstable and easy to decompose under high temperature conditions. Some examples are as follows:

[0125] Example 6

[0126] 1) 4-Chloroaniline (5 g, 39.2 mmol) was suspended in a hydrochloric acid aqueous solution (the preparation method of the hydrochloric acid aqueous solution was: concentrated hydrochloric acid (31.8%, 18.0 g, 156.7 mmol, 4.0 eq) was mixed with 18 g of water), heated to 80°C and stirred for 1 hour, then slowly cooled to room temperature, stirred for 0.5 hour, cooled to 0°C, and a 30% aqueous solution prepared by sodium nitrite (2.84 g, 41.2 mol, 1.05 eq) and 6.63 g of water was slowly added dropwise, the reaction temperature was controlled (0-5°C), the reaction progress was monitored by liquid phase, and the reaction was kept warm for 0.5 hour. The raw material conversion was complete, and the diazo liquid normalization value was 98.3%, which was set aside.

[0127] 2) Add NaOH (2.35g, 58.8mmol, 1.5eq) and 12g water to another reaction bottle, stir at room temperature for 20 minutes, then add nitroethane (3.53g, 47mmol, 1.2eq), stir at room temperature for 0.5 hour, then add sodium carbonate (6.23g, 58.8mmol, 1.5eq), 32g water, stir at room temperature for 0.5 hour, and cool down. Then slowly drip the diazo solution in step 1) at (internal temperature -5 to 0°C), control the internal temperature -5 to 0°C, after addition, pH = 7 to 8, then naturally heat and stir for 0.5 hour, liquid phase detection diazonium salt conversion is complete. Filter, filter cake wet weight 19g, room temperature 16 hours dry filter cake weigh 8.1g, external standard content 89%, equivalent to dry weight 7.2g, yield 85.8%. LC-MS detection revealed an impurity with a molecular weight of 324, and the analytical sample 1,1-bis(4-chlorophenyl)-2-(1-nitroethylidene)hydrazine was obtained by column chromatography.

[0128] The mass spectrometry and H NMR spectrometry results of the 1,1-bis(4-chlorophenyl)-2-(1-nitroethylidene)hydrazine byproduct obtained in this example are as follows: Figure 4 , the analysis data is as follows:

[0129] LC-MS: [M+H]+=324

[0130] 1 H NMR (DMSO-d6, 500 MHz), δ (ppm): 7.93 (d, 4H, J = 15.0 Hz), 7.82 (d, 4H, J = 10.0 Hz), 2.96 (s, 3H) (see Appendix Figure 4 )

[0131] Example 7

[0132] 1) 4-Chloroaniline (20 g, 156.8 mmol, 99%) was suspended in a hydrochloric acid aqueous solution (the preparation method of the hydrochloric acid aqueous solution was: concentrated hydrochloric acid (31.8%, 72 g, 627.1 mmol, 4.0 eq) was mixed with 72 g of water), heated to 80°C and stirred for 1 hour, then slowly cooled to room temperature, stirred for 0.5 hour, cooled to 0°C, and a 30% aqueous solution prepared by sodium nitrite (11.36 g, 164.6 mol, 1.05 eq) and 26.5 g of water was slowly added dropwise, the reaction temperature was controlled (0-5°C), the reaction progress was monitored by liquid phase, and the reaction was kept warm for 0.5 hour. The raw material conversion was complete, and the diazo liquid normalization value was 98.5%.

[0133] 2) Add NaOH (9.4g, 235.2mmol, 1.5eq) and 50g water to another reaction bottle, stir at room temperature for 20 minutes, then add nitroethane (14.12g, 188.1mmol, 1.2eq), stir at room temperature for 0.5 hours, then add sodium carbonate (24.9g, 235.2mmol, 1.5eq) and water (125g), stir at room temperature for 0.5 hours, and cool down. Then slowly drip the prepared diazo solution (internal temperature 0-5°C), control the internal temperature 0-5°C, after addition, pH = 7-8, then naturally heat and stir for 0.5 hours, liquid phase detection diazonium salt conversion is complete. Filter, filter cake wet weight 68g, room temperature 48 hours drying filter cake weighing 34g, external standard content 91.9%, equivalent to dry weight 31.24g, yield 93.1%.

