Preparation method of topramezone

Abstract

The invention discloses a preparation method of topramezone, which comprises the following step: reacting 3-[3-bromo-methyl-6-(methylsulfonyl) phenyl]-4, 5-dihydroisoxazole and 1-methyl-5-hydroxypyrazole in the presence of a palladium catalyst, a phosphine ligand, an acid-binding agent and dimethyl carbonate to obtain the topramezone. The preparation method is mild in reaction conditions, high-pressure conditions are not needed, toxic CO is not needed, topramezone with high content and yield can be prepared, and the preparation method is suitable for industrial application.

Description

Technical Field

[0001] The invention belongs to the technical field of herbicide preparation, and particularly relates to a method for preparing fenpyrotone. Background Art

[0002] Topramezone is the first benzoyl pyrazolone herbicide discovered and developed by BASF. It belongs to the class of hydroxyphenylpyruvate dioxidase inhibitory (HPPD) herbicides. It is absorbed by roots, seedlings and leaves, and is conducted to the top and base of plants to the meristem, inhibiting hydroxyphenylpyruvate dioxidase, indirectly inhibiting the biosynthesis of carotenoids, interfering with the synthesis and function of chloroplasts, and causing chlorosis and necrosis of chlorotic tissues due to the oxidative degradation of chlorophyll. It has a good control effect on weeds resistant to glyphosate, triazines, acetolactate synthase (AIS) inhibitors and acetyl-CoA carboxylase (ACCase) inhibitors. It is a broad-spectrum post-emergence herbicide that can effectively control annual grass and broad-leaved weeds in corn fields. High doses have a certain inhibitory effect on sedge weeds.

[0003] For the synthesis of fenpyroxene, the methods reported at home and abroad are mainly divided into two categories, namely CO insertion carbonyl method and carboxyl chlorination to ester followed by rearrangement method. Among them, the carboxyl chlorination to ester followed by rearrangement method is to use an isoxazole intermediate, namely 3-(2-methyl-6-methylsulfonylbenzoic acid)-4,5-dihydroisoxazole, to condense and rearrange with pyrazole. The process steps of this method are relatively complicated. The CO insertion carbonyl method can be completed in one pot. The current CO insertion carbonyl method synthesis routes mainly include the following:

[0004] Route 1:

[0005]

[0006] Referring to Chinese patent application publication number CN114057715A, the compound of formula II and the compound of formula III are used as raw materials to react in the presence of a Pd catalyst, a ligand, CO and a base to obtain the compound of formula I.

[0007] Route 2:

[0008]

[0009] Referring to Chinese patent application publication number CN112125897A, compound I (3-[3-bromo-2-methyl-6-(methylthio)-phenyl]-4,5-dihydroisoxazole) and compound II (1-methyl-5-hydroxypyrazole) are reacted in the presence of an organic solvent, a base and a cobalt catalyst to obtain fenpyroxetine.

[0010] Route 3: Chinese patent application with publication number CN111440160A reports a scheme in which 3-[3-bromo-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole, 1-methyl-5-hydroxypyrazole, triethylamine, potassium carbonate, palladium chloride and triphenylphosphine are mixed in a preset ratio and added into an autoclave, and then 1,4-dioxane is added as a solvent to prepare fenpyroxene.

[0011] However, the current CO carbonylation synthesis process involves high temperature and high pressure, and the reaction pressure generally exceeds 2 MPa, which is very dangerous during the synthesis. At the same time, the CO used is a toxic gas, which is not conducive to environmental protection. Summary of the invention

[0012] In view of this, the primary purpose of the present invention is to provide a preparation method of fenpyroxetine, which does not require reaction under high pressure and does not require the use of CO, has low risk, simple operation steps, and is environmentally friendly. In addition, the product content and yield of the synthesized fenpyroxetine are relatively high.

[0013] In order to achieve the above object, the present invention adopts the following technical solutions:

[0014] The present invention provides a method for preparing fenpyroxetine, comprising the following steps:

[0015] The method comprises reacting 3-[3-bromo-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole and 1-methyl-5-hydroxypyrazole in the presence of a palladium catalyst, a phosphine ligand, an acid-binding agent and dimethyl carbonate to prepare fenpyrazone.

