阅读说明：本技术 一种5,5-二甲基-4,5-二氢异噁唑-3-酮的合成方法 (Synthesis method of 5, 5-dimethyl-4, 5-dihydroisoxazole-3-ketone ) 是由 宋健 王嵩 郝守志 于 2020-06-02 设计创作，主要内容包括：本发明公开了一种5,5-二甲基-4,5-二氢异噁唑-3-酮的合成方法,该方法由式(Ⅱ)所示的化合物与式(Ⅲ)所示的化合物通过缩合成环反应得到。本发明反应条件温和,不需要过高的温度和高压,对设备要求低,后处理简单粗放,反应时间短,反应转化率高,适合工业化大生产。(The invention discloses a synthesis method of 5, 5-dimethyl-4, 5-dihydroisoxazole-3-ketone, which is obtained by condensation cyclization reaction of a compound shown in a formula (II) and a compound shown in a formula (III). The method has the advantages of mild reaction conditions, no need of overhigh temperature and high pressure, low requirement on equipment, simple and extensive post-treatment, short reaction time and high reaction conversion rate, and is suitable for industrial mass production.)

1. A method for synthesizing 5, 5-dimethyl-4, 5-dihydroisoxazole-3-ketone shown in formula (I) is characterized in that: obtained by reacting a compound shown as a formula (II) with a compound shown as a formula (III), wherein the reaction formula is as follows:

；

in the formula (III), L is OMs, OTs or OTf.

2. The method of synthesis according to claim 1, wherein: the reaction is carried out in the presence of a basic substance which is an alkali metal alkoxide, preferably sodium methoxide, potassium methoxide, sodium ethoxide or potassium ethoxide.

3. The synthesis method according to claim 1 or 2, wherein: the molar ratio of the compound represented by the formula (II) to the basic substance is 1: 2-2.5.

4. The method of synthesis according to claim 1, wherein: the reaction is carried out in the presence of a solvent, which is an alcoholic solvent, preferably methanol or ethanol.

5. The method of synthesis according to claim 1, wherein: the reaction temperature of the compound shown in the formula (II) and the compound shown in the formula (III) is 20-50 ℃.

6. The method of synthesis of claim 1, 2, 4 or 5, wherein: the molar ratio of the compound shown in the formula (II) to the compound shown in the formula (III) is 1: 1.0-1.3.

7. The method of synthesis of claim 1, 2, 4 or 5, wherein: the reaction is carried out under normal pressure and gas protection.

Technical Field

The invention relates to a synthesis method of a sulfonepyrazoxazole intermediate 5, 5-dimethyl-4, 5-dihydroisoxazole-3-ketone, and particularly relates to a synthesis method of 5, 5-dimethyl-4, 5-dihydroisoxazole-3-ketone, which has the advantages of high reaction conversion rate, mild reaction conditions and simple post-treatment.

Background

The 5, 5-disubstituted-4, 5-dihydroisoxazol-3-one is an important intermediate for preparing agricultural chemical components and pharmaceutical components, and the structural formula is as follows:

or。

Patent CN101389625A discloses the synthesis of the intermediate 5, 5-dimethyl-4, 5-dihydroisoxazol-3-one of sulfonepyrazoxazole by condensation reaction of ethyl dimethacrylate and hydroxyurea in methanol solvent in the presence of metallic sodium, followed by acidification reaction treatment. The method has low yield of the 5, 5-dimethyl-4, 5-dihydroisoxazole-3-ketone, and the yield is only 49 percent.

Patent CN109574945A discloses that potassium methoxide replaces sodium metal to catalyze the condensation cyclization reaction of ethyl dimethacrylate and hydroxyurea to synthesize intermediate 5, 5-dimethyl-4, 5-dihydroisoxazole-3-ketone. The method has improved product yield, but the yield is 78.5 percent, and is not very high.

Disclosure of Invention

The invention aims to provide a method for synthesizing 5, 5-dimethyl-4, 5-dihydroisoxazole-3-ketone, which has the advantages of mild reaction conditions, low equipment requirement, high reaction selectivity, simple and extensive post-treatment and convenient industrial application.

The invention takes a compound (N-hydroxyacetamide) with a structural formula (II) and a compound with a structural formula (III) as starting raw materials, 5-dimethyl-4, 5-dihydroisoxazole-3-ketone with a structural formula (I) is obtained by condensation cyclization, and the 5, 5-dimethyl-4, 5-dihydroisoxazole-3-ketone can be used as an intermediate of the xaflufen-ethyl.

The reaction formula is as follows:

。

in the above formula (III), L is OMs, OTs or OTf, preferably OMs or OTs. Wherein OMs is methylsulfonyloxy, OTs is p-toluenesulfonyloxy, and OTf is trifluoromethanesulfonyloxy. The specific structural formula of OMs, OTs or OTf is as follows:

further, in the above method, the reaction is carried out in the presence of an alkaline substance which may be an alkali metal alkoxide, and sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, etc. are commonly used. Each alkaline substance acts similarly.

Further, in the above method, the molar ratio of the compound represented by the formula (ii) to the basic substance is 1: 2-2.5.

