Process for the preparation of a fluoxastrobin intermediate

Abstract

The application discloses a preparation method of flumetover intermediate (E)-(5,6-dihydro-[1,4,2]-dioxazin-3-yl)-(2-hydroxyphenyl)-methanone-O-methyl oxime, which is obtained by converting the configuration of (Z)-(5,6-dihydro-[1,4,2]-dioxazin-3-yl)-(2-hydroxyphenyl)-methanone-O-methyl oxime into (E)-(5,6-dihydro-[1,4,2]-dioxazin-3-yl)-(2-hydroxyphenyl)-methanone-O-methyl oxime by using an acidic reagent in the presence of a phase transfer catalyst. The application innovatively converts the useless (Z) structure, which is usually abandoned as an impurity, into the valuable flumetover intermediate (E) structure through configuration conversion, so that the useless substance can be turned into treasure, resources can be optimized, and the problems in the synthesis of the flumetover intermediate (E) structure in the prior art can be solved.

Description

Technical Field

[0001] This invention belongs to the field of pesticide intermediate preparation technology, specifically relating to a method for preparing fluopyram intermediate (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime. Background Technology

[0002] Fluoxastrobin is a dihydrooxazine compound, also known as a methoxyacrylate fungicide, discovered by Bayer in 1994. It is mainly used in both crop and non-crop fields, with its main markets in Europe and North America. It has excellent systemic properties, a broad fungicidal spectrum, and outstanding "plant health effects".

[0003] (E)-(5,6-dihydro-[1,4,2]-dioxazin-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime is an important intermediate in the synthesis of fluopyram, and its structural formula is as follows:

[0004] .

[0005] Currently, there are two main synthetic routes for (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime:

[0006] (1) Using 4-hydroxycoumarin as the starting material, (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime was obtained through a six-step reaction involving nitration, hydrolysis, methylation, cyclization, etherification, and basic rearrangement. The overall yield of this synthetic route was only 14.3%, which is not suitable for large-scale industrial production.

[0007] (2) Using benzofuran-3-one as the starting material, (E)-(5,6-dihydro-[1,4,2]-dioxazin-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime was obtained through a four-step reaction of methylation, amination, cyclization and basic rearrangement. The overall yield of this synthetic route was also low, and expensive tert-butyl nitrite was used, resulting in high production costs. In particular, the starting material benzofuran-3-one was limited in source and difficult to obtain, making it unsuitable for large-scale industrial production.

[0008] Furthermore, for the last step in the two routes mentioned above, namely the basic rearrangement to obtain (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime, the yield of existing technologies is generally low. This is because the product obtained by the basic rearrangement includes not only the target product (E) structure but also the byproduct (Z) structure. The byproduct (Z) structure is then removed through post-processing, resulting in a low yield of the target product and high post-processing costs.

[0009] Currently, the by-product (Z) structure is discarded as an impurity, resulting in serious waste of resources. Summary of the Invention

[0010] The purpose of this invention is to solve the above-mentioned problems and provide a method for preparing the fluopyram intermediate (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime.

[0011] The technical solution to achieve the objective of this invention is: a method for preparing the fluopyram intermediate (E)-(5,6-dihydro-[1,4,2]-dioxazin-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime, which involves using an acidic reagent to perform configurational conversion on (Z)-(5,6-dihydro-[1,4,2]-dioxazin-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime to obtain (E)-(5,6-dihydro-[1,4,2]-dioxazin-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime in the presence of a phase transfer catalyst.

[0012] The phase transfer catalyst is a quaternary ammonium salt or a polyether; preferably a quaternary ammonium salt; more preferably tetrabutylammonium bromide.

[0013] The amount of the phase transfer catalyst is 1 to 10% of the weight of (Z)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime, preferably 3 to 5%.

[0014] The acidic reagent is an organic acid or an inorganic acid; preferably an organic acid; more preferably acetic acid.

[0015] The molar amount of the acidic reagent is 1 to 5 times, preferably 2 to 3 times, the molar amount of (Z)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime.

[0016] The reaction temperature for the configuration conversion is 50–100°C, preferably 70–90°C.

[0017] The positive effects of this invention are:

[0018] (1) This invention innovatively transforms the useless (Z) structure, which is usually discarded as an impurity, into a valuable fluopyram intermediate (E) structure through configuration conversion. This not only turns waste into treasure and optimizes resources, but also solves many problems in the synthesis of fluopyram intermediate (E) structure in the prior art.