[0016] The specific synthetic route is as follows:

[0017]

[0018] Compound a (3-[3-bromo-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole) and compound b (1-methyl-5-hydroxypyrazole) react under the action of dimethyl carbonate, palladium catalyst, phosphine ligand and acid binding agent to obtain compound I, namely, benzathine. Among them, dimethyl carbonate is subjected to oxidative addition and reduction elimination, and the carbonyl group in dimethyl carbonate is inserted into compound a and cross-coupled with compound b to generate benzathine original drug, and the halogen on the isoxazole molecule and the hydrogen on the pyrazole are combined to form a molecule of HBr, which is then neutralized by the acid binding agent to make the reaction proceed in the forward direction.

[0019] In a further embodiment, the palladium catalyst is at least one of palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, and bistriphenylphosphine palladium dichloride.

[0020] In a further embodiment, the phosphine ligand is at least one of triphenylphosphine, tributylphosphine, and tricyclohexylphosphine.

[0021] In a further embodiment, the acid binding agent is potassium carbonate, sodium carbonate, sodium acetate or triethylamine.

[0022] It is understood that the amounts of the palladium catalyst, the phosphine ligand and the acid binding agent can be adjusted according to the specific conditions of the reaction raw materials based on methods known in the art. In some specific embodiments of the present invention, the molar amount of the palladium catalyst is 3%-5% of 3-[3-bromo-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole, and the molar ratio of the palladium catalyst to the phosphine ligand is 1:2. Preferably, the molar amount of the palladium catalyst is 5% of 3-[3-bromo-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole.

[0023] The molar amount of the acid binding agent is 1.5-3 times that of 3-[3-bromo-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole, preferably 3 times.

[0024] Wherein, in the present invention, dimethyl carbonate is both a solvent and a reactant, therefore, dimethyl carbonate is in excess, and in some specific implementation cases of the present invention, the molar amount of the dimethyl carbonate is 90-150 times that of 3-[3-bromo-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole; preferably, the molar amount of the dimethyl carbonate is 100 times that of 3-[3-bromo-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole.

[0025] In a further embodiment, the preparation of the fenpyroxetine described in the present invention specifically comprises the following steps:

[0026] S1, adding 3-[3-bromo-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole and 1-methyl-5-hydroxypyrazole as well as a palladium catalyst, a phosphine ligand, an acid binding agent and dimethyl carbonate into a reaction vessel;

[0027] S2, slowly heating to reflux reaction while stirring;

[0028] S3. When the content of 3-[3-bromo-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole in the reaction solution is not greater than 0.3%, it indicates that the reaction is substantially complete and the reaction can be terminated, the temperature is lowered and the mother solution is obtained by filtering;

[0029] S4, after rotary evaporation of the mother liquor to obtain a yellow solid, water is added and stirred to completely dissolve;

[0030] S5. Then, the system temperature is lowered to not more than 5° C., and acid solution is slowly added dropwise while stirring to adjust the pH value of the system to 3-4. The system is filtered and dried to obtain fenpyroxetine.

[0031] In a further solution, in step S2, after every 6 hours of reflux reaction, all the solution under reflux on the right side of the water separator is poured out, and the same volume of fresh dimethyl carbonate is added from the upper opening of the condenser.

[0032] In a further scheme, in step S3, the cooling refers to the temperature being reduced to 30-40° C. It should be noted that in this step, the palladium catalyst can be retained by filtering after cooling and can be reused. Experiments have shown that the use of the recovered catalyst for the pyraclostrobin has almost no effect on its content and yield, which can significantly reduce production costs.

[0033] In addition, the content of 3-[3-bromo-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole was measured by HPLC.

[0034] In a further embodiment, in step S5, the temperature after cooling is preferably 0-5°C, and the acid solution used is hydrochloric acid.

