A process for the preparation of a sulfentrazone intermediate

Abstract

The application discloses a preparation method of sulfentrazone intermediate, which comprises the following steps: in a solvent, substitution ring-closing reaction of cis-trans isomer compound (nitro hydrazone) shown in formula II and cyanate salt is carried out to generate sulfentrazone intermediate shown in formula III. The scheme provided by the application solves the problems in the prior art, such as the use of a large amount of inorganic reducing agent, such as sodium sulfite, in the production of raw material phenylhydrazine for preparing triazolinone through phenylhydrazine, generation of a large amount of solid waste, and low atomic economy; the scheme solves the problems in the prior art, such as the use of a large amount of sulfite reducing agent and sodium hypochlorite oxidant in the production of raw material phenylhydrazine for preparing triazolinone through phenylhydrazine, generation of a large amount of mixed salt, and low chloro-substitution selectivity of sulfentrazone prepared by using phenylhydrazine as raw material; the scheme solves the problems, such as the reduction of diazonium salt to hydrazine, the oxidation of hydrazine to hydrazine, and the like; the scheme directly utilizes intermediate hydrazine and then utilizes cyanate salt ring-closing, and compared with the prior art, the scheme is shortened by 3 steps, and energy consumption and labor intensity are greatly reduced.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pesticides, in particular to a preparation method of a mesosulfuron intermediate. BACKGROUND

[0002] Mesosulfuron, also known as sulfonazofone, is a triazolinone herbicide developed by FMC Corporation in 1985 and put on the market in 1996. It is a protoporphyrinogen oxidase inhibitor, mainly used in sugarcane, soybean and sunflower fields to prevent and control annual broadleaf weeds, grass weeds and sedge, etc. before sowing and before seedling.

[0003] At present, the key intermediate III of mesosulfuron is usually prepared from an aromatic amine I as a starting material through a seven-step reaction. 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 scheme); 3 eq of potassium bisulfite is required to prepare hydrazine, which generates 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 cannot be resourcefully treated as solid waste; Chemical Reaction Engineering and Process, Vol. 25, No. 5, October 2012, P412-417 reports a method for preparing intermediate IIIa from 2,4-dichlorophenylhydrazine hydrochloride, with a four-step yield of 88.43% (= 99% x 89.32%) (i.e. the last four steps of the following reaction scheme), but the method has the defect that the diazonium salt needs to be over-reduced to hydrazine and then oxidized back with hypochlorous acid, generating mixed salts of sodium hypochlorite and sodium chloride, which are almost impossible to be resourcefully treated. The total yield of the seven-step reaction route according to CN106565532A for the first three steps and according to Chemical Reaction Engineering and Process for the first four steps is about 79.6%, and a large amount of mixed salts are generated, which cannot be resourcefully treated, greatly increasing the cost of post-treatment. The reaction scheme is as follows:

[0005]

[0006] Similarly, intermediate IIIb is synthesized from 4-chloroaniline as a raw material, as described in patents CN101928246A and CN107629015A. This method also generates a large amount of mixed inorganic salts, which are difficult to be resourcefully treated, and has high waste treatment cost and poor atom economy; on the other hand, this route is long and inefficient.

[0007] However, the above process route uses a large amount of inorganic reducing agent such as sodium sulfite, which produces a large amount of mixed inorganic salt (such as mixed salt of sulfite, sulfate, bisulfate, etc., and mixed salt of sodium hypochlorite and sodium chloride), and due to the difficulty in separation and resource treatment of the mixed inorganic salt, the treatment cost of the three wastes is high, and the atomic economy is poor; on the other hand, the reduction of diazonium salt needs to be reduced to hydrazine, and the hydrazine is further reduced to hydrazine, and finally oxidized to hydrazine, which indicates that the route is long and inefficient. SUMMARY

[0008] Object of the invention

[0009] In order to overcome the above-mentioned deficiencies, the purpose of the present application is to provide a preparation method of sulfentrazone intermediate which reduces solid waste discharge and is green and environmentally friendly. The present application uses a method of converting diazonium salt into a hydrazine intermediate state, avoiding the scheme of excessive reduction and then oxidation, and further using cyanate to close the ring, which not only reduces the operation steps, but also reduces the solid waste discharge (a large amount of inorganic salt is reduced), so that the production process of sulfentrazone intermediate III becomes simple and efficient, and easy to mass produce sulfentrazone intermediate III.

[0010] Solution

[0011] In order to achieve the purpose of the present application, the technical scheme adopted by the present application is as follows:

[0012] In a first aspect, the present application provides a preparation method of sulfentrazone intermediate shown in formula III, which comprises:

[0013] Step one: under acidic conditions, the arylamine shown in formula I and nitrite salt generate diazonium salt product; in a basic system containing nitroethane, the diazonium salt product is added to generate sulfentrazone intermediate shown in formula II;

[0014] Step two: in a solvent, the cis-trans isomer compound (nitrohydrazone) shown in formula II and cyanate undergo substitution and ring closure reaction to generate sulfentrazone intermediate shown in formula III, and the reaction route is as follows:

[0015]

[0016] In the formula, X is Cl or H; M is Na or K.

[0017] In a second aspect, a preparation method of sulfentrazone intermediate shown in formula III is provided, which comprises the following steps:

[0018] 1) Under acidic conditions, the substituted arylamine shown in formula I and nitrite salt generate diazonium salt;

[0019] 2) In a basic system containing nitroethane, the diazonium salt is added to generate nitrohydrazone;

[0020] 3) Substitution-cyclization reaction of nitrohydroxime with cyanate to form sulfentrazone intermediate of formula III;

[0021]

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

[0023] In the cyclization reaction, the cyanate is sodium cyanate and / or potassium cyanate.

[0024] In the cyclization reaction, the molar ratio of the cis-trans isomer compound of formula II to cyanate is 1:(1-2), optionally 1:(1-1.2), and optionally 1:(1.05-1.1). Too high molar ratio will cause side reactions.

[0025] In the cyclization reaction, the solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, alcohol, and acetonitrile; and the alcohol is optionally selected from C1-C6 low carbon alcohol.

[0026] In the cyclization reaction, when X is Cl (the compound of formula II is 2,4-dichloronitrohydroxime), the solvent is alcohol, DMF, or acetonitrile; and the alcohol is optionally one or more of methanol, ethanol, propanol, n-butanol, isopropanol, sec-butanol, tert-butanol, and amyl alcohol; preferably, the solvent is n-butanol; 2,4-dichloronitrohydroxime has relatively good stability and can withstand higher reaction temperature, and the optional solvent is alcohol, DMF, or acetonitrile, but alcohol is preferred, and n-butanol is more preferred.

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

[0028] Further, in the cyclization reaction, the cyclization reaction temperature is 20-80°C.

