阅读说明：本技术 一种砜吡草唑及其中间体的制备方法 (Preparation method of xaflufen and intermediate thereof ) 是由 郝守志 宋健 王嵩 于 2020-06-02 设计创作，主要内容包括：本发明公开了一种砜吡草唑及其中间体的制备方法,将1-甲基-3-(三氟甲基)-1H-吡唑-5-醇、多聚甲醛、环仲胺与5,5-二甲基-3-巯基-4,5-二氢异恶唑在酸性环境下发生mannich反应得到中间体A,中间体A继续与二氟一氯甲烷烷基化得到中间体B,中间体B被双氧水氧化后得到砜吡草唑。本发明路线反应速度快,产物纯度高、收率高、反应条件温和,合成过程粗放,降低了反应的设备成本,而且产生的产品容易分离,简化了生产工艺。(The invention discloses a preparation method of pyraflufen-ethyl and an intermediate thereof, which comprises the steps of carrying out mannich reaction on 1-methyl-3- (trifluoromethyl) -1H-pyrazole-5-ol, paraformaldehyde, cyclic secondary amine and 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole in an acid environment to obtain an intermediate A, continuously alkylating the intermediate A with difluorochloromethane to obtain an intermediate B, and oxidizing the intermediate B by hydrogen peroxide to obtain the pyraflufen-ethyl. The method has the advantages of high reaction speed, high product purity, high yield, mild reaction conditions, extensive synthesis process, reduced reaction equipment cost, easy separation of the produced product and simplified production process.)

1. A preparation method of a sulfonepyrazoxazole intermediate A shown as a formula A is characterized by comprising the following steps: obtained by reacting 1-methyl-3- (trifluoromethyl) -1H-pyrazole-5-ol, paraformaldehyde, cyclic secondary amine and 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole in the presence of acid; the reaction formula is as follows:

。

2. the method of claim 1, wherein: the cyclic secondary amine is pyrrole, morpholine or piperidine.

3. The method according to claim 1 or 2, characterized in that: the acid is an inorganic acid capable of forming a salt with the cyclic secondary amine, preferably hydrochloric acid or sulfuric acid.

4. The method according to claim 1 or 2, characterized in that: firstly, 1-methyl-3- (trifluoromethyl) -1H-pyrazole-5-alcohol, paraformaldehyde and cyclic secondary amine react in the presence of acid, and then 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole is added for reaction.

5. The method according to any one of claims 1 to 4, wherein: the temperature of the whole reaction is 60-80 ℃.

6. The method according to claim 1 or 2, characterized in that: the solvent for the reaction is a mixture of water and an organic solvent, the organic solvent being an organic solvent miscible with water; preferably, the organic solvent is an alcohol solvent, more preferably ethanol.

7. The method according to claim 1 or 2, characterized in that: 1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-ol, paraformaldehyde, cyclic secondary amine, and 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole as described in 1: 1.0-1.5: 1.0-1.5: 1.0 to 1.3 in a molar ratio.

8. A preparation method of sulfuryl pyraflufen-ethyl is characterized by comprising the following steps: the method comprises the step of synthesizing an intermediate A according to the synthesis method of the intermediate A of the sulfone pyraflufen-ethyl shown as the formula A in any one of claims 1 to 7.

9. The method of claim 8, wherein: the method also comprises the steps of carrying out alkylation reaction on the intermediate A and difluorochloromethane to obtain an intermediate B, and carrying out oxidation reaction on the intermediate B and hydrogen peroxide to obtain the topramezone, wherein the reaction formula is as follows:

。

10. the method of claim 9, wherein: the reaction of the intermediate A and the monochlorodifluoromethane is carried out in the presence of an acid-binding agent, wherein the acid-binding agent is preferably sodium carbonate, potassium carbonate or triethylamine; preferably, the molar ratio of intermediate a to difluoromethane chloride is 1: 1.2-3; preferably, the reaction solvent of the intermediate A and the chlorodifluoromethane is acetonitrile, and the reaction temperature is 10-30 ℃; preferably, the reaction temperature of the intermediate B and hydrogen peroxide is 60-80 ℃, and the molar ratio of the intermediate B to the hydrogen peroxide is 1: 5-10.