[0035] Beneficial effects of the present invention:

[0036] The synthesis method of fenpyroxene provided in the present invention does not require the use of an autoclave and carbon monoxide, has a low degree of danger, simple steps, and the dimethyl carbonate used is low-toxic and pollution-free, and is an environmentally friendly green raw material. In addition, the palladium catalyst used can be recycled and reused, which is conducive to reducing production costs. In addition, the content and yield of fenpyroxene synthesized using the method in the present invention are also relatively high, and are suitable for industrial applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 The HPLC characterization spectrum of fenpyrazone in Example 1 is shown in FIG.

[0038] Figure 2 This is the HPLC characterization spectrum of fenpyrazone in Example 2. DETAILED DESCRIPTION

[0039] Embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. In addition, unless otherwise specified, methods that do not specifically record conditions or steps are conventional methods, and the reagents and materials used can be obtained from commercial sources.

[0041] Example 1

[0042] S1. Build a reaction apparatus with a 1000ml four-necked flask, a thermometer, a stirrer, a water separator and a condenser. Add 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole (0.1 mol) and 1-methyl-5-hydroxypyrazole (0.11 mol) into the four-necked flask, then add palladium chloride (0.89 g, 0.005 mol) and triphenylphosphine (2.6 g, 0.01 mol), and finally add potassium carbonate (25 g, 0.18 mol) and dimethyl carbonate (900 g, 9.99 mol) and stir to dissolve.

[0043] S2. Stir for 5 minutes, open the condensing water, and start to heat slowly until reflux. After every 6 hours of reflux reaction, pour out all the refluxed solution on the right side of the water separator, and add the same volume of fresh dimethyl carbonate from the top of the condenser.

[0044] S3. After reflux reaction for 24 hours, samples were taken for in-process control detection of residues, among which the content of 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole was 0.15%, indicating that the reaction was basically complete.

[0045] S4. Cool down to 35°C, pour all the solution in the flask into a filter funnel for separation, and filter out the dark catalyst for retention.

[0046] S5. Rotary evaporate the mother liquor to dryness. There is a large amount of yellow solid in the bottle. Add 1000 ml of water and stir until it is completely dissolved (if it is not completely dissolved, add a small amount of potassium carbonate).

[0047] S6. Cool the ice water to 5°C and slowly add hydrochloric acid while stirring to adjust the pH value of the solution to 3-4.

[0048] S7. Filter out the acid water to obtain a yellow solid, and dry it to obtain fenpyroxetine.

[0049] The content of the product was 96.5% as determined by HPLC. Based on the amount of 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole, the yield of the reaction in this embodiment was 94.5%. Figure 1 .

[0050] Example 2

[0051] S1. Using the same reaction apparatus as in Example 1, 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole (0.1 mol) and 1-methyl-5-hydroxypyrazole (0.11 mol) were added into a four-necked flask, followed by palladium chloride (0.9 g, 0.005 mol) and triphenylphosphine (2.7 g, 0.01 mol), and finally potassium carbonate (30 g, 0.217 mol) and dimethyl carbonate (950 g, 10.546 mol) were added and stirred to dissolve.

[0052] S2. Stir for 5 minutes, open the condensing water, and start to heat slowly until reflux. After every 6 hours of reflux reaction, pour out all the refluxed solution on the right side of the water separator, and add the same volume of fresh dimethyl carbonate from the top of the condenser.

[0053] S3. Reflux the reaction for 24 hours, take samples for in-process control and detect the residues, among which the content of 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole is 0.07%, indicating that the reaction is almost complete.

[0054] S4. Cool down to 35°C, pour all the solution in the flask into a filter funnel for separation, and filter out the dark catalyst for retention.

[0055] S5. Rotary evaporate the mother liquor to dryness. There is a large amount of yellow solid in the bottle. Add 1000 ml of water and stir until it is completely dissolved (if it is not completely dissolved, add a small amount of potassium carbonate).

[0056] S6. Cool the ice water to 5°C and slowly add hydrochloric acid while stirring to adjust the pH value of the solution to 3-4.

[0057] S7. Filter out the acid water to obtain a yellow solid, and dry it to obtain fenpyroxetine.