[0134] Example 8

[0135] 1) 4-Chloroaniline (65 g, 509.5 mmol, 99%) was suspended in a hydrochloric acid aqueous solution (the preparation method of the hydrochloric acid aqueous solution was: concentrated hydrochloric acid (31.8%, 233.9 g, 2038 mmol, 4.0 eq) was mixed with 233.9 g of water), heated to 80°C and stirred for 1 hour, then slowly cooled to room temperature, stirred for 0.5 hour and then cooled to 0°C, and a 30% aqueous solution prepared by sodium nitrite (36.9 g, 535 mol, 1.05 eq) and 86.2 g of water was slowly added dropwise, the reaction temperature was controlled (0-5°C), the reaction progress was monitored by the liquid phase, and the reaction was kept warm for 0.5 hour. The raw material conversion was complete, and the diazo liquid normalization value was 98.3%.

[0136] 2) Add NaOH (30.6g, 764.3mmol, 1.5eq) and 153g water to another reaction bottle, stir at room temperature for 20 minutes, then add nitroethane (45.9g, 611.4mmol, 1.2eq), stir at room temperature for 0.5 hour, then add sodium carbonate (81g, 764.3mmol, 1.5eq) and water (405g), stir at room temperature for 0.5 hour, and cool down. Then slowly drip the diazo solution in the first step (internal temperature 5-10°C), control the internal temperature at 5-10°C, after addition, pH = 7-8, then naturally heat and stir for 0.5 hour, liquid phase detection diazonium salt conversion is complete. Filter, filter cake wet weight 236g. The filter cake weighed 108.5g after drying at room temperature for 72 hours, with an external standard content of 98.9%, equivalent to a dry weight of 107.3g, and a yield of 98.4%.

[0137] The two isomers were analyzed by H NMR. Figure 5 , 6 , the relevant data are as follows:

[0138] LC-MS: [M+H] + =214

[0139] 1 H NMR (DMSO-d6, 500 MHz), (E-isomer) δ (ppm): 7.83-7.90 (m, 1H), 7.70-7.72 (s, 1H), 7.33-7.38 (m, 3H), 2.50-2.52 (m, 3H) (see Figure 5 ); (Z-isomer) δ (ppm): 10.68 (brs., 1H), 7.36 (s, 4H), 2.18 (m, 3H) (see Figure 6 ).

[0140] The target product IIb has two isomers, Z and E, with the Z-isomer being the main isomer. The molar ratio of Z-isomer to E-isomer is about 3:1.

[0141]

[0142] Example 9

[0143] 1) 4-Chloroaniline (5 g, 39.2 mmol, 99%) was suspended in a hydrochloric acid aqueous solution (the preparation method of the hydrochloric acid aqueous solution was: concentrated hydrochloric acid (31.8%, 18.0 g, 156.7 mmol, 4.0 eq) was mixed with 18 g of water), heated to 80°C and stirred for 1 hour, then slowly cooled to room temperature, stirred for 0.5 hour, cooled to 0°C, and a 30% aqueous solution prepared by sodium nitrite (2.84 g, 41.2 mol, 1.05 eq) and 6.63 g of water was slowly added dropwise, the reaction temperature was controlled (0-5°C), the reaction progress was monitored by liquid phase, and the reaction was kept warm for 0.5 hour. The raw material conversion was complete, and the diazo liquid normalization value was 98.3%.