[0029] In the cyclization reaction, when X is Cl, the compound of formula I is 2,4-dichloroaniline; the compound of formula II formed therefrom is denoted as IIa, which has Z and E isomers; and due to the steric hindrance effect of the ortho chlorine atom, the main isomer is E-isomer, and the molar ratio of Z-isomer to E-isomer is about 1:5.

[0030]

[0031] When X is H, the compound of formula I is 4-chloroaniline; the compound of formula II formed is denoted as IIb, which also has two isomers of Z and E. For IIb, due to the low hydrogen bond energy in the molecule, the Z-isomer is mainly formed, and the molar ratio of the Z-isomer to the E-isomer is about 3:1. The difference in configuration has an important influence on the subsequent ring-closing reaction.

[0032] The ring-closing reaction of sodium cyanide with p-nitrophenylhydrazone is relatively complex, and the steric hindrance of the 2-substituent has a greater influence. Under the same room temperature conditions, IIb is much easier to obtain than IIa, so the ring-closing reaction of IIa requires a higher reaction temperature than that of IIb. On the other hand, the configuration of the intermediate II may have a greater influence on the reaction. For the p-nitrophenylhydrazone, the ratio of the Z-form to the E-form of IIa is about 1:5, and the ratio of the Z-form to the E-form of IIb is about 3:1. For the Z-form structure, a reaction similar to SN1 may occur, and the intermediate M is generated, and then the intramolecular ring-closing reaction is performed to obtain IIIb. However, for the E-form isomer, N is generated. Obviously, a higher reaction activation energy is required, that is, heating is required to flip the configuration to complete the ring-closing reaction. In the reaction process, the existence of the intermediate state isocyanate is detected by liquid chromatography-mass spectrometry, which is guessed to be trans-N.

[0033]

[0034] According to Examples 14-16, the reaction results are good at room temperature (generally 25°C). However, 4-chloronitrophenylhydrazone is not stable at room temperature and is easy to decompose and release nitrogen, and is sensitive to water vapor and temperature. If the temperature is too high, the decomposition rate of the raw material is fast, and the selectivity of the reaction is poor. The main reason is that nitrous acid salt is generated in the reaction process, and nitrophenylhydrazone is a reducing agent, and the byproduct nitrous acid salt oxidizes the raw material II. If the reaction time is prolonged, sodium nitrite will also oxidize the ring-closing product, resulting in complex products.

[0035] Alternatively, in the ring-closing reaction, when X is Cl, the reaction temperature is 40-80°C, optionally 55-65°C, and optionally 60-65°C.

[0036] Alternatively, in the ring-closing reaction, when X is H, 4-chlorophenyl nitrophenylhydrazone is more sensitive to the reaction temperature. If the temperature is too high, the decomposition rate of the raw material is fast, and if the temperature is too low, the reaction rate is slow. If the reaction time is prolonged, the yield will be reduced due to the oxidation of the product by nitrous acid salt. Therefore, the ring-closing reaction temperature is 20-60°C, optionally 20-40°C, optionally 20-30°C, and optionally 25-30°C.

[0037] The 4-chlorophenyl nitrohydroxime (IIb) is better than the 2,4-dichloronitrohydroxime (IIa) in the selection of substrates, the main reason is that the existence of 2-chloro has obvious steric effect, which makes the ring-closing reaction and the subsequent fluoromethylation reaction more difficult.

[0038] Considering that the nitrohydroxime and the intermediates M and N can be stabilized by the coordination of metal ions, and the decomposition of the nitrohydroxime is alleviated, in the ring-closing reaction, a coordination metal salt is also added to the reaction system, optionally, the coordination metal salt is a halide salt, and optionally, the coordination metal salt is selected from lithium chloride and / or zinc chloride. 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 above first aspect or second aspect, in the basic system containing nitroethane, the pH value at the end of the reaction is controlled to be 7-9, and optionally 7-8.

[0041] Optionally, in the basic system containing nitroethane, the amount of the basic substance is added to keep the pH value of the reaction system at the end of the reaction at 6-9, and preferably 7-8.

[0042] If the pH value is less than 7, the generated nitroethane anion is easy to quench, so the yield is low; if the pH value is greater than 8, the diazonium salt is unstable, which also causes the yield to be low. With the continuous addition of diazonium salt into the reaction system, a sodium bicarbonate-carbonate buffer system is formed, and it is found through research that when the end point pH value is controlled to be between 7 and 8, the reaction is best, and a very high yield can be obtained.

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

[0044] In the basic system containing nitroethane, the basic substance contains a strong inorganic base and a weak acid strong base salt, the strong inorganic base is used to form a nitroethane anion (the main function of the strong base is to abstract hydrogen), and the weak acid strong base salt is used to form an alkaline buffer system to control the pH in the reaction to a relatively stable level, and the end point pH is between 7 and 8.

[0045] Optionally, the weak acid strong base salt is an alkali metal weak acid salt; optionally, the alkali metal weak acid salt is one or both of a carbonate salt and a bicarbonate salt; optionally, the alkali metal weak acid salt is one or both of an alkali metal carbonate salt and an alkali metal bicarbonate salt; optionally, the inorganic strong base comprises an alkali metal hydroxide, optionally the alkali metal hydroxide is 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, 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 arylamine of Formula I to nitroethane is 1:(1-2), preferably 1:(1-1.5), more preferably 1:(1.1-1.2);

[0048] Optionally, when the alkali metal weak acid salt is an alkali metal carbonate salt, the molar ratio of OH - in the inorganic strong base to the alkali metal carbonate salt is 1:(0.6-1.01), optionally 1:(0.8-1.01), optionally 1:(0.9-1.01);

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

[0050] and / or, the molar ratio of the substituted arylamine of Formula I to OH - in the inorganic strong base 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 molar ratio of the substituted arylamine of Formula I, H + in the acid, nitrite salt 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 arylamine of Formula I is a free amine;

[0054] Alternatively, in the diazonium salt reaction, H in the substituted arylamine of formula I + , and the molar ratio of the 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 arylamine of 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 a strong inorganic acid, and the strong inorganic acid is preferably selected from HCl and H2SO4.

[0058] Further, 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 0-40°C, and is optionally 20-35°C; the stability of 2,4-dichlorophenyl diazonium salt is relatively high, and it is more resistant 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 0-15°C, and is optionally 5-15°C. When 4-chloroaniline is used to prepare IIb, the diazonium salt may be unstable and prone to decomposition at a higher temperature; but if the temperature is too low, the reaction rate is slow, and the diazonium salt is also unstable and prone to decomposition into free radicals to further react with nitrohydrazone; when the temperature is 0-15°C, the yield is higher, and the yield is highest when the temperature is controlled at 5-10°C. The possible reason is that the 4-chlorophenyl diazonium salt is stable and has a relatively high reaction rate at this temperature range.