Technical Field

The invention relates to a preparation method of a topramezone intermediate, in particular to a method for synthesizing a topramezone intermediate A by adopting 1-methyl-3- (trifluoromethyl) -1H-pyrazole-5-ol, paraformaldehyde, cyclo-secondary amine and 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole and a method for synthesizing topramezone by adopting the novel process route, belonging to the technical field of topramezone synthesis.

Background

Sulfoxantrozole (Pyroxasulfone) is an isoxazole herbicide, which has been developed by Nippon Kabushiki Kaisha under the chemical name of 3- [5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) pyrazol-4-ylmethylsulfonyl ] -4, 5-dihydro-5, 5-dimethyl-1, 2-isoxazole and is classified intoSub-formula is C₁₂H₁₄F₅N₃O₄S, molecular weight 391.32, CAS registry number 447399-55-5. The sulfonepyrazoxazole can be used as a pre-emergence soil treatment agent in most crop fields, is absorbed by young roots and young buds of weeds after being applied, inhibits the early growth of seedlings, destroys meristems and coleoptiles, and is a serious potential inhibitor in the biosynthesis of VLCFA (very long chain fatty acid) (C20-C30) in plants. The structure is as follows:

at present, the synthesis process of the xaflufen is rarely reported, and the following process route is disclosed in patent CN 102666502:

under the alkaline condition, 1-methyl-3- (trifluoromethyl) -1H-pyrazole-5-alcohol, formaldehyde water solution and 5, 5-dimethyl-4, 5-dihydro isoxazole sulfamidine hydrochloride are subjected to condensation reaction in water to obtain an intermediate A, the intermediate A is alkylated with monochlorodifluoromethane to obtain an intermediate B, and the intermediate B is oxidized by hydrogen peroxide to obtain the pyraflufen-ethyl.

In the process route, the yield of the sulfonepyraflufen-ethyl is too low, and the formaldehyde aqueous solvent is easy to cause distortion and has great harm to the environment and human beings.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides a preparation method of the intermediate A of the sulfuryl pyraoxystrobin, and the method provides a new idea for the synthesis of the intermediate A.

The invention provides a preparation method of a topramezone intermediate A shown in a formula A, wherein the intermediate A is obtained by reacting 1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-ol, paraformaldehyde, cyclic secondary amine and 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole in the presence of acid; the reaction formula is as follows:

。

further, in the above preparation method, the cyclic secondary amine is a cyclic secondary amine capable of reacting with 1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-ol and paraformaldehyde to form a mannich base, which has a saturated or unsaturated five-membered ring or six-membered ring, a secondary amine group is located on the ring, the ring has a heteroatom except nitrogen or no heteroatom except nitrogen, and the ring has a substituent or no substituent. Preferably, the cyclic secondary amine is pyrrole, morpholine or piperidine.

Further, in the above production method, the reaction is carried out in the presence of an acid. The acid is an inorganic acid capable of forming a salt with the cyclic secondary amine, such as hydrochloric acid, sulfuric acid, or the like. The acid is added in an equimolar amount to the cyclic secondary amine, or the acid may be in slight excess.

Further, in the above production method, the reaction is carried out in the presence of a solvent. The reactants are reacted in the presence of water and an organic solvent, the water being introduced by an acid, the organic solvent being selected from organic solvents which are miscible with water and keep the reaction homogeneous and non-reactive with the reactants and products, such as alcohol solvents, and the organic solvent used is preferably ethanol, in view of environmental protection, cost, and the like.

Furthermore, in the preparation method, each organic solvent has little influence on the reaction, the dosage of the organic solvent has no special requirement, and the homogeneous reaction of each reactant and the easier reaction can be ensured, and the utilization rate of the reaction vessel is higher.

Further, the 1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-ol used in the present invention can be prepared according to the methods reported in the prior art, for example, according to the literature: the preparation method disclosed in Journal of Agricultural and Food Chemistry (2008), 56(22), 10805-10810. 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole is commercially available.

