Process for the synthesis of (E)-(5,6-dihydro-[1,4,2]-dioxazin-3-yl)-(2-hydroxyphenyl)-methanone-O-methyl oxime

Abstract

The application discloses a synthesis method of (E)-(5,6-dihydro-[1,4,2]-dioxazin-3-yl)-(2-hydroxyphenyl)-methanone-O-methyl oxime, which comprises the following steps: taking benzofuran-2,3-diketone-2-[O-(2-hydroxyethyl)oxime]-3-(O-methyl oxime) as raw material, performing ring closure and rearrangement in a sodium ethoxide-ethanol solution; then cooling the reaction solution, adding water, and precipitating sodium salt; and finally acidifying the sodium salt to obtain (E)-(5,6-dihydro-[1,4,2]-dioxazin-3-yl)-(2-hydroxyphenyl)-methanone-O-methyl oxime. According to the method, ring closure and rearrangement are performed in a sodium ethoxide-ethanol solution, then a certain amount of water is added, so that the target product is precipitated from the reaction system in the form of sodium salt, the reaction yield of the method can reach nearly 80%, and the product purity can reach more than 98%.

Description

Technical Field

[0001] This invention belongs to the field of pesticide intermediate synthesis technology, specifically relating to a method for synthesizing (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] The final step in the existing synthetic methods for (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime is basically obtained by cyclization and rearrangement of benzofuran-2,3-dione-2-[O-(2-hydroxyethyl)oxime]-3-(O-methyl oxime). Based on the differences in the starting materials, these methods can be further divided into the following three categories: I. Using (E)-benzofuran-2,3-dione-2-[O-(2-hydroxyethyl)oxime]-3-(O-methyloxime) directly as a raw material, cyclization and rearrangement under alkaline conditions yield (E)-(5,6-dihydro-[1,4,2]-dioxazin-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyloxime with a yield of 88-98% [see Chinese patent document CN105518003A].

[0005] The drawback of this method is that (E)-benzofuran-2,3-dione-2-[O-(2-hydroxyethyl)oxime]-3-(O-methyloxime) has limited sources and is difficult to prepare, making it unsuitable for large-scale industrial production.

[0006] II. Using (Z)-benzofuran-2,3-dione-2-[O-(2-hydroxyethyl)oxime]-3-(O-methyloxime) directly as a raw material, cyclization and rearrangement under acidic conditions yielded (E)-(5,6-dihydro-[1,4,2]-dioxazin-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyloxime, with a yield of 65% [see Chinese patent document CN107690428A].

[0007] The drawbacks of this method are that (Z)-benzofuran-2,3-dione-2-[O-(2-hydroxyethyl)oxime]-3-(O-methyloxime) is also limited in source and difficult to prepare, making it unsuitable for large-scale industrial production. Furthermore, the reaction yield of this method is relatively low, at only 65%.

[0008] III. Using benzofuran-2,3-dione-2-[O-(2-hydroxyethyl)oxime]-3-(O-methyloxime) [i.e., a racemic mixture containing (E) and (Z) formulas] as raw material, cyclization and rearrangement are carried out in an aqueous solution of sodium hydroxide or potassium hydroxide to obtain (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyloxime.

[0009] This method is currently the conventional industrial method. However, this method can only convert the (E) structure in the raw material into the target product, but cannot convert the (Z) structure. This not only requires recrystallization to obtain the target product, which increases the cost, but also the reaction yield is only about 50%. Summary of the Invention

[0010] The purpose of this invention is to solve the above-mentioned problems and provide a method for synthesizing (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime by converting both isomers in the raw materials into the target compound, thereby obtaining high yield and high purity.

[0011] The technical solution for achieving the objective of this invention is: a method for synthesizing (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime, comprising the following steps: ① Using benzofuran-2,3-dione-2-[O-(2-hydroxyethyl)oxime]-3-(O-methyloxime) [that is, a racemic mixture containing (E) and (Z) formulas] as raw material, cyclization and rearrangement are carried out in sodium ethoxide-ethanol solution to obtain a reaction solution with (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyloxime as the main product (content above 70%); ② Cool the reaction solution obtained in step ①, add water, and precipitate the sodium salt of (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime; ③ Acidify the sodium salt obtained in step ② to obtain (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime.

[0012] The reaction formula is as follows: .