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

[0062]

[0063] Advantages

[0064] The scheme provided by the present application solves the problems in the prior art 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 from phenylhydrazine, 3-4 equivalents of sodium sulfite are needed for the generation of diazonium salt in the prior art, a large amount of solid waste is generated, and the atomic economy is low; the scheme solves the problem in the prior art that a large amount of mixed salt is generated by using a large amount of sulfite reducing agent and sodium hypochlorite oxidant in the production of raw material phenylhydrazine in the preparation of triazolinone from phenylhydrazine, in the process from diazonium salt to hydrazone, the generated inorganic salt is 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 sodium nitrite is very small and can be ignored, that is, the inorganic salt in the reaction route of the present application can be recycled, which is superior to the traditional technology; the scheme also solves the problem of low chlorination selectivity of methanesulfonamide prepared from phenylhydrazine, and solves the difficult problem of reduction of diazonium salt to hydrazine and oxidation of hydrazine to hydrazine; the present application directly uses the intermediate state hydrazine and then uses cyanate to close the ring, which is 3 steps shorter than the prior art, greatly reduces the energy consumption and labor intensity, and has a good application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0065] One or more embodiments are illustrated by way of example in the figures that form a part of this disclosure and which are shown by way of example, and not limitation, as being illustrative of the principles of the embodiments. The explicit mention of references numbering in the description is only for the purpose of facilitating the understanding of the embodiments and does not constitute a limitation of the embodiments.

[0066] Figure 1 The nuclear magnetic hydrogen spectrum of (E)-1-(2,4-dichlorophenyl)-2-(1-nitroethylidene) hydrazine of the present application embodiment 3.

[0067] Figure 2 The nuclear magnetic hydrogen spectrum of (E)-1-(2,4-dichlorophenyl)-2-(1-nitroethylidene) hydrazine of the present application embodiment 3. Figure 1 The nuclear magnetic hydrogen spectrum of (E)-1-(2,4-dichlorophenyl)-2-(1-nitroethylidene) hydrazine of the present application embodiment 3.

[0068] Figure 3 The nuclear magnetic hydrogen spectrum of (E)-1-(2,4-dichlorophenyl)-2-(1-nitroethylidene) hydrazine of the present application embodiment 3.

[0069] Figure 4 The nuclear magnetic hydrogen spectrum of (E)-1-(2,4-dichlorophenyl)-2-(1-nitroethylidene) hydrazine of the present application embodiment 3.

[0070] Figure 5 The nuclear magnetic hydrogen spectrum of (E)-1-(2,4-dichlorophenyl)-2-(1-nitroethylidene) hydrazine of the present application embodiment 3.

[0071] Figure 6 The nuclear magnetic hydrogen spectrum of (E)-1-(2,4-dichlorophenyl)-2-(1-nitroethylidene) hydrazine of the present application embodiment 3.

[0072] Figure 7 Temperature profile for the dropwise addition of 4-chlorophenyl diazonium salt of the present application.

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

[0074] In order to make the objectives, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely below. Obviously, the described embodiments are some but not all of the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative efforts should fall within the scope of the present application.

[0075] In addition, in order to better illustrate the present application, numerous specific details are given in the following detailed description. Those skilled in the art should understand that the present application can be implemented without some specific details. In some embodiments, the raw materials, schemes, methods, means and the like which are well known to those skilled in the art are not described in detail, so as to highlight the main idea of the present application.

[0076] Unless otherwise clearly indicated, in the entire specification and claims, the term "comprise" or its variants such as "contain" or "include" and the like shall be understood to encompass the stated elements or components, without excluding other elements or components.

[0077] The product content in the following examples is confirmed by liquid chromatography or gas chromatography, and the tracking in the reaction process uses area normalization method, and the selectivity of some reactions uses reaction system area normalization method for determination.

[0078] LCMS: Liquid chromatography mass spectrometry.

[0079] GCMS: Gas chromatography mass spectrometry.

[0080] HPLC: High Performance Liquid Chromatography.

[0081] GC: Gas chromatography.

[0082] NMR: Nuclear magnetic resonance spectrometry.

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

[0084] The preparation of mesosulfuron 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-triazol-3-one (IIIb) of formula III of the present application is shown in the following reaction scheme:

[0085]

[0086] I. 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, which is a coupling reaction of aromatic diazonium salt with enol isomer of compounds containing active methylene under the catalysis of alkaline medium to generate arylhydrazone compounds. Sodium acetate / sodium hydroxide is considered as a preferred combination as an alkaline medium catalyst, but the inventors found that there are more side reactions when using sodium acetate / sodium hydroxide as an alkaline medium for verification, resulting in low purity and yield, such as 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 aqueous hydrochloric acid solution (which was prepared by mixing hydrochloric acid (14.54 g, 123.5 mmol, 4.0 eq of HCl) with water (14.54 g)), and the mixture was stirred at 80 °C for 1 h until the starting material was dissolved. The mixture was then slowly cooled to room temperature and stirred for 0.5 h, and then cooled to 0 °C. A 30% aqueous solution of sodium nitrite (2.24 g, 32.4 mmol, 1.05 eq) in water (5.23 g) was added dropwise to the mixture, and the reaction temperature was controlled at 0-5 °C. The reaction progress was monitored by HPLC, and the reaction was continued for 0.5 h until the starting material was completely converted. The resulting 2,4-dichlorophenyl diazonium salt solution was normalized to 99.6%.

[0091] 2) NaOH (1.85 g, 46.3 mmol, 1.5 eq) was added to water (9.25 g), and the mixture was stirred at room temperature for 20 min. Nitroethane (2.78 g, 37 mmol, 1.2 eq) was then added, and the mixture was stirred at room temperature for 0.5 h. Sodium acetate (7.6 g, 92.6 mmol, 3.0 eq) and water (31 g) were then added, and the mixture was stirred at room temperature for 10 min. The freshly prepared 2,4-dichlorophenyl diazonium salt solution of step 1) was then slowly added to the mixture at room temperature (28-30 °C), and the internal temperature was controlled at 30-35 °C. After the addition was completed, the pH was adjusted to 5-6, and the mixture was stirred at room temperature for 0.5 h. The system was brown, and the conversion of the diazonium salt was monitored by HPLC. The mixture was filtered, and the filter cake was dried at room temperature for 16 h to give a light brown solid (3.55 g, 46.4% yield).

[0092] The brown oil produced in the filtrate of this 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 compound. The structures are shown below:

[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) and stirred at room temperature for 20 minutes, then nitroethane (2.78 g, 37 mmol, 1.2 eq) was added and stirred at room temperature for 0.5 hour, 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 diazonium salt of 2,4-dichlorophenyl prepared in step 1) was slowly added dropwise at room temperature (internal temperature 28-30 °C), the internal temperature was controlled at 30-35 °C, after the addition was completed, pH = 9-10, then stirred at room temperature for 0.5 hour, the system was brown, HPLC tracking diazonium salt conversion was complete. Filtration, wet cake weight 11.3 g. The filter cake was dried at room temperature for 16 hours to obtain a light yellow solid, 5.99 g, yield 78.3%.