[0144] 2) Add NaOH (2.35g, 58.8mmol, 1.5eq) to another reaction bottle and add it to 12g of water, stir at room temperature for 20 minutes, then add nitroethane (3.53g, 47mmol, 1.2eq), stir at room temperature for 0.5 hour, then add sodium carbonate (6.23g, 58.8mmol, 1.5eq) and water (32g), stir at room temperature for 0.5 hour, and cool down. Then slowly drop the prepared diazo solution (internal temperature -5 to 0°C), control the internal temperature -5 to 0°C, after the addition, pH = 7 to 8, then naturally heat and stir for 0.5 hour, liquid phase detection diazonium salt conversion is complete. Filter, filter cake wet weight 16g. The filter cake weighed 83g after drying at room temperature for 16 hours, with an external standard content of 94.5%, equivalent to a dry weight of 7.84g, and a yield of 93.4%.

[0145] Example 10

[0146] 1) Prepare the diazonium salt by referring to step 1) of Example 7.

[0147] 2) Add NaOH (9.4g, 235.2mmol, 1.5eq) and water (50g) to another reaction bottle, stir at room temperature for 20 minutes, then add nitroethane (14.12g, 188.1mmol, 1.2eq), stir at room temperature for 0.5 hours, then add sodium carbonate (24.9g, 235.2mmol, 1.5eq) and water (125g), stir at room temperature for 0.5 hours and then cool down. Then (internal temperature 15-20℃) slowly drip the prepared diazo solution, control the internal temperature 0-5℃, after addition, pH=7-8, then naturally heat and stir for 0.5 hours, liquid phase detection diazonium salt conversion is complete. Filter, filter cake wet weight 56g. Dry at room temperature for 48 hours and weigh 32g, external standard content 89.9%, equivalent to dry weight 28.76g, yield 85.7%.

[0148] The results of Examples 5 to 10 are shown in Table 2.

[0149] Table 2. Comparison of the yield of 4-chlorophenyl nitrohydrazone by dropping diazonium salt at different temperatures

[0150] Example Internal temperature(℃) Yield (%) Example 5 25～30 58.6 Example 6 -5～0 85.8 Example 7 0～5 93.1 Example 8 5～10 98.4 Example 9 10～15 93.4 Example 10 15～20 85.7

[0151] The results in Table 2 show that when 4-chloroaniline is used as the substrate, the temperature when the diazonium salt is added has a relatively large effect, which is very different from the case of 2,4-dichloroaniline. It is possible that under higher temperature conditions, 4-chlorophenyl diazonium salt is unstable and easily decomposes; but when the temperature is too low, the reaction rate is slow, and the diazonium salt is unstable and easily decomposes into free radicals to further react with nitrohydrazone (as shown in the following formula). For yield data, see Example 6.

[0152]

[0153] According to Table 2, when the temperature is 0-15°C, the yield is higher, especially when the temperature is controlled at 5-10°C, the yield is the highest. The possible reason is that 4-chlorophenyl diazonium salt is both stable and has a high reaction rate in this temperature range. The relationship between yield and temperature is as follows: Figure 7 .

[0154] Comparing the stability of 2,4-dichlorophenyl diazonium salt and 4-chlorophenyl diazonium salt, it can be seen that the former is more stable than the latter and has better temperature tolerance. For aromatic diazonium salts, the more electron-withdrawing groups on the benzene ring, the more stable the diazonium salt.

[0155] The intermediate II prepared according to different substrates (2,4-dichloroaniline, 4-chloroaniline) are respectively as shown in formula IIa and IIb. Among them, for IIa, due to the steric hindrance effect of the adjacent chlorine atom, the E-isomer is mainly formed, and the molar ratio of Z-isomer: E-isomer is about 1:5; and for IIb, due to the low hydrogen bond energy in the molecule, the Z-isomer is mainly formed, and the molar ratio of Z-isomer: E-isomer is about 3:1. The different configurations have an important influence on the subsequent ring-closing reaction.