[0058] The content of the product was 97.3% as determined by HPLC. Based on the amount of 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole, the yield of the reaction in this embodiment was 95.6%. Figure 2 .

[0059] Example 3

[0060] S1. Using the same reaction apparatus as in Example 1, 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole (0.1 mol) and 1-methyl-5-hydroxypyrazole (0.11 mol) were added into a four-necked flask, and then palladium chloride (0.9 g, 0.005 mol, recovered in Examples 1 and 2) and triphenylphosphine (2.7 g, 0.01 mol) were added, and finally potassium carbonate (30 g, 0.217 mol) and dimethyl carbonate (950 g, 10.546 mol) were added and stirred to dissolve.

[0061] S2. Stir for 5 minutes, open the condensing water, and start to heat slowly until reflux. After every 6 hours of reflux reaction, pour out all the refluxed solution on the right side of the water separator, and add the same volume of fresh dimethyl carbonate from the top of the condenser.

[0062] S3. Reflux the reaction for 24 hours, take samples for in-process control and detect the residues, among which the content of 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole is 0.13%, indicating that the reaction is almost complete.

[0063] S3. Cool down to 35°C, pour all the solution in the flask into a filter funnel for separation, and filter out the dark catalyst for retention.

[0064] S4. Rotary evaporate the mother liquor to dryness. There is a large amount of yellow solid in the bottle. Add 1000 ml of water and stir until it is completely dissolved (if it is not completely dissolved, add a small amount of potassium carbonate).

[0065] S5. Cool the ice water to 5°C, and slowly add hydrochloric acid while stirring to adjust the pH value of the solution to 3-4.

[0066] S6. Filter out the acid water to obtain a yellow solid, and dry it to obtain fenpyroxetine.

[0067] The content of the product was 96.8% as determined by HPLC. Calculated based on the amount of 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole, the reaction yield in this example was 94.7%.

[0068] Example 4

[0069] S1. Using the same reaction apparatus as in Example 1, 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole (0.1 mol) and 1-methyl-5-hydroxypyrazole (0.11 mol) were added into a four-necked flask, followed by palladium acetate (0.674 g, 0.003 mol) and tributylphosphine (1.21 g, 0.006 mol), and finally sodium acetate (24.6 g, 0.3 mol) and dimethyl carbonate (810.7 g, 9 mol) were added and stirred to dissolve.

[0070] S2. Stir for 5 minutes, open the condensing water, and start to heat slowly until reflux. After every 6 hours of reflux reaction, pour out all the refluxed solution on the right side of the water separator, and add the same volume of fresh dimethyl carbonate from the top of the condenser.

[0071] S3. Reflux the reaction for 24 hours, take samples for in-process control and detect the residues, among which the content of 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole is 0.21%, indicating that the reaction is almost complete.

[0072] S3. Cool down to 35°C, pour all the solution in the flask into a filter funnel for separation, and filter out the dark catalyst for retention.

[0073] S4. Rotary evaporate the mother liquor to dryness. There is a large amount of yellow solid in the bottle. Add 1000 ml of water and stir until it is completely dissolved (if it is not completely dissolved, add a small amount of potassium carbonate).

[0074] S5. Cool the ice water to 5°C, and slowly add hydrochloric acid while stirring to adjust the pH value of the solution to 3-4.

[0075] S6. Filter out the acid water to obtain a yellow solid, and dry it to obtain fenpyroxetine.

[0076] The content of the product was 96.0% as determined by HPLC. Calculated based on the amount of 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole, the reaction yield in this example was 94.1%.

[0077] Example 5

[0078] S1. Using the same reaction apparatus as in Example 1, 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole (0.1 mol) and 1-methyl-5-hydroxypyrazole (0.11 mol) were added into a four-necked flask, followed by bistriphenylphosphine palladium dichloride (2.81 g, 0.004 mol) and tricyclohexylphosphine (2.24 g, 0.008 mol), and finally sodium carbonate (31.8 g, 0.3 mol) and dimethyl carbonate (1351.1 g, 15 mol) were added and stirred to dissolve.