[0097] Example 3

[0098] 1) The diazonium salt of 2,4-dichloroaniline was prepared according to step 1) of Example 1, the raw material was scaled up by 10 times.

[0099] 2) NaOH (18.5 g, 460 mmol, 1.5 eq) was dissolved in water (92.6 g) and stirred at room temperature for 20 minutes, then nitroethane (27.8 g, 370 mmol, 1.2 eq) was added and stirred at room temperature for 0.5 hour, 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 hour. Then the diazonium salt of 2,4-dichlorophenyl prepared in step 1) was slowly added dropwise at room temperature (internal temperature 28-30 °C), the internal temperature was controlled at 30-35 °C, after the addition was completed, pH = 7-8, then stirred at room temperature for 0.5 hour, the system was light yellow, liquid phase detection diazonium salt conversion was complete. Filtration, wet cake weight 112 g. The filter cake was dried at room temperature for 16 hours to obtain a light brown solid 75 g, which contained 2.95% water by Karl Fischer method, yield 95.4%.

[0100] The product contains two isomers, 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) (seeFigure 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 Figure 1). Figure 3 )

[0105] The target product IIa has two isomers, Z and E, but mainly E-isomer, and the molar ratio of Z-isomer to 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, and the amount of sodium carbonate added is 49 g (463 mmol, 1.5 eq), and after the addition of diazonium salt is completed, pH = 7-8, and the yield is 96.3%.

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

[0110] Table 1, the effect of pH at the end of the reaction on the reaction:

[0111] Example pH value 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 of the reaction is less than 7, and the reaction yield is only 46.8%, and the inventors speculate that if the pH value is less than 7, the nitroethane anion generated is easy to quench, so the yield is low.

[0113] The inventors unexpectedly found that when sodium acetate is replaced by sodium carbonate or sodium bicarbonate, the yield is unexpectedly improved, for example, Examples 2-4, but the yield of Example 2 is slightly lower, and the inventors believe that the pH value at the end of Example 2 is greater than 8, which causes the diazonium salt to be unstable, which also causes the yield to be lower. The yield of Examples 3 and 4 can be as high as 95%, which may be because as the diazonium salt is continuously added to the reaction system, a sodium bicarbonate-carbonate buffer system is formed, and the pH value at this time is just between 7-8, and the reaction yield is higher.

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

[0115] In step 2), sodium carbonate or sodium bicarbonate is mainly used as a buffer system, or one or more of other alkali metal carbonates and alkali metal bicarbonates can be used. Preferably, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate are used; when sodium carbonate or potassium carbonate is used as a buffer system, the amount of addition can be appropriately reduced to avoid excessive pH in the final reaction, which can be 1-3 eq, preferably 1-1.8 eq, and more preferably 1.3-1.8 eq.

[0116] Preferably, the molar ratio of MOH to M2CO3 (sodium hydroxide-sodium carbonate) is 1:0.6-1.0, and the molar ratio of MOH to MHCO3 (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 6-9; preferably 7-8.

[0118] It should be noted that the inorganic salts produced in the whole process of the present application are mainly sodium chloride, sodium carbonate, and sodium bicarbonate, which can be converted into single sodium chloride by treatment with hydrochloric acid. The waste salt can be recycled and easily treated, which is the reason why this technology has a greater advantage than the 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 is replaced with 4-chloroaniline, specifically:

[0122] 1) 4-chloroaniline (65 g, 509.5 mmol) is suspended in an aqueous hydrochloric acid solution (the preparation method of the aqueous hydrochloric acid solution is: concentrated hydrochloric acid (31.8%, 233.9 g, 2038 mmol, 4.0 eq) is mixed with 233.9 g of water), and the temperature is raised to 80°C and stirred for 1 hour, then slowly cooled to room temperature, and after stirring for 0.5 hours, it is cooled to 0°C, and a 30% aqueous solution of sodium nitrite (36.9 g, 535 mol, 1.05 eq) and 86.2 g of water is slowly added dropwise, the reaction temperature is controlled (0-5°C), the reaction progress is monitored by liquid phase, and the reaction is incubated for 0.5 hours, the raw material is completely converted, and the diazonium liquid is normalized to 98.3%.

[0123] 2) In another flask, add NaOH (23.5g, 588mmol, 1.5eq) into 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 slowly drop the prepared diazonium liquid into it (internal temperature 25-30°C), control the internal temperature at 25-30°C, after adding, pH = 7-8, then natural temperature rise and stir for 0.5 hour, liquid phase detection diazonium salt conversion complete. Filter, filter cake wet weight 136g. Room temperature 16 hours drying, weighing 96g, external standard content 66.6%, equivalent to dry weight 63.9g, yield 58.6%.

[0124] The substrate of this example 5 is slightly different from example 4, and the yield difference is large. The inventors found through continuous research that the 4-chlorophenyl diazonium salt may be unstable and easy to decompose at higher temperature conditions. Some example cases are as follows:

[0125] Example 6

[0126] 1) 4-chloroaniline (5g, 39.2mmol) is suspended in aqueous hydrochloric acid solution (the preparation method of aqueous hydrochloric acid solution is: concentrated hydrochloric acid (31.8%, 18.0g, 156.7mmol, 4.0eq) is mixed with 18g water), heated to 80°C and stirred for 1 hour, slowly cooled to room temperature, stirred for 0.5 hour, then cooled to 0°C, slowly drop 30% aqueous solution of sodium nitrite (2.84g, 41.2mol, 1.05eq) and 6.63g water, control the reaction temperature (0-5°C), liquid phase monitoring reaction process, keep the reaction for 0.5 hour, the raw material is completely converted, the diazonium liquid is normalized to 98.3%, ready for use.

[0127] 2) In another flask, add NaOH (2.35g, 58.8mmol, 1.5eq) and 12g 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), 32g water, stir at room temperature for 0.5 hour, cool down. Then slowly drop the diazonium liquid of step 1) into it (internal temperature -5-0°C), control the internal temperature at -5-0°C, after adding, pH = 7-8, then natural temperature rise and stir for 0.5 hour, liquid phase detection diazonium salt conversion complete. Filter, filter cake wet weight 19g, room temperature 16 hours drying filter cake weighing 8.1g, external standard content 89%, equivalent to dry weight 7.2g, yield 85.8%. LC-MS detection found that the impurity with molecular weight of 324, through column chromatography to get the analysis sample 1,1-bis(4-chlorophenyl)-2-(1-nitroethylidene)hydrazine.