[0019] (2) The configuration conversion of the present invention, using tetrabutylammonium bromide as a phase transfer catalyst and acetic acid as an acidic reagent, can achieve a high reaction yield and product purity, which is suitable for large-scale industrial production. Detailed Implementation

[0020] (Example 1)

[0021] The specific preparation method of (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime in this embodiment is as follows:

[0022] Under nitrogen protection, 100 mL of dichloroethane was added to a 250 mL four-necked reaction flask. 2.36 g of (Z)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime (0.01 mol) was added with stirring for 30 min. Then, 0.1 g of tetrabutylammonium bromide was added, followed by the slow dropwise addition of 15 g of acetic acid (0.25 mol) at room temperature, which was completed in about 1 h. After the addition was complete, the mixture was heated to reflux. The reaction was terminated when the (Z) content was detected by HPLC at a level of <0.5%.

[0023] After the reaction was completed, the temperature of the reaction solution was lowered to below 0℃, filtered, and the filter cake was washed with water and dried to obtain 1.84 g of (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime, which appeared as a pale yellow powder with a yield of 78.0% and a purity of 96.6% (HPLC).

[0024] (Examples 2 to 5)

[0025] The preparation methods of (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime in each embodiment are basically the same as those in Example 1, except for the types of acidic reagents, as shown in Table 1.

[0026] Table 1

[0027] acid reagents product yield purity Example 1 0.25 mol / L acetic acid 1.84g 78．0% 96.6% Example 2 0.25 mol formic acid 1.65g 69.9% 96.5% Example 3 0.25 mol / L propionic acid 1.77g 75.0% 95.8% Example 4 0.25 mol hydrochloric acid 1.06g 44.9% 95.4% Example 5 0.25 mol sulfuric acid 1.18g 50.0% 90.0%

[0028] As shown in Table 1, the reaction yield and product purity are highest when acetic acid is used as the acidic reagent; the reaction yield and product purity are slightly reduced when organic acids such as formic acid and propionic acid are used; and the reaction yield and product purity are significantly reduced when inorganic acids such as hydrochloric acid and sulfuric acid are used.

[0029] (Examples 6-7)

[0030] The preparation methods of (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime in each embodiment are basically the same as those in Example 1, except for the type of phase transfer catalyst, as shown in Table 2.

[0031] (Comparative Examples 1 to 3)

[0032] The preparation methods of (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime in each comparative example are basically the same as those in Example 1, except for the type of phase transfer catalyst, as shown in Table 2.

[0033] Table 2

[0034] Phase transfer catalyst product yield purity Example 1 0.1g tetrabutylammonium bromide 1.84g 78.0% 96.6% Example 6 0.1g tetrabutylammonium chloride 1.50g 63.6% 91.0% Example 7 0.1g dodecyltrimethylammonium chloride 1.30g 55.1% 88.2% Comparative Example 1 0.1g cyclodextrin 0.70g 29.7% 71.3% Comparative Example 2 0.1g polyethylene glycol 600 0.66g 28.0% 66.6% Comparative Example 3 0.1g Tributylamine 0.28g 11.9% 48.5%

[0035] As shown in Table 2, the reaction yield and product purity are highest when tetrabutylammonium bromide is used as the phase transfer catalyst; the reaction yield and product purity are reduced when other quaternary ammonium salts are used as phase transfer catalysts; and the reaction yield and product purity are very unsatisfactory when other types of phase transfer catalysts are used.

Claims

1. A process for the preparation of a fluoxastrobin intermediate, characterized by: It is in the presence of phase transfer catalyst, using acid reagent, (Z) - (5, 6-dihydro- [1, 4, 2] -dioxazine-3-yl) - (2-hydroxyphenyl) -methanone-O-methyl oxime is converted to (E) - (5, 6-dihydro- [1, 4, 2] -dioxazine-3-yl) - (2-hydroxyphenyl) -methanone-O-methyl oxime; The phase transfer catalyst is tetrabutylammonium bromide; The acid reagent is acetic acid.

2. The method of preparing a fluoxastrobin intermediate according to claim 1, characterized in that: The amount of the phase transfer catalyst is 1-10% of the weight of the (Z) - (5, 6-dihydro- [1, 4, 2] -dioxazine-3-yl) - (2-hydroxyphenyl) -methanone-O-methyl oxime.

3. The method of preparing a fluoxastrobin intermediate according to claim 1, characterized in that: The molar amount of the acid reagent is 1-5 times of the molar amount of the (Z) - (5, 6-dihydro- [1, 4, 2] -dioxazine-3-yl) - (2-hydroxyphenyl) -methanone-O-methyl oxime.

4. The method of preparing a fluoxastrobin intermediate according to claim 1, characterized in that: The reaction temperature of the configuration conversion is 50-100 DEG C.