[0013] Through extensive experiments, the applicant discovered that cyclization and rearrangement in a sodium ethoxide-ethanol solution could convert some of the (Z)-structured raw materials into the target product with an E-structure. However, conventional post-processing methods made it difficult to separate the product from the reaction system, resulting in a low yield. Surprisingly, the applicant found that adding water could salt the product, and the sodium salt of the target product could precipitate from the ethanol system, thereby obtaining (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime with high yield and high purity.

[0014] However, the amount of water added is also important. Adding too much water will cause some of the sodium salt of the target product to dissolve in the water, thus affecting the yield; adding too little water will result in less sodium salt of the target product precipitated, which will also affect the reaction yield; and adding too little water will prevent the sodium salt of the target product from precipitating.

[0015] In step ② above, the amount of water added is 6% to 20% of the amount of sodium ethoxide ethanol solution used, preferably 13% to 17%, and more preferably 15%.

[0016] In step ① above, the cyclization and rearrangement reaction temperature is 50–100°C.

[0017] In step ① above, the molar ratio of benzofuran-2,3-dione-2-[O-(2-hydroxyethyl)oxime]-3-(O-methyloxime) to sodium ethoxide is 1:1 to 1:1.5.

[0018] The ratio of the two isomers of benzofuran-2,3-dione-2-[O-(2-hydroxyethyl)oxime]-3-(O-methyloxime) used in step ① above is 1:0.5 to 1:2.

[0019] The positive effects of this invention are as follows: The method of this invention cyclizes and rearranges the target product in a sodium ethoxide-ethanol solution to obtain a reaction solution mainly composed of the target product. Then, by adding a certain amount of water, the target product is precipitated from the reaction system in the form of a sodium salt. Finally, the sodium salt is acidified to obtain the target product. This method can achieve a reaction yield of nearly 80% and a product purity of over 98%, which is significantly advantageous compared to the yield of about 50% in the prior art. Attached Figure Description

[0020] Figure 1 The HPLC chromatogram of benzofuran-2,3-dione-2-[O-(2-hydroxyethyl)oxime]-3-(O-methyloxime) used in step ① of Example 1 is shown.

[0021] Figure 2The image shows the HPLC spectrum of the reaction solution after cyclization and rearrangement in step ① of Example 1.

[0022] Figure 3 The image shows the HPLC spectrum of the filtrate obtained in step ② of Example 1.

[0023] Figure 4 The image shows the HPLC spectrum of the filter cake obtained in step ② of Example 1.

[0024] Figure 5 The image shows the HPLC spectrum of the final product obtained in step ③ of Example 1. Detailed Implementation

[0025] (Example 1) The method for synthesizing (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime in this embodiment includes the following steps: ① Add 300g of benzofuran-2,3-dione-2-[O-(2-hydroxyethyl)oxime]-3-(O-methyloxime) and 600g of 16wt% sodium ethoxide-ethanol solution to a 1000mL four-necked reaction flask. Stir and heat to 80±5℃, and keep the reaction at this temperature for 6 hours. Take a sample and test the content of benzofuran-2,3-dione-2-[O-(2-hydroxyethyl)oxime]-3-(O-methyloxime) to determine if it is less than 0.5%. The reaction is then complete.

[0026] The HPLC chromatogram of the raw material benzofuran-2,3-dione-2-[O-(2-hydroxyethyl)oxime]-3-(O-methyloxime) used in this embodiment is shown in [reference needed]. Figure 1 It can be seen that the ratio of the two isomers is approximately 1:1.

[0027] The HPLC spectrum of the reaction solution obtained in this embodiment is shown below. Figure 2 It can be seen that the main product is (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime, with a content of over 80%.

[0028] ② After the reaction is complete, cool the reaction solution to 20-30℃, then add 90g of water, keep warm and stir for 1 hour. A large amount of solid precipitates out. Continue cooling to 0℃, keep warm and stir for 2 hours, centrifuge and filter. The HPLC chromatogram of the filtrate is shown in [Figure number missing]. Figure 3 It can be seen that the filtrate contains a certain amount of sodium salt with (Z) structure and a very small amount of sodium salt with (E) structure.

[0029] The filter cake was washed with 100g of anhydrous ethanol to obtain 310g of sodium salt, the HPLC chromatogram of which is shown below. Figure 4 It can be seen that the sodium salt is basically a sodium salt with an (E) structure, and its content is close to 99%.

[0030] ③ Add 310g of the above-mentioned sodium salt and 1200g of water to a 2000mL four-necked reaction flask, stir and add hydrochloric acid dropwise to adjust the pH to <2, cool, centrifuge and filter. Wash the filter cake with 100g of water and dry it at 90-100℃ to obtain 240g of (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime, with a yield of 80.0% and an HPLC purity of 99.98% (see [link to relevant documentation]). Figure 5 ).