[0128] The by-product of 1,1-bis(4-chlorophenyl)-2-(1-nitroethylidene)hydrazine obtained in this example was analyzed by mass spectrometry and nuclear magnetic resonance hydrogen spectrum, and the results were as follows Figure 4

[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 Figure 1) Figure 4

[0131] Example 7

[0132] 1) 4-Chloroaniline (20 g, 156.8 mmol, 99%) was suspended in an aqueous hydrochloric acid solution (the aqueous hydrochloric acid solution was prepared by mixing concentrated hydrochloric acid (31.8%, 72 g, 627.1 mmol, 4.0 eq) with 72 g of water), and the temperature was raised to 80°C and stirred for 1 hour, then slowly cooled to room temperature, and after stirring for 0.5 hours, cooled to 0°C, and a 30% aqueous solution of sodium nitrite (11.36 g, 164.6 mmol, 1.05 eq) prepared by dissolving sodium nitrite (11.36 g, 164.6 mmol, 1.05 eq) in 26.5 g of water was slowly added dropwise, the reaction temperature was controlled (0-5°C), the reaction progress was monitored by liquid chromatography, and the reaction was incubated for 0.5 hours, and the starting material was completely converted, and the diazonium liquid had a normalized value of 98.5%.

[0133] 2) In another reaction bottle, NaOH (9.4 g, 235.2 mmol, 1.5 eq) and 50 g of water were added, and stirred at room temperature for 20 minutes, then nitroethane (14.12 g, 188.1 mmol, 1.2 eq) was added, and stirred at room temperature for 0.5 hours, then sodium carbonate (24.9 g, 235.2 mmol, 1.5 eq) and water (125 g) were added, and stirred at room temperature for 0.5 hours, and then cooled. Then slowly drop the prepared diazonium liquid (internal temperature 0-5°C), control the internal temperature at 0-5°C, after the addition, pH = 7-8, then naturally warm up and stir for 0.5 hours, and the diazonium salt conversion is complete by liquid chromatography detection. Filter, filter cake wet weight 68 g, dry the filter cake at room temperature for 48 hours, and weigh 34 g, external standard content 91.9%, equivalent to dry weight 31.24 g, yield 93.1%.

[0134] Example 8

[0135] ​​1) 4-chloroaniline (65 g, 509.5 mmol, 99%) was suspended in aqueous hydrochloric acid (aqueous hydrochloric acid was prepared by mixing concentrated hydrochloric acid (31.8%, 233.9 g, 2038 mmol, 4.0 eq) with 233.9 g of water), and the mixture was warmed to 80°C and stirred for 1 hour. The mixture was then slowly cooled to room temperature and stirred for 0.5 hour. The mixture was then cooled to 0°C and a 30% aqueous solution of sodium nitrite (36.9 g, 535 mmol, 1.05 eq) in 86.2 g of water was slowly added dropwise. The reaction temperature was controlled (0-5°C) and the reaction progress was monitored by liquid chromatography. The reaction was maintained for 0.5 hour and the conversion of the starting material was complete. The diazonium solution had a normalized value of 98.3%.

[0136] 2) In another reaction flask, NaOH (30.6 g, 764.3 mmol, 1.5 eq) and 153 g of water were stirred at room temperature for 20 minutes. Nitroethane (45.9 g, 611.4 mmol, 1.2 eq) was then added and the mixture was stirred at room temperature for 0.5 hour. Sodium carbonate (81 g, 764.3 mmol, 1.5 eq) and water (405 g) were then added and the mixture was stirred at room temperature for 0.5 hour and then cooled. The diazonium solution from the first step was then slowly added dropwise while controlling the internal temperature at 5-10°C. After the addition was complete, the pH was adjusted to 7-8 and the mixture was then allowed to warm to room temperature and stirred for 0.5 hour. The conversion of the diazonium salt was complete as determined by liquid chromatography. The mixture was filtered and the filter cake had a wet weight of 236 g. The filter cake was allowed to dry at room temperature for 72 hours and then weighed. The filter cake had a weight of 108.5 g and an external standard content of 98.9%, which corresponded to a dry weight of 107.3 g and a yield of 98.4%.

[0137] The two isomers had the following results by nuclear magnetic resonance hydrogen spectrum Figure 5 、 6 , and the following relevant data:

[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 (br s., 1H), 7.36 (s, 4H), 2.18 (m, 3H) (see Figure 6 ).

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

[0141]

[0142] Example 9

[0143] 1) 4-Chloroaniline (5 g, 39.2 mmol, 99%) was suspended in aqueous hydrochloric acid (aqueous hydrochloric acid was prepared by mixing concentrated hydrochloric acid (31.8%, 18.0 g, 156.7 mmol, 4.0 eq) with 18 g of water), and warmed to 80°C with stirring for 1 hour. The temperature was slowly decreased to room temperature, and after stirring for 0.5 hour, the temperature was decreased to 0°C. A 30% aqueous solution of sodium nitrite (2.84 g, 41.2 mmol, 1.05 eq) in 6.63 g of water was slowly added dropwise, and the temperature was controlled (0-5°C). The progress of the reaction was monitored by liquid chromatography, and the reaction was maintained for 0.5 hour. The conversion of the starting material was complete, and the diazonium solution had a normalized value of 98.3%.

[0144] 2) In another reaction flask, NaOH (2.35 g, 58.8 mmol, 1.5 eq) was added to 12 g of water, and stirred at room temperature for 20 minutes. Nitroethane (3.53 g, 47 mmol, 1.2 eq) was then added, and stirred at room temperature for 0.5 hour. Sodium carbonate (6.23 g, 58.8 mmol, 1.5 eq) and water (32 g) were then added, and stirred at room temperature for 0.5 hour. The temperature was then decreased. The prepared diazonium solution was then slowly added dropwise, and the internal temperature was controlled at -5-0°C. After the addition was completed, the pH was adjusted to 7-8, and the temperature was then increased to room temperature with stirring for 0.5 hour. The conversion of the diazonium salt was complete, as determined by liquid chromatography. The filter cake had a wet weight of 16 g. The filter cake was allowed to dry at room temperature for 16 hours, and had a weight of 83 g. The external standard content was 94.5%, which was equivalent to a dry weight of 7.84 g, and the yield was 93.4%.

[0145] Example 10

[0146] 1) The diazonium salt was prepared according to the procedure of Example 7, Step 1).

[0147] 2) In another reaction flask, NaOH (9.4 g, 235.2 mmol, 1.5 eq) and water (50 g) were added, and stirred at room temperature for 20 minutes. Nitroethane (14.12 g, 188.1 mmol, 1.2 eq) was then added, and stirred at room temperature for 0.5 hour. Sodium carbonate (24.9 g, 235.2 mmol, 1.5 eq) and water (125 g) were then added, and stirred at room temperature for 0.5 hour. The temperature was then decreased. The prepared diazonium solution was then slowly added dropwise, and the internal temperature was controlled at 15-20°C. After the addition was completed, the pH was adjusted to 7-8, and the temperature was then increased to room temperature with stirring for 0.5 hour. The conversion of the diazonium salt was complete, as determined by liquid chromatography. The filter cake had a wet weight of 56 g. The filter cake was allowed to dry at room temperature for 48 hours, and had a weight of 32 g. The external standard content was 89.9%, which was equivalent to a dry weight of 28.76 g, and the yield was 85.7%.