[0156]

[0157] 3. Preparation of 2-(2,4-dichlorophenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (IIIa)

[0158] On the basis of the above-mentioned preparation of nitrohydrazone, nitrohydrazone is further reduced to amidohydrazone (see patent application CN202311260068.9 ("A method for preparing an iminohydrazone intermediate"), and amidohydrazone can be cyclized with urea to prepare the key intermediate III of sulfentrazone (see patent application CN 202311257922.6 "A method for preparing sulfentrazone and triadimefon intermediates"). The main problem of this method is that the generated nitrohydrazone is not very stable, especially under higher temperature conditions, there are more urea cyclization byproducts. So it was imagined whether intermediate II could be directly cyclized with cyanate. Fortunately, intermediate IIa was heated to 60°C in n-butanol to generate the target product IIIa, but the yield was only 64.2% (see Example 12), and only 34.1% in DMF (see Example 11). If IIa is replaced with IIb, the yield can be as high as 70% or more (see Examples 24 and 25).

[0159] Embodiment 11

[0160] NaOCN (151 mg, 2.32 mmol, 1.05 eq) and DMF (5 mL) were added to a reaction bottle, heated to 60° C. and stirred, then 2,4-dichlorophenylnitrohydrazone (540 mg) was added, and the mixture was stirred at this temperature for 48 hours until the raw material disappeared. The content was measured by external standard method and was 34.1%.

[0161] Example 12

[0162] The difference from Example 11 is that the solvent DMF is replaced with n-butanol. After the reaction is completed, the solvent is removed by vortexing, and the residue is added with water, extracted with ethyl acetate, and concentrated and crystallized to obtain a light brown solid with a yield of 64.2%.

[0163] Embodiment 13

[0164] The difference from Example 11 is that the temperature was changed to room temperature and stirred for 48 hours, and the selectivity was 24.1%.

[0165] 4. Preparation of 2-(4-chlorophenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Ⅲb)

[0166] Embodiment 14

[0167] NaOCN (151 mg, 2.32 mmol, 1.05 eq) and DMF (5 mL) were added to the reaction bottle, heated to 90 ° C and stirred, and a DMF (5 mL) solution of 4-chlorophenyl nitrohydrazone (472 mg, 2.21 mmol) was slowly added dropwise, and the addition was completed for 45 min. TLC detected that there was a residue of raw materials, and continued stirring for 1 h. TLC detected that the raw materials reacted completely. The filtrate weighed 19.2 g, and the content was measured by external standard method 0.35%, the actual weight was 67.2 mg, and the reaction selectivity was 14.5%.

[0168] Embodiment 15

[0169] The difference from Example 14 is that the temperature was only raised to 60° C. and stirred for 1.2 h, and the reaction selectivity was 28.9%.

[0170] Example 16

[0171] 4-Chlorophenylnitrohydrazone (2.00 g, 9.36 mmol, 1 eq), sodium cyanate (0.64 g, 9.83 mmol, 1.05 eq)) and DMF (20 ml) were added to a reaction bottle and stirred at 25 °C for 56 hours. The reaction was monitored by TLC (petroleum ether-ethyl acetate 1-5:1). After the reaction was completed, the mixture was filtered and concentrated under reduced pressure at 60 °C. The concentrate was slurried with petroleum ether-ethyl acetate (4:1) and filtered to obtain 1.04 g of an off-white solid with a yield of 53.0%.

[0172] Embodiment 17

[0173] In a 100 mL reaction bottle, 4-chlorophenylnitrohydrazone (2.00 g, 9.36 mmol, 1 eq), calcium chloride (104 mg, 0.1 eq), sodium cyanate (0.64 g, 9.83 mmol, 1.05 eq) and DMF (20 ml) were added. The mixture was stirred at room temperature for 19 hours. The reaction was monitored by TLC (petroleum ether-ethyl acetate 1-5:1). After the reaction was completed, the mixture was filtered and concentrated under reduced pressure at 60°C. The concentrate was slurried with petroleum ether-ethyl acetate (4:1) and filtered to obtain 1.10 g of an off-white solid with a yield of 56.0%.