[0031] (Examples 2 to 9) The synthesis 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 amount of water added in step ②, as shown in Table 1.

[0032] (Comparative Example 1) The synthetic method of (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime in this comparative example comprises the following steps: ① Same as Example 1.

[0033] ② After the reaction was completed, the reaction solution was cooled to 20-30℃, and then 30g of water was added. The mixture was kept warm and stirred for 2 hours. No solid precipitated. Hydrochloric acid was added dropwise while stirring to adjust the pH to <2. The mixture was then cooled, centrifuged and filtered. The filter cake was washed with 100g of water and dried at 90-100℃ to obtain 154g of (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime, with a yield of 51.3% and an HPLC purity of 92.1%.

[0034] (Comparative Examples 2 to 3) The synthesis 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 comparative example 1, except for the amount of water added, as shown in Table 1.

[0035] (Comparative Example 4) The synthetic method of (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime in this comparative example comprises the following steps: ① Same as Example 1.

[0036] ② After the reaction was completed, the reaction solution was cooled to 20-30℃, and hydrochloric acid was added dropwise to the reaction solution with stirring to adjust the pH to <2. The solution was then cooled, centrifuged and filtered. The filter cake was washed with 100g of water and dried at 90-100℃ to obtain 150g of (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime, with a yield of 50.0% and an HPLC purity of 92.4%.

[0037] Table 1 Example 1 90g 310g precipitated 240g 80.0% 99.98% Example 2 100g 278g was extracted 216g 72.0% 99.85% Example 3 110g 252g was extracted 195g 65.0% 99.63% Example 4 120g 225g was extracted 178g 59.3% 99.26% Example 5 80g 292g precipitated 224g 74.6% 99.90% Example 6 70g 247g was extracted 189g 63.0% 99.60% Example 7 60g 199g was extracted 158g 52.6% 99.12% Example 8 50g 186g was extracted 145g 48.3% 98.54% Example 9 40g 170g was extracted 130g 43.3% 98.15% Comparative Example 1 30g No precipitation 154g 51.3% 92.1% Comparative Example 2 20g No precipitation 152g 50.7% 91.8% Comparative Example 3 10g No precipitation 152g 50.7% 91.8%

[0038] As can be seen from Table 1: (1) Adding a certain amount of water can precipitate more sodium salt solids. If more water is added, some sodium salt of the target product will dissolve in the water, thus reducing the reaction yield. If less water is added, less sodium salt of the target product will precipitate, which will also reduce the reaction yield.

[0039] (2) If very little water is added or no water is added, the sodium salt of the target product will not precipitate. The purity and reaction yield of the final product obtained by conventional post-processing methods are both low.

Claims

1. A method for synthesizing (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime, characterized in that... It includes the following steps: ① Using benzofuran-2,3-dione-2-[O-(2-hydroxyethyl)oxime]-3-(O-methyloxime) as a starting material, cyclization and rearrangement were carried out in sodium ethoxide-ethanol solution to obtain a reaction solution with (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyloxime as the main product; ② Cool the reaction solution obtained in step ①, add water, and precipitate the sodium salt of (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime; ③ Acidify the sodium salt obtained in step ② to obtain (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime.

2. The method for synthesizing (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime according to claim 1, characterized in that: In step ① above, the cyclization and rearrangement reaction temperature is 50–100°C.

3. The method for synthesizing (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime according to claim 1, characterized in that: In step ① above, the molar ratio of benzofuran-2,3-dione-2-[O-(2-hydroxyethyl)oxime]-3-(O-methyloxime) to sodium ethoxide is 1:1 to 1:1.

5.

4. The method for synthesizing (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime according to claim 1, characterized in that: The ratio of the two isomers of benzofuran-2,3-dione-2-[O-(2-hydroxyethyl)oxime]-3-(O-methyloxime) used in step ① above is 1:0.5 to 1:

2.

5. The method for synthesizing (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime according to any one of claims 1 to 4, characterized in that: In step ② above, the amount of water added is 6% to 20% of the amount of sodium ethoxide ethanol solution used.

6. The method for synthesizing (E)-(5,6-dihydro-[1,4,2]-dioxazine-3-yl)-(2-hydroxyphenyl)-methyl ketone-O-methyl oxime according to claim 5, characterized in that: In step ② above, the amount of water added is 13% to 17% of the amount of sodium ethoxide ethanol solution used.

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