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

[0149] Table 2, yield comparison of 4-chlorophenyl nitrohydroxime at different temperatures with dropwise addition of diazonium salt

[0150] Example Internal temperature (°C) 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 of Table 2 show that when 4-chloroaniline is used as the substrate, the temperature at which the diazonium salt is added has a relatively large effect, which is quite different from the case of 2,4-dichloroaniline. At a higher temperature, the 4-chlorophenyl diazonium salt is unstable and tends to decompose; but at a too low temperature, the reaction rate is slow and the diazonium salt is also unstable and tends to decompose into free radicals to further react with the nitrohydroxime (as shown in the following formula). The yield data are given in Example 6.

[0152]

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

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

[0155] According to the different substrates (2,4-dichloroaniline, 4-chloroaniline) for preparing the intermediate II, the prepared intermediates are shown in formula IIa and IIb, respectively. For IIa, due to the steric hindrance effect of the ortho chlorine atom, the main isomer is E-isomer, and the molar ratio of Z-isomer to E-isomer is about = 1:5; and for IIb, due to the low intramolecular hydrogen bond energy, the main isomer is Z-isomer, and the molar ratio of Z-isomer to E-isomer is about = 3:1. The different configurations have an important influence on the subsequent ring-closing reaction.

[0156]

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

[0158] Based on the above preparation of nitrohydrazone, the nitrohydrazone was further reduced to aminohydrazone (see patent application CN202311260068.9, "A Method for Preparing Iminohydrazone Intermediates"). The aminohydrazone can be cyclized with urea to prepare the key intermediate III of mesotrione (see patent application CN 202311257922.6, "A Method for Preparing Mesotrione and Triadimefon Intermediates"). The main problem with this method is that the generated nitrohydrazone is not very stable, especially under high temperature conditions, there are many byproducts of urea cyclization. Therefore, it was considered 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 was replaced with IIb, the yield could be as high as 70% or more (see Examples 24 and 25).

[0159] Example 11

[0160] Add NaOCN (151 mg, 2.32 mmol, 1.05 eq) and DMF (5 mL) to a reaction flask, heat to 60 °C and stir. Then add 2,4-dichlorophenylnitrohydrazone (540 mg), keep warm and stir for 48 hours until the starting material disappears, and the content is 34.1% by external standard method.

[0161] Example 12

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

[0163] Example 13

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

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

[0166] Example 14

[0167] Add NaOCN (151 mg, 2.32 mmol, 1.05 eq) and DMF (5 mL) to a reaction flask, heat to 90 °C and stir. Slowly add a DMF (5 mL) solution of 4-chlorophenylnitrohydrazone (472 mg, 2.21 mmol) dropwise over 45 min. TLC showed residual starting material; continue stirring for 1 h. TLC showed complete reaction of the starting material. The filtrate weighed 19.2 g, and the content was determined to be 0.35% using external standard method. The actual weight was 67.2 mg, and the reaction selectivity was 14.5%.

[0168] Example 15

[0169] The difference between example 14 is only to stir at 60 °C for 1.2 h, the reaction selectivity is 28.9%.

[0170] Example 16

[0171] 4-Chlorophenyl nitrohydroxime (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 into a reaction flask, the reaction was stirred at 25 °C for 56 h, TLC was used to monitor the reaction (petroleum ether-ethyl acetate 1-5:1), after the reaction was completed, it was filtered, concentrated under reduced pressure at 60 °C, the concentrate was reslurried with petroleum ether-ethyl acetate (4:1), filtered to obtain a white solid 1.04 g, yield 53.0%.

[0172] Example 17

[0173] 4-Chlorophenyl nitrohydroxime (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 into a 100 mL reaction flask, the reaction was stirred at room temperature for 19 h, TLC was used to monitor the reaction (petroleum ether-ethyl acetate 1-5:1), after the reaction was completed, it was filtered, concentrated under reduced pressure at 60 °C, the concentrate was reslurried with petroleum ether-ethyl acetate (4:1), filtered to obtain a white solid 1.10 g, yield 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 attached figure Figure 8

[0177] Example 18

[0178] The difference between example 17 is only to replace calcium chloride with magnesium chloride (27 mg, 0.03 eq) to stir the reaction at room temperature for 21 h, yield 58.6%.

[0179] Example 19 ​​

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

[0181] Example 20

[0182] The difference with example 17 is that only zinc chloride (13 mg, 0.01 eq) is used instead of calcium chloride and the reaction is carried out for 48 hours with a yield of 63.4%.

[0183] Example 21

[0184] 4-Chlorophenyl nitrohydroxime (2.00 g, 1 eq), sodium cyanate (151 mg, 1.05 eq) and DMF (20 ml) are added to the reaction flask, oxygen is bubbled and the reaction is stirred at room temperature for 120 hours, the reaction is monitored by TLC (petroleum ether-ethyl acetate 1-5:1) and after the reaction is completed it is filtered and concentrated under reduced pressure, the concentrate is reslurried with petroleum ether-ethyl acetate (4:1) and filtered to obtain a white solid 1.11 g with a yield of 56.5%.

[0185] Example 22

[0186] 4-Chlorophenyl nitrohydroxime (2.00 g, 1 eq), sodium cyanate (151 mg, 1.05 eq) and methanol (20 ml) are added to the reaction flask, the reaction is stirred at room temperature for 120 hours, the reaction is monitored by TLC until it is completed, it is filtered and concentrated under reduced pressure, the concentrate is reslurried with petroleum ether-ethyl acetate (4:1) and filtered to obtain a white solid 0.93 g with a yield of 47.4%.

[0187] Example 23

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

[0189] Example 24

[0190] The difference with example 22 is that only the solvent is replaced by acetonitrile and the reaction is carried out at 25°C for 16 hours with a selectivity of 76.7% and a yield of 71.2% after work-up.

[0191] Example 25

[0192] The difference with example 24 is that only sodium cyanate is replaced by potassium cyanate and the reaction is carried out at 25°C for 16 hours with a selectivity of 78.2% and a yield of 73.4% after work-up.

[0193] Example 26

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

[0195] According to the above Examples 11-25, the ring closure reaction of sodium cyanide to nitrohydrazone is relatively complex, the steric hindrance of the 2-position substituent has a greater influence, under the same room temperature conditions, IIb is much easier to obtain than IIa, so the ring closure of IIa requires a higher reaction temperature than that of IIb; on the other hand, the configuration of the intermediate II can have a greater influence on the reaction, for the 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 can occur, generating the intermediate M, and then intramolecular ring closure to obtain IIIb; however, for the E form isomer, N is generated, which obviously requires a higher reaction activation energy, i.e. heating is required to complete the ring closure reaction, and during the reaction process, we detected the presence of an intermediate state isocyanate by liquid chromatography-mass spectrometry, which is guessed to be trans-N.

[0196]

[0197] Among them, the influence of temperature on ring closure can be seen from Examples 14-16, and the comparison results are shown in Table 3.