[0079] S2. Stir for 5 minutes, open the condensing water, and start to heat slowly until reflux. After every 6 hours of reflux reaction, pour out all the refluxed solution on the right side of the water separator, and add the same volume of fresh dimethyl carbonate from the top of the condenser.

[0080] S3. Reflux the reaction for 24 hours, take samples for in-process control and detect the residues, among which the content of 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole is 0.10%, indicating that the reaction is almost complete.

[0081] S3. Cool down to 35°C, pour all the solution in the flask into a filter funnel for separation, and filter out the dark catalyst for retention.

[0082] S4. Rotary evaporate the mother liquor to dryness. There is a large amount of yellow solid in the bottle. Add 1000 ml of water and stir until it is completely dissolved (if it is not completely dissolved, add a small amount of potassium carbonate).

[0083] S5. Cool the ice water to 5°C, and slowly add hydrochloric acid while stirring to adjust the pH value of the solution to 3-4.

[0084] S6. Filter out the acid water to obtain a yellow solid, and dry it to obtain fenpyroxetine.

[0085] The content of the product was 96.9% as determined by HPLC. Calculated based on the amount of 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole, the reaction yield in this example was 95.2%.

[0086] It can be seen from the above examples that the preparation method of the present invention can not only produce benzathine with high product content and yield, but also has mild reaction conditions, does not require high pressure conditions and the use of toxic CO, and is safer to operate; in addition, the dimethyl carbonate used is low-toxic and pollution-free, and is environmentally friendly.

[0087] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0088] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing fenpyrazone, characterized in that: The following steps are involved: The method comprises reacting 3-[3-bromo-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole and 1-methyl-5-hydroxypyrazole in the presence of a palladium catalyst, a phosphine ligand, an acid-binding agent and dimethyl carbonate to prepare fenpyrazone.

2. The method for preparing fenpyrazone as claimed in claim 1, characterized in that: The palladium catalyst is at least one of palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, and bistriphenylphosphine palladium dichloride.

3. The method for preparing fenpyrazone as claimed in claim 1, characterized in that: The phosphine ligand is at least one of triphenylphosphine, tributylphosphine and tricyclohexylphosphine.

4. The method for preparing fenpyrazone as claimed in claim 1, characterized in that: The acid binding agent is potassium carbonate, sodium carbonate, sodium acetate or triethylamine.

5. The method for preparing fenpyrazone as claimed in claim 1, characterized in that: The molar amount of the palladium catalyst is 3%-5% of 3-[3-bromo-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole, and the molar ratio of the palladium catalyst to the phosphine ligand is 1:

2.

6. The method for preparing fenpyrazone as claimed in claim 1, characterized in that: The molar amount of the acid binding agent is 1.5-3 times that of 3-[3-bromo-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole.

7. The method for preparing fenpyrazone as claimed in claim 1, characterized in that: The molar amount of the dimethyl carbonate is 90-150 times that of 3-[3-bromo-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole.

8. The method for preparing fenpyrazone according to any one of claims 1 to 7, characterized in that: The following steps are involved: S1, adding 3-[3-bromo-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole and 1-methyl-5-hydroxypyrazole as well as a palladium catalyst, a phosphine ligand, an acid binding agent and dimethyl carbonate into a reaction vessel; S2, slowly heating to reflux reaction while stirring; S3, when the content of 3-[3-bromo-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole in the detection reaction solution is not greater than 0.3%, cooling and filtering to obtain a mother liquor; S4, after rotary evaporation of the mother liquor to obtain a yellow solid, water is added and stirred to completely dissolve; S5. Then, the system temperature is lowered to not more than 5° C., and acid solution is slowly added dropwise while stirring to adjust the pH value of the system to 3-4. The system is filtered and dried to obtain fenpyroxetine.

9. The preparation method according to claim 8, characterized in that: In step S3, the cooling refers to lowering the temperature to 30-40°C.

10. The preparation method according to claim 8, characterized in that: In step S5, the acid solution is hydrochloric acid.

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