Further, during the reaction, Mannich reaction is carried out on 1-methyl-3- (trifluoromethyl) -1H-pyrazole-5-ol, paraformaldehyde and cyclic secondary amine in the presence of acid, and then 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole is added for reaction to obtain an intermediate A. The adding sequence of the 1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-ol, the paraformaldehyde, the cyclic secondary amine, the acid and the solvent is not strict, the materials can be mixed according to random adding sequence, and can be added at one time, added in batches, added continuously, added in a pure substance form, or dissolved in the solvent in advance and added in a solution form. The 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole can be added in one portion, in portions, continuously, in a pure form, or dissolved in a solvent to form a solution.

Further, in the above-mentioned preparation method, 1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-ol, paraformaldehyde, cyclic secondary amine and 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole may be reacted in a theoretical molar ratio, and it is preferable to carry out the reaction with a slight excess of paraformaldehyde, cyclic secondary amine and 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole. In one embodiment of the invention, 1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-ol, paraformaldehyde, cyclic secondary amine, and 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole are present in a ratio of 1: 1.0-1.5: 1.0-1.5: 1.0-1.3, and the molar weight of paraformaldehyde is calculated as formaldehyde.

Furthermore, in the preparation method, the temperature of the Mannich reaction is 60-80 ℃, the reaction can be rapidly carried out at the reaction temperature, the reaction time is slightly different due to different temperature ranges, and the reaction is judged to be finished when the content of the raw materials is extremely low. Adding 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole, and reacting at 60-80 ℃.

Further, in the preparation method, 1-methyl-3- (trifluoromethyl) -1H-pyrazole-5-alcohol, paraformaldehyde, cyclic secondary amine, acid and a solvent are mixed and reacted at 60-80 ℃ until the 1-methyl-3- (trifluoromethyl) -1H-pyrazole-5-alcohol is reacted completely, then 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole is added and the reaction is continued under heat preservation until the 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole is reacted completely. The progress of the reaction can be checked by HPLC methods.

Furthermore, in the preparation method, the post-treatment of the reaction liquid is simple and extensive, the organic solvent is removed from the reaction liquid after the reaction, then a proper amount of water is added, the mixture is stirred and crystallized, and the final product can be obtained by suction filtration. The organic solvent can be removed from the reaction solution by distillation, reduced pressure distillation, rotary evaporation, or the like.

The invention also provides a preparation method of the sulfuryl pyraflufen-ethyl, which comprises the step of synthesizing the intermediate A according to the method.

Further, the method for synthesizing the sulfuryl pyraflufen-ethyl comprises the steps of performing alkylation reaction on the intermediate A and difluorochloromethane to obtain an intermediate B and performing oxidation reaction on the intermediate B and hydrogen peroxide to obtain the sulfuryl pyraflufen-ethyl. The process route of the whole reaction process is as follows:

。

further, the specific processes for synthesizing the intermediate B and synthesizing the xaflufen-ethyl from the intermediate B can be performed according to methods reported in the prior art, for example, according to the method described in patent CN102666502A, which belongs to the prior art and is not described herein again.

In a specific embodiment of the present invention, the reaction between the intermediate a and the monochlorodifluoromethane is performed in the presence of an organic solvent and an acid-binding agent, wherein the acid-binding agent is any substance reported in the prior art that can consume an acid formed by the reaction, and sodium carbonate, potassium carbonate, and triethylamine are commonly used. The organic solvent is a feasible organic solvent reported in the prior art, such as acetonitrile and the like.

In one embodiment of the invention, the molar ratio of intermediate a to difluoromethane chloride is 1: 1.2-3, the reaction temperature is 10-30 ℃, the content of the intermediate A is detected by HPLC in the reaction process, and the reaction is finished when the intermediate A is completely reacted. After the reaction is finished, the by-product salt is removed by filtration, and the reaction solution can be directly used for the next reaction without extracting a product.