[0198] Table 3, Influence of temperature on ring closure reaction

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

[0200] Table 3 shows that the reaction results are good at room temperature (generally 25°C), but nitrohydrazone is not stable at room temperature and is prone to decomposition and release of nitrogen, and is sensitive to water vapor and temperature, the decomposition rate of the raw material is fast at a higher temperature, and the selectivity of the reaction is poor, the main reason can be that nitrite is generated during the reaction process, and nitrohydrazone is a reducing agent, and the byproduct nitrite oxidizes the raw material II; if the reaction time is prolonged, sodium nitrite will also oxidize the ring closure product, resulting in complex products.

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

[0202] Table 4, Influence of coordination effect of metal halides on reaction

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

[0204] The results of Table 4 show that the coordination effect of metal ions can stabilize nitrohydrazone and intermediates M and N, and the reaction is improved after the addition of halide salt, among which lithium chloride and zinc chloride have better effects, at the same time, we also consider trying to oxidize sodium nitrite by introducing oxygen into the reaction system (see Example 21), but the results are still not satisfactory.

[0205] The stability experiment of intermediate II in solvent shows that nitrohydroxamic acid is not stable in DMF solvent system and its decomposition speed is fast, but in methanol, ethanol, butanol and acetonitrile, the decomposition speed is very slow.

[0206] We further investigated the influence of different solvents on the reaction yield, and the results are shown in Table 5. Using alcohol as the reaction solvent, sodium cyanate is almost insoluble in alcohol, so the reaction rate is very low. DNF as the solvent achieves a moderate yield, but in acetonitrile, the intermediate has good stability and reaction selectivity, and the separation yield can be as high as 70% or more.

[0207] Table 5 Influence of solvent on reaction

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

[0209] In summary, for 4-chlorophenyl nitrohydroxamic acid, the choice of solvent is also crucial to inhibit the decomposition of nitrohydroxamic acid. The solvents that can be selected include DMF, alcohol, acetonitrile, etc. Among them, nitrohydroxamic acid is easy to decompose in DMF, but the reaction rate is high. Although nitrohydroxamic acid is stable in alcohol solvents, the reaction rate is too slow. Acetonitrile meets the requirements of stability and high reaction rate of nitrohydroxamic acid, so the solvents that can be selected include DMF, DCE (N,N-dimethylacetamide), acetonitrile, and acetonitrile is preferred. For 2,4-dichloronitrohydroxamic acid, because its stability is higher than that of 4-chlorophenyl nitrohydroxamic acid, it can withstand higher reaction temperature. The solvents that can be selected include alcohol, DMF, acetonitrile, but alcohol is preferred, and butanol is preferred.

[0210] 4-chlorophenyl nitrohydroxamic acid is more sensitive to reaction temperature. The higher the temperature, the faster the decomposition of the raw material. The lower the temperature, the slower the reaction rate. Prolonging the reaction time will reduce the yield due to the oxidation of the product by nitrite. Therefore, a suitable reaction temperature is necessary. The general reaction temperature is controlled between 20-60°C, preferably between 25-40°C. The reaction temperature of 2,4-dichloronitrohydroxamic acid is controlled between 40-80°C, preferably between 55-65°C.

[0211] The cyclization cyanate can use sodium salt and potassium salt. The molar ratio of cyanate to nitrohydroxamic acid in the reaction can be 1-2:1, and the optimal molar ratio is 1-1.2:1. Too high 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, and the physicochemical properties of nitrohydroxamic acid itself are the primary factor in the cyclization reaction. In the selection of substrates, 4-chlorophenyl nitrohydroxamic acid (IIb) is superior to 2,4-dichloronitrohydroxamic acid (IIa).

[0214] The scheme provided by the present application solves the problems in the prior art that a large amount of inorganic reducing agent such as sodium sulfite is used in the production of raw material phenylhydrazine for preparing triazolinone by phenylhydrazine, a large amount of solid waste is generated, and the atomic economy is low; meanwhile, the problem of low chlorination selectivity in the preparation of sulfentrazone 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 the energy consumption and labor intensity, and has a good application prospect.

[0215] Finally, it should be noted that: the above examples are only used to illustrate the technical solutions of the present application, but not to limit them; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that: it can still modify the technical solutions recorded in the foregoing examples, or make equivalent replacement for part of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present application.

Claims

1. A method for preparing a mesotrione intermediate of Formula III, characterized in that, It comprises: Step one: under acidic conditions, the substituted aniline of formula I reacts with nitrite to form diazonium salt product; The diazonium salt product is added to a basic system containing nitroethane to form the mesosulfuron intermediate of formula II; Step two: the cis-trans isomer compound of formula II undergoes substitution-cyclization reaction with cyanate in a solvent to form the mesosulfuron intermediate of formula III, and the reaction route is as follows: ； In the formula, X is Cl or H; M is Na or K; In the cyclization reaction, the cyanate is sodium cyanate and / or potassium cyanate; In the cyclization reaction, the solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, alcohol, and acetonitrile; the alcohol is selected from C1-C6 low-carbon alcohol; The cyclization reaction temperature is 20-80℃.

2. The production method according to claim 1, characterized by, In the cyclization reaction, the molar ratio of the cis-trans isomer compound of formula II to cyanate is 1:(1-2).

3. The preparation method according to claim 1, characterized in that, In the cyclization reaction, the molar ratio of the cis-trans isomer compound of formula II to cyanate is 1:(1-1.2).

4. The preparation method according to claim 1, characterized in that, In the cyclization reaction, the molar ratio of the cis-trans isomer compound of formula II to cyanate is 1:(1.05-1.1).

5. The preparation method according to claim 1, characterized in that, In the cyclization reaction, when X is Cl, the solvent is alcohol, DMF, acetonitrile, and the alcohol is one or more of methanol, ethanol, propanol, n-butanol, isopropanol, sec-butanol, tert-butanol, and amyl alcohol.

6. The method of claim 1, wherein, In the cyclization reaction, when X is Cl, the solvent is n-butanol.

7. The preparation method according to claim 1, characterized in that, In the cyclization reaction, when X is H, the solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and acetonitrile.

8. The method of claim 1, wherein, In the cyclization reaction, when X is H, the solvent is N,N-dimethylformamide and / or acetonitrile.

9. The method of claim 1, wherein, In the cyclization reaction, when X is Cl, the cyclization reaction temperature is 40-80℃.

10. The method of claim 1, wherein, In the cyclization reaction, when X is Cl, the cyclization reaction temperature is 55-65℃.

11. The method of claim 1, wherein, In the cyclization reaction, when X is Cl, the cyclization reaction temperature is 60-65℃.

12. The method of claim 1, wherein, In the cyclization reaction, when X is H, the cyclization reaction temperature is 20-60℃.

13. The method of claim 1, wherein, In the cyclization reaction, when X is H, the cyclization reaction temperature is 20-40℃.

14. The method of claim 1, wherein, In the cyclization reaction, when X is H, the cyclization reaction temperature is 20-30℃.

