A process for the preparation of a mesosulfuron intermediate

Abstract

The present application relates to the synthesis of pesticide compounds, in particular to a method for preparing a pyrasulfotole intermediate. The method comprises: (1) using p-chlorotoluene as a raw material, through nitration, chlorination, hydrolysis, or chlorination, hydrolysis, nitration, to obtain 3-nitro-4-chlorobenzaldehyde, (2) fluorination and reduction of 3-nitro-4-chlorobenzaldehyde to obtain 4-fluoro-3-amino benzaldehyde; (3) 4-fluoro-3-amino benzaldehyde is then contacted with chloroformate for reaction, and then chlorination to obtain compound IV; (4) compound IV is contacted with trifluorobutanamine ester under alkaline conditions for reaction to obtain compound I. The process for preparing compound I avoids using expensive raw material 2-chloro-4-fluorobenzoic acid, effectively reduces the cost of raw materials, reduces the three wastes generated in the process, and at the same time, the total yield of the reaction is high, and it is suitable for industrial mass production.

Description

Technical Field

[0001] This invention relates to the synthesis of pesticide compounds, and more specifically to a method for preparing an intermediate of pyrimethanil. Background Technology

[0002] Bensulfuron-methyl is a pesticide with broad crop applicability and an excellent broadleaf weed control spectrum. CN100558714A, CN1890222A, and CN1383425A disclose processes for producing bensulfuron-methyl. However, existing processes suffer from drawbacks such as low reaction yield, demanding conditions and long routes, low intermediate synthesis yield, high levels of waste, high hazard, and difficulty in large-scale production.

[0003] Therefore, the preparation process of bensulfuron-methyl intermediate still needs improvement. Summary of the Invention

[0004] The present invention aims to solve at least one of the above-mentioned technical problems or to provide at least one useful commercial option.

[0005] This invention provides a method for preparing the intermediate of benzosulfuron, the preparation route of which is as follows:

[0006] (1) Using p-chlorotoluene as a raw material, compound II (3-nitro-4-chlorobenzaldehyde) is obtained by nitration, chlorination and hydrolysis; or, using p-chlorotoluene as a raw material, compound II (3-nitro-4-chlorobenzaldehyde) is obtained by chlorination, hydrolysis and nitration.

[0007]

[0008] (2) Fluoride and reduce compound II to obtain compound III (4-fluoro-3-aminobenzaldehyde);

[0009]

[0010] (3) Compound III reacts with chloroformate and then chlorinates to give compound IV, wherein R is methyl, ethyl, propyl or butyl;

[0011]

[0012] (4) Compound IV reacts with compound V (trifluorocrotidine) under alkaline conditions to give compound I.

[0013]

[0014] The process for preparing compound I (i.e., the intermediate of pyrimisulfuron-methyl) in this invention avoids the use of expensive raw material 2-chloro-4-fluorobenzoic acid, effectively reducing the cost of raw materials and reducing the three wastes generated in the process. At the same time, the overall reaction yield is high, making it suitable for large-scale industrial production.

[0015] According to an embodiment of the present invention, the route for preparing compound II in step 1) is as follows:

[0016]

[0017] In step 1), the p-chlorotoluene is nitrated with nitric acid, and the preferred molar ratio of p-chlorotoluene to nitric acid is 1:(1-2); the preferred reaction temperature is -10℃ to 10℃ (e.g., 0-5℃). Studies have found that under these conditions, there are fewer reaction isomers and separation is simple.

[0018] In step 1), the 4-chloro-5-nitrotoluene generated by the reaction is chlorinated by reacting with chlorine gas, and the chlorination temperature is preferably 90-200℃. The molar ratio of 4-chloro-5-nitrotoluene to chlorine gas is preferably 1:(2-5); the solvent can be 3,4-dichlorotrifluorotoluene, dichloroethane, or no solvent.

[0019] In step 1), the hydrolysis reaction is carried out, and the preferred hydrolysis temperature is 40-100℃.

[0020] In step 2), compound II undergoes fluorination and reduction reactions to obtain compound III, and the preparation route is as follows:

[0021]

[0022] In step 2), compound II is fluorinated with potassium fluoride; the preferred molar ratio of compound II to potassium fluoride is 1:(1-3), and the preferred fluorination temperature is 90-200℃ (e.g., 120-130℃). After fluorination, compound VI (4-fluoro-3-nitro-5-benzaldehyde) is formed.