[0174] Analytical data of 2-(4-chlorophenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one ( Figure 8):

[0175] LCMS: M+1=210

[0176] 1 H NMR (DMSO-d6, 400 MHz), δ (ppm): 12.022 (s, 1H), 7.916 (d, J = 8.8 Hz, 2H), 7.475 (d, J = 8.8 Hz, 2H), 2.194 (s, 3H) (see Appendix Figure 8 )

[0177] Embodiment 18

[0178] The difference from Example 17 is that magnesium chloride (27 mg, 0.03 eq) is used instead of calcium chloride and the reaction is stirred at room temperature for 21 hours with a yield of 58.6%.

[0179] Embodiment 19

[0180] The difference from Example 17 is that lithium chloride (40 mg, 0.1 eq) is used instead of calcium chloride. The reaction is carried out for 50 hours and the yield is 63.4%.

[0181] Embodiment 20

[0182] The difference from Example 17 is that zinc chloride (13 mg, 0.01 eq) is used instead of calcium chloride to react for 48 hours with a yield of 63.4%.

[0183] Embodiment 21

[0184] 4-Chlorophenylnitrohydrazone (2.00 g, 9.36 mmol, 1 eq), sodium cyanate (151 mg, 1.05 eq) and DMF (20 ml) were added to a reaction bottle, oxygen was introduced and bubbling was maintained, and the reaction was stirred at room temperature for 120 hours. The reaction was monitored by TLC (petroleum ether-ethyl acetate 1-5:1). After the reaction was completed, the mixture was filtered and concentrated under reduced pressure at 60°C. The concentrate was then slurried with petroleum ether-ethyl acetate (4:1) and filtered to obtain 1.11 g of an off-white solid with a yield of 56.5%.

[0185] Embodiment 22

[0186] 4-Chlorophenylnitrohydrazone (2.00 g, 1 eq), sodium cyanate (151 mg, 1.05 eq) and methanol (20 ml) were added to a reaction bottle and stirred at room temperature for 120 hours. The reaction was monitored by TLC until the reaction was completed. The product was filtered and concentrated under reduced pressure. The concentrate was slurried with petroleum ether-ethyl acetate (4:1) and filtered to obtain 0.93 g of an off-white solid with a yield of 47.4%.

[0187] Embodiment 23

[0188] The difference from Example 22 is that the solvent is replaced with n-butanol, and the reaction is stirred at room temperature for 48 hours, with a yield of 23.7%.

[0189] Embodiment 24

[0190] The difference from Example 22 is that the solvent is replaced with acetonitrile, the reaction is carried out at 25° C. for 16 hours, the reaction selectivity is 76.7%, and the yield after post-treatment is 71.2%.

[0191] Embodiment 25

[0192] The difference from Example 24 is that sodium cyanate is replaced by potassium cyanate, the reaction is carried out at 25° C. for 16 hours, the reaction selectivity is 78.2%, and the yield after post-treatment is 73.4%.

[0193] Embodiment 26

[0194] The difference from Example 24 is that 0.1 eq of zinc chloride was added, the reaction was carried out at 25° C. for 16 hours, the reaction selectivity was 84.2%, and the yield after post-treatment was 76.8%.

[0195] According to the above Examples 11 to 25, the ring-closure reaction of sodium cyanide on nitrohydrazone is relatively complicated, and the steric hindrance of the 2-position substituent has a greater impact. Under the same room temperature conditions, Ⅱb is much easier than Ⅱa, so the ring-closure of Ⅱa requires a higher reaction temperature than Ⅱb; on the other hand, the configuration of intermediate Ⅱ may have a greater impact on the reaction. For nitrohydrazone, the ratio of Z-form to E-form of Ⅱa is about 1:5, and the ratio of Z-form to E-form of Ⅱb is about 3:1. For the Z-form structure, a reaction similar to SN1 may occur to generate intermediate M, and then the intramolecular ring closure obtains Ⅲb; however, for the E-form isomer, N is generated, which obviously requires a higher reaction activation energy, that is, heating is required to complete the ring-closure reaction, and during the reaction, we detected the presence of intermediate isocyanate by liquid chromatography, which is speculated to be trans N.

[0196]

[0197] The effect of temperature on ring closure can be seen in Examples 14 to 16, and the comparison results are shown in Table 3.