In a specific embodiment of the invention, the molar ratio of the intermediate B to the hydrogen peroxide is 1: 5-10, and the reaction temperature of the intermediate B and the hydrogen peroxide is 60-80 ℃. The concentration of the hydrogen peroxide can be selected at will, and generally higher concentration is selected. The content of intermediate B was checked by HPLC at all times during the reaction, and the reaction was completed when intermediate B was completely reacted. And after the reaction is finished, removing the organic solvent by reduced pressure distillation, and filtering the generated solid to obtain the sulfuryl pyraflufen-ethyl.

The invention has the advantages that:

(1) 1-methyl-3- (trifluoromethyl) -1H-pyrazole-5-alcohol, paraformaldehyde, cyclic secondary amine and 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole are reacted to obtain an intermediate A, and a new idea is provided for the synthesis of the intermediate A.

(2) And in the synthesis process of the intermediate A, paraformaldehyde is used for replacing an easily teratogenic formaldehyde aqueous solvent, so that the method is more environment-friendly.

(3) The reaction condition for synthesizing the intermediate A is mild, excessive temperature and high pressure are not needed, and the requirement on equipment is low.

(4) The post-treatment of the intermediate A is simple and extensive, the reaction product is easy to separate, the production process is simplified, and the method is more suitable for industrial mass production.

(5) The reaction of the intermediate A does not need a special catalyst, the reaction selectivity is high, the reaction yield is high, the product purity is high, and the total yield of the sulfonepyraflufen-ethyl is more than 81%.

Detailed description of the preferred embodiment

The present invention is further illustrated by the following specific examples. The following description is exemplary only, and is not intended to limit the scope of protection. Other embodiments, which may be made by those skilled in the art without inventive faculty, are also within the scope of the invention.

In the following examples, unless otherwise specified, the concentrations are mass percent concentrations.

In the following examples, all the raw materials were commercially available products unless otherwise specified.

In the following examples, yield = actual mass of product x purity/theoretical mass of product.

Example 1

1. Synthesis of an intermediate A:

adding 16.6g of 1-methyl-3- (trifluoromethyl) -1H-pyrazole-5-ol, 3g of paraformaldehyde, 8.5g of piperidine and 10g of 37% hydrochloric acid aqueous solution into 40mL of ethanol in sequence at room temperature, heating to 80 ℃, stirring for reaction for 4 hours, adding 21.6g of 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole after HPLC (high performance liquid chromatography) detects that no 1-methyl-3- (trifluoromethyl) -1H-pyrazole-5-ol remains, continuing to react, adding 21.6g of 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole after HPLC detects that the reaction is complete, evaporating ethanol under reduced pressure after the reaction is finished, adding 20mL of water, pulping for 2 hours, performing suction filtration to obtain a white solid precipitate, drying to obtain 28.8g of solid, this was intermediate A, which had a purity of 99.4% by HPLC and a yield of 92.6% based on 1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-ol.

2. And (3) synthesizing an intermediate B:

6.9g of potassium carbonate and 14.4g of intermediate A were added to 40mL of acetonitrile, stirred at 20 ℃ for 2hr, then 8.5g of monochlorodifluoromethane gas was slowly introduced under normal pressure, after 8hr, the intermediate A was detected by HPLC to be reacted completely, after the reaction was completed, the solid was removed by filtration, and the mother liquor was used directly for the next reaction.

3. Synthesis of the sulfone pyraflufen-ethyl:

adding 28.3g of 30wt% hydrogen peroxide into the reaction liquid in the step 2 at room temperature, stirring for 1hr, slowly heating to 60 ℃ for reaction, and after 4hr, detecting by HPLC to show that the reaction is finished. After removing acetonitrile by vacuum concentration, the reaction liquid is cooled to room temperature, and is filtered to obtain 16.8g of white solid, namely the sulfuryl pyraoxystrobin, the content of which is 98.4 percent by the intermediate A through HPLC detection, and the yield of the sulfuryl pyraoxystrobin is 84.5 percent.