[0023] In step 2), the generated compound VI undergoes a reduction reaction with hydrogen. The preferred molar ratio of compound VI to hydrogen is 1:(10-20). The preferred reaction solvent is methanol, ethanol, or isopropanol, and the preferred reaction temperature is 50-80°C. A catalyst, such as PA / c-palladium / carbon, may be added.

[0024] Further, in step 2), the generated compound VI undergoes a reduction reaction with hydrogen gas under acidic conditions. Inorganic acids such as hydrochloric acid (concentrated hydrochloric acid), sulfuric acid, nitric acid, and phosphoric acid are commonly used, with hydrochloric acid being preferred. The advantages of using hydrochloric acid are high reaction yield, good selectivity, and ease of industrialization. Organic acids such as sulfonic acid, sulfinic acid, thiocarboxylic acid, formic acid, and acetic acid can also be used. The reduction reaction in step 2) readily produces byproducts and coupling compounds. Studies have found that carrying out the reduction reaction under acidic conditions can significantly reduce byproducts and increase the yield.

[0025] In some embodiments, the molar ratio of compound II (or compound VI) to concentrated hydrochloric acid is preferably 1:(1-1.2).

[0026] In step 3), compound III reacts with chloroformate in a polar solvent, followed by chlorination to synthesize compound IV. The chloroformate can be selected from methyl chloroformate, ethyl chloroformate, propyl chloroformate, or butyl chloroformate. The polar solvent can be selected from one or more of dichloroethane, toluene, chlorobenzene, and xylene. The preferred molar ratio of compound III to chloroformate is 1:(1.1-1.5).

[0027] Furthermore, after compound III reacts with chloroformate, the solvent is removed before chlorination.

[0028] In step 3) the chlorination reaction, the preferred molar ratio of compound III to chlorine is 1:(1.1-2); the preferred reaction temperature is 0-40℃, for example, room temperature.

[0029] Furthermore, step 3) chlorination is carried out in the presence of acetonitrile. Typically, the yield of step 3) chlorination is extremely low (approximately 10%). The inventors unexpectedly discovered that using acetonitrile as a solvent for chlorination significantly improves the yield compared to other solvents or no solvent at all. In some embodiments, the yield of compound IV can reach over 85%.

[0030] According to an embodiment of the present invention, compound IV and compound V react in an aprotic polar solvent under alkaline conditions to yield compound I.

[0031] In step 4), compound IV is first protected to form a condensate of compound IV, which then reacts with compound V under alkaline conditions, followed by hydrolysis to prepare compound I. The preferred protecting reagent is ethylene glycol, propylene glycol, methanol, or ethanol. Studies have shown that if compound IV is not protected, numerous side reactions occur, resulting in very few major products. Protecting compound IV before subsequent reactions yields the target compound with extremely high selectivity and very few byproducts.

[0032] In step 4), the alkali used is preferably potassium carbonate. The molar ratio of compound IV to potassium carbonate is preferably 1:(2.1-3).

[0033] In step 4), the solvent used is one or more of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), dimethyl sulfoxide (DMSO), and N-methylpyrrolidone (NMP).

[0034] In step 4), the hydrolysis is performed in a sulfuric acid or hydrochloric acid solution.

[0035] In step 4), the ring-closing reaction temperature is 120-230℃.

[0036] Based on common knowledge in the field, the above-mentioned technical features of this invention can be arbitrarily combined to obtain the preferred embodiments of this invention.

[0037] Specifically, the method for preparing the bensulfuron-methyl intermediate includes:

[0038] (1) Compound II is obtained by nitration, chlorination and hydrolysis of p-chlorotoluene as a raw material; or, compound II is obtained by chlorination, hydrolysis and nitration of p-chlorotoluene as a raw material.

[0039]

[0040] (2) Compound II was fluorinated and reduced to obtain compound III; the preparation route is as follows:

[0041]

[0042] Among them, compound VI undergoes a reduction reaction with hydrogen under acidic conditions, and hydrochloric acid is preferred as the acid used.

[0043] (3) Compound III reacts with chloroformate and then chlorinates to give compound IV, wherein R is methyl, ethyl, propyl or butyl;

[0044]

[0045] The chlorination reaction is carried out in the presence of acetonitrile;

[0046] (4) Compound IV is first protected to form a condensate of compound IV, and then reacts with compound V under alkaline conditions to give compound I.

[0047]

[0048] The preferred protective reagents are ethylene glycol, propylene glycol, methanol, or ethanol.

[0049] This invention has at least one of the following beneficial effects:

[0050] 1) The preparation conditions of the method described in this invention are mild, and the requirements for equipment and raw materials are not high, which is conducive to large-scale promotion;

[0051] 2) The raw materials used in the method described in this invention are low in cost, and the product yield and purity are high.