[0198] Table 3. Effect of temperature on ring-closing reaction

[0199] Example Temperature(℃) Selectivity or yield (%) Embodiment 14 90 14.5 Embodiment 15 60 28.9 Example 16 25 53.0

[0200] The results in Table 3 show that the reaction results are better at room temperature (generally 25°C), but nitrohydrazone is also unstable at room temperature and is easy to decompose and release nitrogen and is sensitive to water vapor and temperature. At higher temperatures, the raw materials decompose faster and the selectivity of the reaction becomes worse. The main reason may be that nitrite is generated during the reaction, and nitrohydrazone is a reducing agent. The generated by-product nitrite oxidizes the raw material II; if the reaction time is prolonged, sodium nitrite will also oxidize the ring-closed product, causing the product to become more complicated.

[0201] The effects of the coordination of selected metal ions on the ring closure are shown in Table 4.

[0202] Table 4 Effect of metal halide coordination on the reaction

[0203] Example Halogenated salts Yield (%) Example 16 none 53.0 Embodiment 17 Calcium chloride 56.0 Embodiment 18 Magnesium chloride 58.6 Embodiment 19 Lithium chloride 63.4 Embodiment 20 Zinc chloride 63.4

[0204] The results in Table 4 show that the nitrohydrazone and the intermediates M and N can be stabilized by the coordination of metal ions. The reaction is improved when a halide salt is added, among which lithium chloride and zinc chloride have better effects. We also considered introducing oxygen into the reaction system to try to oxidize sodium nitrite (see Example 21), but the results were still unsatisfactory.

[0205] Through the stability experiment of intermediate II in solvents, it was found that nitrohydrazone was not stable in the DMF solvent system and decomposed quickly, but decomposed very slowly in methanol, ethanol, butanol and acetonitrile.

[0206] We further investigated the effect of different solvents on the reaction yield. The results are shown in Table 5. When alcohol was used as the reaction solvent, sodium cyanate was almost insoluble in alcohol, so the reaction rate was very low. DNF was used as a solvent to achieve a moderate yield, but in acetonitrile, the intermediate showed good stability and reaction selectivity, and the separation yield could be as high as over 70%.

[0207] Table 5 Effect of solvent on reaction

[0208] Example Solvents Yield (%) Example 16 DMF 53.0 Embodiment 22 Methanol 47.4 Embodiment 23 n-Butanol 23.7 Embodiment 24 Acetonitrile 71.2 Embodiment 26 Acetonitrile 76.8

[0209] In summary, for 4-chlorophenyl nitrohydrazone, the choice of solvent is also critical to inhibiting the decomposition of nitrohydrazone. The solvents that can be selected include DMF, alcohols, acetonitrile, etc. Among them, nitrohydrazone is easy to decompose in DMF, but the reaction rate is high. Although nitrohydrazone is stable in alcohol solvents, the reaction rate is too slow. Acetonitrile meets both the requirements of nitrohydrazone for stability and the requirements of high reaction rate. Therefore, the solvents that can be selected include DMF, DCE (N, N-dimethylacetamide), and acetonitrile, and acetonitrile is preferred; for 2,4-dichloronitrohydrazone, since its stability is higher than that of 4-chlorophenyl nitrohydrazone and it can withstand higher reaction temperatures, the solvents that can be selected include alcohols, DMF, and acetonitrile, but alcohols are better, and butanol is preferred.

[0210] 4-Chlorophenyl nitrohydrazone is highly sensitive to reaction temperature. The decomposition of raw materials is accelerated at high temperature, while the reaction rate is slow at low temperature. Prolonging the reaction time will cause the product to be oxidized due to the presence of nitrite, which reduces the yield. Therefore, a suitable reaction temperature is necessary. Generally, the reaction temperature is controlled between 20 and 60°C, preferably between 25 and 40°C; the reaction temperature of 2,4-dichloronitrohydrazone is controlled between 40 and 80°C, preferably between 55 and 65°C.