Further, in the above method, the reaction is carried out in the presence of a solvent, the solvent is a solvent that provides a suitable reaction environment for the reaction of the raw materials, and the reaction solvent is selected from organic solvents that do not react with the raw materials and the product and that can provide a good homogeneous reaction environment, for example, alcohol solvents and the like that are often used as solvents in organic reactions, and methanol or ethanol are often used. The reaction solvent can ensure the reaction to be well carried out, and the usage amount can be selected according to the conditions of the utilization rate of the reaction vessel, the reaction efficiency, the difficulty of the reaction and the like.

Further, the compound represented by the formula (II) can be directly purchased from the market. The compound shown in the formula (III) can be obtained by reacting methyl 3-hydroxy-3-methylbutyrate with an acylating reagent, and the reaction formula is as follows:

furthermore, the molar ratio of the compound of the formula (II) to the compound of the formula (III) is 1:1.0 to 1.3, the two reactants can be reacted in the theoretical molar ratio, and the compound of the formula (III) can be slightly in excess. The compound represented by the formula (II), the compound represented by the formula (III), the reaction solvent and the basic substance may be mixed in any order, and in order to convert the reaction raw material more rapidly and efficiently, it is preferable that the compound represented by the formula (II), the reaction solvent and the basic substance are mixed uniformly and then the compound represented by the formula (III) is added to the mixture to carry out the reaction. The reactants may be added at one time, or may be added in batches or continuously for better uniform mixing, and the reactants may be added directly or may be dissolved in a reaction solvent and added in the form of a solution.

Further, in the method, the reaction temperature of the compound shown in the formula (II) and the compound shown in the formula (III) is 20-50 ℃. The reaction time is slightly different according to the temperature, and the reaction is judged to be finished when the content of the raw materials is extremely low.

Further, the reaction of the compound represented by the formula (II) and the compound represented by the formula (III) is carried out under normal pressure and under gas protection. The protective gas may be nitrogen or an inert gas.

Further, in the above method, the compound of formula (II) and the compound of formula (III) undergo a condensation cyclization reaction in the presence of a basic substance to give a product of formula (I) and an acetate by-product. The reaction solution after the reaction is subjected to post-treatment, and the final product can be simply and easily obtained. The post-treatment may be performed by any means commonly used in the art, such as one or more of filtration, concentration, distillation, extraction, acid adjustment, etc., and the following post-treatment means are disclosed in one embodiment of the present invention: and (3) removing the solvent from the reaction solution by distillation, reduced pressure distillation, rotary evaporation and other modes, adding water to dissolve the remainder, adjusting the pH value to acidity, extracting by using an organic extractant, and removing the extractant from the organic phase obtained by extraction to obtain the product. The acid for adjusting the pH may be a conventional acid such as hydrochloric acid, the concentration of hydrochloric acid is optionally selected, and the pH is preferably adjusted to 5 or less, more preferably between 1 and 3. The organic extractant used for extraction can be halogenated alkane such as dichloromethane, the volume ratio of water to the extractant is about 1:0.5-1, and the extractant is removed from the organic phase obtained by extraction by means of distillation, reduced pressure distillation, rotary evaporation and the like.

The invention has the advantages that:

(1) the reaction conversion rate is high, the reaction time is short, the yield of the obtained product is high and is over 84 percent;

(2) the reaction condition is mild, excessive temperature and high pressure are not needed, and the requirement on equipment is low;

(3) the post-treatment is simple and extensive, and is suitable for industrial mass production.

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, the compound of formula (II) is a commercially available product, and the compound of formula (III) is synthesized according to the following method, and the following synthetic processes are reported in the prior art and are not repeated herein.

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

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

Example 1

To a dry 250ml four-necked flask, anhydrous methanol (100 ml) was added under nitrogen protection, potassium methoxide solid (14 g,0.2 mol) was slowly added and dissolved with stirring, then N-hydroxyacetamide (7.5 g,0.1 mol) was added, methyl 3-methyl-3- ((methanesulfonyl) oxy) butyrate (21 g,0.1 mol) was added dropwise, and after completion of the dropwise addition, stirring was carried out at 30 ℃ for 12 hours. After the reaction, the by-product is removed by suction filtration, the filtrate is decompressed and rotary evaporated to remove methanol, water (100 ml) is added into the residue, the mixture is stirred at room temperature until the mixture is completely dissolved, hydrochloric acid (2 mol/L) is used for adjusting the pH value to 2, dichloromethane (60 ml) is added for extraction, then liquid separation and organic phase decompression and rotary evaporation are carried out to remove dichloromethane, white solid 5, 5-dimethyl isoxazolidine-3-ketone (10 g) is obtained, and the purity of the product is 99.1% and the yield is 86.2% through HPLC detection.