[0052] 3) The method of this invention is relatively environmentally friendly, with low emissions of waste, low cost, and low risk of accidents, making it suitable for large-scale industrial production. Detailed Implementation

[0053] The following provides a detailed description of specific embodiments of the present invention. It should be understood that the specific embodiments described herein are for illustrative purposes only and are not intended to limit the scope of the invention.

[0054] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0055] The present invention will be described in detail below through embodiments. The following embodiments include:

[0056] The amounts of reactants and products were determined by liquid chromatography (Agilent HPLC 1260).

[0057] The conversion rate and selectivity of the reaction are calculated using the following formulas:

[0058] Conversion rate = (molar amount of raw material input - molar amount of raw material remaining in the product) / molar amount of raw material input × 100%.

[0059] Selectivity = (Actual molar amount of target product / Theoretical molar amount of target product) × 100%

[0060] Unless otherwise specified, all raw materials used are commercially available products, and the room temperature is 25±5℃.

[0061] The following compounds:

[0062]

[0063] Example 1

[0064] Preparation of Compound II

[0065] 1) In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, add 0.1 mol of p-chlorotoluene and 0.5 mol of sulfuric acid, cool to 5°C, add 0.11 mol of nitric acid dropwise, and after the reaction is deemed satisfactory, add dichloroethane for extraction.

[0066] 2) After removing the solvent, add 3,4-dichlorotrifluorotoluene, heat to 130℃, introduce 0.25 mol of chlorine gas, react for 4 hours, and the reaction is qualified by liquid phase detection;

[0067] 3) After removing the solvent under reduced pressure, add 85% formic acid solution and hydrolyze for 5 hours. After the liquid phase test is qualified, remove the formic acid to obtain compound II; purity 95%, yield 90% (based on p-chlorotoluene).

[0068] Preparation of Compound III

[0069] In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 0.1 mol of compound II, 100 g of DMF, and 0.3 mol of potassium fluoride were added. The mixture was heated to 130°C and reacted for 12 h. After the reaction was deemed satisfactory, the mixture was cooled to room temperature, filtered to remove salt, and the mother liquor was depressurized to recover DMF. The product was dissolved in methanol and added to an autoclave. Hydrogen gas was introduced at a pressure of 10 kg, and 1 g of catalyst PA / c-palladium / carbon and 0.11 mol of hydrochloric acid were added. The mixture was heated to 50°C and added dropwise until the reaction was complete. After the reaction was deemed complete, the solvent was removed under reduced pressure. The crude product was crystallized from methanol to obtain compound III with a purity of 98% and a yield of 85% (based on compound II).

[0070] Preparation of Compound IV

[0071] In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 0.1 mol of compound III and 100 g of dichloroethane were added. The mixture was heated to 80 °C and 0.11 mol of methyl chloroformate was added dropwise. After the addition was complete, the reaction was continued for 1 hour. After the reaction was deemed satisfactory, the mixture was cooled to room temperature, and solvent was removed under reduced pressure. Then, 100 g of hexanilide was added, and chlorine gas was passed through at room temperature. After the reaction was deemed complete, the solvent was removed under reduced pressure to obtain compound IV with a purity of 98%. The yield of compound IV was 85% (calculated based on compound III).

[0072] In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 0.1 mol of compound IV and 100 g of dichloroethane were added. The mixture was heated to 80 °C and 0.11 mol of ethylene glycol was added dropwise. After the addition was complete, the mixture was refluxed for 1 hour. After the reaction was deemed satisfactory, the mixture was cooled to room temperature and dissolved under reduced pressure to obtain the condensate of compound IV with a purity of 98% and a yield of 98% (calculated based on compound IV).

[0073] Preparation of Compound I

[0074] 1) In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, add 0.1 mol of compound IV condensate, 100 g of DMF, and 0.3 mol of potassium carbonate. Heat to reflux, then add 0.12 mol of compound V dropwise. After the addition is complete, reflux for 10 hours. After the liquid phase test is qualified, cool to room temperature, filter, and remove DMF from the mother liquor. Add dichloroethane to dissolve the product.

[0075] 2) The above dichloroethane mother liquor was added to a 15% hydrochloric acid aqueous solution and heated under reflux for 5 hours. After the liquid phase test showed that the reaction was qualified, the temperature was lowered and the mixture was allowed to stand and separate into layers. After removing the dichloroethane under reduced pressure, 100g of methanol was added to the system, and the temperature was gradually lowered to crystallize the mixture to obtain compound I with a purity of 98% and a yield of 80% (calculated based on compound IV).