[0211] The ring-closed cyanate can be sodium salt or potassium salt. During the reaction, the molar ratio of cyanate to nitrohydrazone can be 1 to 2:1, and the optimal molar ratio is 1 to 1.2:1. Too high a molar ratio will produce side reactions.

[0212]

[0213] Among them, different cyanates - sodium cyanate and potassium cyanate - have roughly the same effect on the reaction. The structure of the substrate has a decisive influence on the reaction, among which the physical and chemical properties of the nitrohydrazone itself are the primary factor in the ring-closing reaction. In terms of substrate selection, 4-chlorophenylnitrohydrazone (Ⅱb) is better than 2,4-dichloronitrohydrazone (Ⅱa).

[0214] The solution provided by the present invention solves the problem that in the prior art, a large amount of inorganic reducing agents such as sodium sulfite is used in the production of phenylhydrazine, a raw material of triazolinone, which generates a large amount of solid waste and has low atom economy; at the same time, the problem of low chlorination selectivity of sulfentrazone prepared by using phenylhydrazine as a raw material is solved; finally, the synthesis route of the technology is shortened by 3 steps compared with the prior art, which greatly reduces energy consumption and labor intensity and has a good application prospect.

[0215] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a sulfentrazone intermediate represented by formula III, characterized in that: It includes: Step 1: Under acidic conditions, the substituted aromatic amine shown in formula I reacts with nitrite to generate a diazonium salt product; Adding a diazonium salt product to an alkaline system containing nitroethane to generate a sulfentrazone intermediate shown in formula II; Step 2: In a solvent, the cis-trans isomer compound shown in Formula II undergoes a substitution ring-closing reaction with cyanate to generate the sulfentrazone intermediate shown in Formula III. The reaction route is as follows: Wherein, X is Cl or H; M is Na or K.

2. A method for preparing a sulfentrazone intermediate represented by formula III, characterized in that The steps include: 1) Under acidic conditions, the substituted aromatic amine shown in formula I reacts with nitrite to form a diazonium salt; 2) Adding a diazonium salt to an alkaline system containing nitroethane to generate a nitrohydrazone; 3) Nitrohydrazone and cyanate undergo substitution ring-closing reaction to generate the sulfentrazone intermediate shown in formula III; Wherein, X is Cl or H; M is Na or K.

3. The preparation method according to claim 1 or 2, characterized in that: In the ring-closing reaction, the cyanate is sodium cyanate and / or potassium cyanate; And / or, in the ring-closing reaction, the molar ratio of the cis-trans isomer compound represented by formula II to the cyanate is 1:(1-2), optionally 1:(1-1.2), optionally 1:(1.05-1.1).

4. The preparation method according to any one of claims 1 to 3, characterized in that: In the ring-closing reaction, the solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, alcohols, and acetonitrile; optionally, the alcohol is selected from C1-C6 low-carbon alcohols; Optionally, in the ring-closing reaction, when X is Cl, the solvent is alcohol, DMF, acetonitrile, and the alcohol includes one or more of methanol, ethanol, propanol, n-butanol, isopropanol, sec-butanol, tert-butanol, and pentanol; preferably, the solvent is n-butanol; Optionally, in the ring-closing reaction, when X is H, the solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and acetonitrile; optionally, the solvent is N,N-dimethylformamide and / or acetonitrile.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The ring-closing reaction temperature is 20-80°C; Optionally, in the ring-closing reaction, when X is Cl, the ring-closing reaction temperature is 40 to 80°C, optionally 55 to 65°C, optionally 60 to 65°C; Optionally, in the ring-closure reaction, when X is H, the ring-closure reaction temperature is 20 to 60°C, optionally 20 to 40°C, optionally 20 to 30°C, optionally 25 to 30°C.

6. The preparation method according to any one of claims 1 to 5, characterized in that: In the ring-closing reaction, a coordinating metal salt may be added to the reaction system. Optionally, the coordinating metal salt is a halogenated salt. Optionally, the coordinating metal salt is selected from lithium chloride and / or zinc chloride.