15. The method of claim 1, wherein, In the cyclization reaction, when X is H, the cyclization reaction temperature is 25-30℃.

16. The method of claim 1, wherein, In the cyclization reaction, a complex metal salt can also be added to the reaction system, and the complex metal salt is selected from lithium chloride and / or zinc chloride.

17. The method of claim 1, wherein, In the basic system containing nitroethane, the pH at the end of the reaction is controlled to be 7-9.

18. The method of claim 1, wherein, In the basic system containing nitroethane, the pH at the end of the reaction is controlled to be 7-8.

19. The method of making according to any one of claims 1 to 18, wherein, In the basic system containing nitroethane, a basic substance is used, and the basic substance comprises a strong inorganic base and a weak acid-strong base salt, the strong inorganic base is used to form a negative ion of nitroethane, and the weak acid-strong base salt is used to form a basic buffer system.

20. The method of claim 19, wherein, The weak acid-strong base salt is an alkali metal weak acid salt.

21. The method of claim 20, wherein, The alkali metal weak acid salt is one or both of an alkali metal carbonate and an alkali metal bicarbonate.

22. The preparation method according to claim 20, characterized in that, The strong inorganic base comprises an alkali metal hydroxide.

23. The preparation method according to claim 22, characterized in that, The alkali metal hydroxide is selected from sodium hydroxide and / or potassium hydroxide.

24. The method of claim 21, wherein, The alkali metal weak acid salt is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.

25. The preparation method according to claim 19, characterized in that, The molar ratio of the inorganic strong base to nitroethane is (1.1-1.5):

1.

26. The method of claim 19, wherein, The molar ratio of the inorganic strong base to nitroethane is (1.2-1.5):

1.

27. The preparation method according to claim 19, characterized in that, The molar ratio of the substituted arylamine of formula I to nitroethane is 1:(1-2).

28. The preparation method according to claim 19, characterized in that, The molar ratio of the substituted arylamine of formula I to nitroethane is 1:(1-1.5).

29. The preparation method according to claim 19, characterized in that, The molar ratio of the substituted arylamine of formula I to nitroethane is 1:(1.1-1.2).

30. The method of claim 21, wherein, When the alkali metal weak acid salt is an alkali metal carbonate, the molar ratio of OH - to the alkali metal carbonate is 1 : (0.6-1.01).

31. The method of claim 21, wherein, When the alkali metal weak acid salt is an alkali metal carbonate, the molar ratio of OH - to the alkali metal carbonate is 1 : (0.8-1.01).

32. The method of claim 21, wherein the method is carried out at a temperature of about 20°C to about 30°C. When the alkali metal weak acid salt is an alkali metal carbonate, the molar ratio of OH - to the alkali metal carbonate is 1 : (0.9-1.01).

33. The method of claim 21, wherein the method is carried out at a temperature of about 20°C to about 30°C. When the acid salt of an alkali metal is an alkali metal bicarbonate, the OH- in the inorganic strong base... - The molar ratio with alkali metal bicarbonate is 1:(1 to 2.02).

34. The method of claim 21, wherein the method is carried out at a temperature of about 20°C to about 30°C. When the alkali metal weak acid salt is an alkali metal bicarbonate, and when X is Cl, the OH- in the inorganic strong base... - The molar ratio with alkali metal bicarbonate is 1:(1.2 to 2.02).

35. The method of claim 21, wherein, When the alkali metal weak acid salt is an alkali metal bicarbonate, and when X is Cl, the OH- in the inorganic strong base... - The molar ratio with alkali metal bicarbonates is 1:(1.8~2.02).

36. The method of claim 21, wherein, When the alkali metal weak acid salt is an alkali metal bicarbonate, and when X is H, the OH- in the inorganic strong base... - The molar ratio with alkali metal bicarbonate is 1:(1 to 2.02).

37. The method of claim 19, wherein the method is carried out at a temperature of about 20°C to about 30°C. The molar ratio of the substituted arylamine represented by Formula I to OH - in the inorganic strong base is 1: (1.1-2).

38. The method of claim 25, wherein, The molar ratio of the substituted arylamine represented by Formula I to OH - in the inorganic strong base is 1: (1.1-2).

39. The method of claim 19, wherein, The molar ratio of the substituted arylamine represented by Formula I to OH - of the inorganic strong base is 1: (1.3~1.8).

40. The method of claim 19, wherein, The molar ratio of the substituted arylamine represented by Formula I to OH - in the inorganic strong base is 1: (1.3~1.5).

41. The method of claim 19, wherein, In the diazonium reaction, the molar ratio of the substituted arylamine of formula I, H + , and nitrite is 1: (3-5): (1-2).

42. The method of claim 19, wherein, In the diazonium reaction, the molar ratio of the substituted arylamine of formula I, H + , and nitrite is 1 : (3.5-4.5) : (1-1.2).

43. The method of claim 19, wherein the method is carried out at a temperature of about 20°C to about 30°C. In the diazonium reaction, the molar ratio of the substituted arylamine of formula I, H + , nitrite is 1: (3-4): 1.

05.

44. The method of claim 19, wherein the method is carried out at a temperature of about 20°C to about 30°C. In the diazonium reaction, the molar ratio of the substituted arylamine of formula I, H + , and nitrite is 1:4:1.

05.

45. The method of claim 19, wherein the method is carried out at a temperature of about 20°C to about 30°C. In the diazonium reaction, the molar ratio of the substituted arylamine of formula I, H + , and nitrite is 1: (2~4): (1~2).

46. The method of claim 19, wherein the method is carried out at a temperature of about 20°C to about 30°C. In the diazonium reaction, the molar ratio of the substituted arylamine of formula I, H + , and nitrite is 1:3:1.

05.

47. The method of claim 19, wherein the method is carried out at a temperature of about 20°C to about 30°C. In the diazonium salt reaction, the nitrite is selected from sodium nitrite and potassium nitrite.

48. The method of claim 19, wherein, In the diazonium salt reaction, the acid used in the diazotization reaction is a protonic acid.

49. The method of claim 48, wherein, The protonic acid is selected from inorganic strong acids.

50. The method of claim 49, wherein, The inorganic strong acid is selected from HCl and H2SO4.

51. The method of claim 19, wherein, The reaction temperature of the diazonium salt and nitroethane is 0-40℃.

52. The method of claim 19, wherein the method is carried out at a temperature of about 20°C to about 30°C. When X is Cl, the reaction temperature of the diazonium salt and nitroethane is 0-40℃.

53. The method of claim 19, wherein, When X is Cl, the reaction temperature of the diazonium salt and nitroethane is 20-35℃.

54. The method of claim 19, wherein, When X is H, the reaction temperature of the diazonium salt and nitroethane is 0-15℃.

55. The method of claim 19, wherein the method is carried out at a temperature of about 20°C to about 30°C. When X is H, the reaction temperature of the diazonium salt and nitroethane is 5-15℃.

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