Example 2

To a dry 250ml four-necked flask, anhydrous methanol (100 ml) was added under nitrogen protection, potassium methoxide solid (14 g,0.2 mol) was slowly added and dissolved with stirring, then N-hydroxyacetamide (7.5 g,0.1 mol) was added, methyl 3-methyl-3- ((trifluoromethyl) sulfonyl) oxy) butyrate (26.4 g,0.1 mol) was added dropwise, and after completion of the dropwise addition, stirring was carried out at 20 ℃ for 24 hours. After the reaction, the by-product is removed by suction filtration, the filtrate is decompressed and rotary evaporated to remove methanol, water (100 ml) is added into the residue, the mixture is stirred at room temperature until the mixture is completely dissolved, hydrochloric acid (2 mol/L) is used for adjusting the pH value to 2, dichloromethane (60 ml) is added for extraction, then liquid separation and organic phase decompression and rotary evaporation are carried out to remove dichloromethane, white solid 5, 5-dimethyl isoxazolidine-3-ketone (9.8 g) is obtained, the purity of the product is 98.9% through HPLC detection, and the yield is 84.3%.

Example 3

To a dry 250ml four-necked flask, anhydrous methanol (100 ml) was added under nitrogen protection, potassium methoxide solid (14 g,0.2 mol) was slowly added and dissolved with stirring, and then N-hydroxyacetamide (7.5 g,0.1 mol) was added thereto, and methyl 3-methyl-3- (p-toluenesulfonyloxy) butyrate (28.6 g,0.1 mol) was added dropwise and, after completion of the dropwise addition, stirred at 50 ℃ for 8 hours. After the reaction, the by-product is removed by suction filtration, the filtrate is decompressed and rotary evaporated to remove methanol, water (100 ml) is added into the residue, the mixture is stirred at room temperature until the mixture is completely dissolved, hydrochloric acid (2 mol/L) is used for adjusting the pH value to 2, dichloromethane (60 ml) is added for extraction, then liquid separation and organic phase decompression and rotary evaporation are carried out to remove dichloromethane, white solid 5, 5-dimethyl isoxazolidine-3-ketone (10 g) is obtained, and the purity of the product is 98.9% and the yield is 86.0% through HPLC detection.

Example 4

To a dry 250ml four-necked flask, absolute ethanol (100 ml) was added under nitrogen protection, potassium ethoxide solid (16.8 g,0.2 mol) was slowly added, dissolved with stirring, and then N-hydroxyacetamide (7.5 g,0.1 mol) was added thereto, methyl 3-methyl-3- ((methanesulfonyl) oxy) butyrate (21 g,0.1 mol) was added dropwise, and after completion of the dropwise addition, stirred at 30 ℃ for 12 hours. After the reaction, the by-product is removed by suction filtration, the filtrate is decompressed and rotary evaporated to remove ethanol, water (100 ml) is added into the residue, the mixture is stirred at room temperature until the mixture is completely dissolved, hydrochloric acid (2 mol/L) is used for adjusting the pH value to 2, dichloromethane (60 ml) is added for extraction, then liquid separation and organic phase decompression and rotary evaporation are carried out to remove dichloromethane, white solid 5, 5-dimethyl isoxazolidine-3-ketone (10.2 g) is obtained, the purity of the product is 98.9% through HPLC detection, and the yield is 87.7%.

Example 5

To a dry 250ml four-necked flask, anhydrous methanol (100 ml) was added under nitrogen protection, potassium methoxide solid (14 g,0.2 mol) was slowly added and dissolved with stirring, then N-hydroxyacetamide (7.5 g,0.1 mol) was added, methyl 3-methyl-3- ((trifluoromethyl) sulfonyl) oxy) butyrate (26.4 g,0.1 mol) was added dropwise, and after completion of the dropwise addition, stirring was carried out at 20 ℃ for 24 hours. After the reaction, the by-product is removed by suction filtration, the filtrate is decompressed and rotary evaporated to remove methanol, water (100 ml) is added into the residue, the mixture is stirred at room temperature until the mixture is completely dissolved, the pH is adjusted to 2 by hydrochloric acid (2 mol/L), dichloromethane (60 ml) is added for extraction, then liquid separation and organic phase decompression and rotary evaporation are carried out to remove dichloromethane, white solid 5, 5-dimethyl isoxazolidine-3-ketone (10.3 g) is obtained, the purity of the product is 98.8% through HPLC detection, and the yield is 88.5%.

Example 6

To a dry 250ml four-necked flask, anhydrous methanol (100 ml) was added under nitrogen protection, potassium methoxide solid (14 g,0.2 mol) was slowly added and dissolved with stirring, and then N-hydroxyacetamide (7.5 g,0.1 mol) was added thereto, and methyl 3-methyl-3- (p-toluenesulfonyloxy) butyrate (28.6 g,0.1 mol) was added dropwise and, after completion of the dropwise addition, stirred at 50 ℃ for 8 hours. After the reaction, the by-product is removed by suction filtration, the filtrate is decompressed and rotary evaporated to remove methanol, water (100 ml) is added into the residue, the mixture is stirred at room temperature until the mixture is completely dissolved, hydrochloric acid (2 mol/L) is used for adjusting the pH value to 2, dichloromethane (60 ml) is added for extraction, then liquid separation and organic phase decompression and rotary evaporation are carried out to remove dichloromethane, white solid 5, 5-dimethyl isoxazolidine-3-ketone (10.1 g) is obtained, the purity of the product is 99.1% through HPLC detection, and the yield is 87.0%.