[0076] Example 2

[0077] The preparation of compound II differed from that in Example 1 only in that it underwent nitration followed by chlorination and hydrolysis, with the reaction conditions remaining the same. Compound II was obtained with a purity of 90% and a yield of 80% (based on p-chlorotoluene).

[0078] Comparative Example 1

[0079] The preparation of compound III differed from that in Example 1 only in that hydrochloric acid was not added during the reduction reaction. Compound III was obtained with a purity of 25% and a yield of 40% (based on compound II).

[0080] Comparative Example 2

[0081] Preparation of Compound IV

[0082] In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 0.1 mol of compound III and 100 g of dichloroethane were added. The mixture was heated to 80 °C and 0.11 mol of methyl chloroformate was added dropwise. After the addition was complete, the reaction was continued for 1 hour. After the reaction was deemed satisfactory, the mixture was cooled to room temperature, and the solvent was removed under reduced pressure. Then, 100 g of dichloroethane was added, and chlorine gas was passed through at room temperature. After the reaction was deemed complete, the solvent was removed under reduced pressure to obtain compound IV with a purity of 50%. The yield of compound IV was 10% (calculated based on compound III).

[0083] Comparative Example 3

[0084] The preparation of compound I differed from that in Example 1 only in that it was prepared using compound IV instead of the condensate of compound IV. Results: Compound I was obtained with a purity of 35% and a yield of 39% (based on compound IV).

[0085] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for preparing a bensulfuron-methyl intermediate, characterized in that, The preparation route is as follows: (1) Compound II is obtained by nitration, chlorination and hydrolysis of p-chlorotoluene as raw material; or, compound II is obtained by chlorination, hydrolysis and nitration of p-chlorotoluene as raw material. ； (2) Compound II is fluorinated to obtain compound VI, and compound VI is reduced under acidic conditions to obtain compound III. The preparation route is as follows: ； (3) Compound III reacts with chloroformate in a polar solvent, and then the solvent is removed before chlorination under acetonitrile conditions to remove acetonitrile and synthesize compound IV, wherein R is methyl, ethyl, propyl or butyl; ； (4) Compound IV is first protected to form a condensate of compound IV, and then reacts with compound V under alkaline conditions to give compound I. ； Step (2) Compound VI undergoes a reduction reaction with hydrogen. The molar ratio of compound VI to hydrogen is 1:(10~20). The reaction solvent is methanol, ethanol or isopropanol. The reaction temperature is 50~80℃. The reaction catalyst is PA / c-palladium / carbon. Concentrated hydrochloric acid is used under acidic conditions for the reduction reaction. The molar ratio of compound II to concentrated hydrochloric acid is 1:(1-1.2). The protective reagent in step (4) is ethylene glycol, propylene glycol, methanol or ethanol.

2. The method according to claim 1, characterized in that, The route for preparing compound II is as follows: ； 。 3. The method according to claim 1, characterized in that, In step (1), the p-chlorotoluene is nitrated with nitric acid, and the molar ratio of p-chlorotoluene to nitric acid is 1:(1-2); the reaction temperature is -10 to 10℃.

4. The method according to claim 1, characterized in that, In step (1), the 4-chloro5-nitrotoluene generated by the reaction is chlorinated by reacting with chlorine gas at a temperature of 90-200℃; the molar ratio of the 4-chloro5-nitrotoluene to chlorine gas is 1:(2-5).

5. The method according to claim 1, characterized in that, In step (2), compound II is fluorinated with potassium fluoride; the molar ratio of compound II to potassium fluoride is 1:(1-3), and the fluorination temperature is 90-200℃.

6. The method according to claim 1, characterized in that, The chloroformate in step (3) is selected from methyl chloroformate, ethyl chloroformate, propyl chloroformate, and butyl chloroformate; The polar solvent is selected from one or more of dichloroethane, toluene, chlorobenzene, and xylene; The molar ratio of compound III to chloroformate is 1:(1.1-1.5).

7. The method according to claim 6, characterized in that, In step (3) the chlorination reaction, the molar ratio of compound III to chlorine is 1:(1.1-2); the reaction temperature is 0-40℃.

8. The method according to claim 1, characterized in that, Compound IV and compound V react in an aprotic polar solvent under basic conditions to give compound I; and / or, In step (4), the base used is potassium carbonate; the molar ratio of compound IV to potassium carbonate is 1:(2.1-3); and / or, In step (4), the solvent used is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone; and / or, In step (4), the ring-closing reaction temperature is 120-230℃.

Images