Example 2

1. Synthesis of an intermediate A:

adding 33.2g of 1-methyl-3- (trifluoromethyl) -1H-pyrazole-5-ol, 6g of paraformaldehyde, 14.2g of pyrrole and 20g of 37% hydrochloric acid aqueous solution into 80mL of ethanol in sequence at room temperature, heating to 75 ℃, stirring for reaction for 4 hours, adding 43.2g of 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole after HPLC (high performance liquid chromatography) detects that no 1-methyl-3- (trifluoromethyl) -1H-pyrazole-5-ol remains, continuing to react for 4 hours, ending the HPLC detection reaction, evaporating the reaction liquid under reduced pressure to remove ethanol, adding 20mL of water, pulping for 2 hours, performing suction filtration to obtain a white solid precipitate, drying to obtain 57.5g of solid, this was intermediate A, which had a purity of 99.2% by HPLC and a yield of 92.3% based on 1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-ol.

2. And (3) synthesizing an intermediate B:

adding 10.6g of sodium carbonate and 30.9g of intermediate A into 40mL of acetonitrile, stirring at 20 ℃ for 2hr, slowly introducing difluorochloromethane gas at normal pressure for 15g, detecting the complete reaction of the intermediate A by HPLC after 8hr, filtering to remove solids after the reaction is finished, and directly using the mother liquor for the next reaction.

3. Synthesis of the sulfone pyraflufen-ethyl:

adding 113.3g of 30wt% hydrogen peroxide into the reaction solution in the step 2 at room temperature, stirring for 1hr, slowly heating to 60 ℃ for reaction, and after 4hr, detecting by HPLC to show that the reaction is finished. Concentrating under reduced pressure to remove acetonitrile, cooling to room temperature, and filtering to obtain 34.1g of white solid, namely the sulfuryl pyraflufen-ethyl, wherein the content of the sulfuryl pyraflufen-ethyl is 98.1% by HPLC detection, and the yield of the sulfuryl pyraflufen-ethyl is 87.5% by the intermediate A.

Example 3

Synthesis of an intermediate A:

adding 33.2g of 1-methyl-3- (trifluoromethyl) -1H-pyrazole-5-ol, 6g of paraformaldehyde, 17.4g of morpholine and 20g of 37% hydrochloric acid aqueous solution into 80mL of ethanol in sequence at room temperature, heating to 60 ℃, stirring and reacting for 4 hours, detecting by HPLC that no 1-methyl-3- (trifluoromethyl) -1H-pyrazole-5-ol is left, adding 43.2g of 5, 5-dimethyl-3-mercapto-4, 5-dihydroisoxazole, continuing to react for 4 hours, detecting by HPLC to finish the reaction, evaporating ethanol under reduced pressure after the reaction, adding 20mL of water, pulping for 2 hours, performing suction filtration to obtain a white solid precipitate, drying to obtain 56.8g of solid, this was intermediate A, which had a purity of 99.3% by HPLC and a yield of 91.3% based on 1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-ol.

2. And (3) synthesizing an intermediate B:

adding 10.6g of sodium carbonate and 30.9g of intermediate A into 40mL of acetonitrile, stirring at 20 ℃ for 2hr, slowly introducing difluorochloromethane gas at normal pressure for 16g, detecting the completion of the reaction of the intermediate A by HPLC after 8hr, filtering to remove solids after the reaction is finished, and directly using the mother liquor for the next reaction.

3. Synthesis of the sulfone pyraflufen-ethyl:

adding 56.6g of 30wt% hydrogen peroxide into the reaction liquid in the step 2 at room temperature, stirring for 1hr, slowly heating to 80 ℃ for reaction, and after 4hr, detecting by HPLC to show that the reaction is finished. Concentrating under reduced pressure to remove acetonitrile, cooling to room temperature, and filtering to obtain 33.1g of white solid, namely the sulfuryl pyraflufen-ethyl, wherein the content of the sulfuryl pyraflufen-ethyl is 98.7% by HPLC detection, and the yield of the sulfuryl pyraflufen-ethyl is 83.5% by the intermediate A.