7. The preparation method according to any one of claims 1 to 6, characterized in that: In an alkaline system containing nitroethane, the pH at the reaction end point is controlled to be 7 to 9, optionally 7 to 8; And / or, in an alkaline system containing nitroethane, the amount of alkaline substance added is such that the pH value of the reaction system at the end point is maintained at 6 to 9; preferably 7 to 8; And / or, in an alkaline system containing nitroethane, the alkaline substance comprises an inorganic strong base and a weak acid strong base salt, the inorganic strong base is used to make nitroethane form negative ions, and the weak acid strong base salt is used to form an alkaline buffer system; Optionally, the weak acid and strong base salt is an alkali metal weak acid salt; Optionally, the alkali metal weak acid salt is one or both of carbonate and bicarbonate; Optionally, the alkali metal weak acid salt is one or both of alkali metal carbonate and alkali metal bicarbonate; Optionally, the inorganic strong base includes an alkali metal hydroxide, and the alkali metal hydroxide is optionally selected from sodium hydroxide and / or potassium hydroxide; Optionally, the alkali metal weak acid salt is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; Optionally, the molar ratio of the inorganic strong base to nitroethane is (1.1-1.5):1, optionally (1.2-1.5):1; Optionally, the molar ratio of the substituted aromatic amine shown in Formula I to nitroethane is 1:(1-2), preferably 1: (1-1.5), more preferably 1:(1.1-1.2); Alternatively, when the alkali metal weak acid salt is an alkali metal carbonate, the OH - The molar ratio of the alkali metal carbonate is 1:(0.6-1.01), optionally 1:(0.8-1.01), optionally 1:(0.9-1.01); Optionally, when the alkali metal acid salt is an alkali metal bicarbonate, the OH - The molar ratio of X to alkali metal bicarbonate is 1:(1-2.02); optionally, when X is Cl, OH in the inorganic strong base - The molar ratio of the inorganic strong base to the alkali metal bicarbonate is 1:(1.2-2.02), optionally 1:(1.8-2.02); optionally, when X is H, the OH in the inorganic strong base is - The molar ratio to alkali metal bicarbonate is 1:(1-2.02).

8. The preparation method according to any one of claims 1 to 7, characterized in that: The substituted aromatic amine shown in formula I reacts with OH in an inorganic strong base - The molar ratio is 1:(1.1-2), optionally 1:(1.3-1.8), optionally 1: (1.3～1.5)。 9. The preparation method according to claim 7 or 8, characterized in that: In the diazonium salt reaction, the substituted aromatic amine shown in Formula I and the H + The molar ratio of nitrite is 1:(3-5):(1-2), preferably 1:(3.5-4.5):(1-1.2), optionally 1:(3-4):1.05, more preferably 1:4: 1.05; Optionally, the substituted aromatic amine represented by formula I is a free amine; Alternatively, in the diazonium salt reaction, the substituted aromatic amine shown in Formula I, the H + , the molar ratio of nitrite is 1:(2-4):(1-2), preferably 1:(2.5-3.5):1:1.2, more preferably 1:3:1.05; optionally, the substituted aromatic amine shown in formula I is an ammonium salt; Optionally, in the diazonium salt reaction, the nitrite is selected from sodium nitrite and potassium nitrite; Optionally, in the diazonium salt reaction, the acid used in the diazotization reaction is a protonic acid, and the protonic acid is optionally selected from an inorganic strong acid, and preferably the inorganic strong acid is selected from HCl and H2SO4.

10. The preparation method according to any one of claims 7 to 9, characterized in that: The reaction temperature of the diazonium salt and nitroethane is 0-40°C; Optionally, when X is Cl, the reaction temperature of the diazonium salt and nitroethane is 0 to 40°C, optionally 20 to 35°C; Optionally, when X is H, the reaction temperature of the diazonium salt and nitroethane is 0 to 15°C, optionally 5 to 15°C.

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