Method for efficiently preparing Freraner key intermediate

Abstract

The invention provides a method for efficiently preparing a furalan key intermediate, which comprises the following steps: (a) adding 2-methyl-4-acylbenzoic acid, 3, 5-dichlorotrifluoroethyl acetophenone, an organic solvent and triethylamine into a reaction container, heating to 50-60 DEG C, and reacting for 8-24 hours to obtain a first reaction mixed solution; (b) cooling the first reaction mixed solution to 30-40 DEG C, adding 4-dimethylaminopyridine, then dropwise adding acetic anhydride, and carrying out heat preservation reaction for 3-5 hours to obtain a second reaction mixed solution; and (c) cooling the second reaction mixed solution to-5-0 DEG C, adding alkali and hydroxylamine hydrochloride, carrying out a heat preservation reaction for 1-2 h, recovering the organic solvent at 50-60 DEG C under negative pressure, adjusting the acid, crystallizing with ethanol, and filtering to obtain the Frerala key intermediate 9. The target product is synthesized by a three-step reaction one-pot method (without intermediate treatment), the post-treatment is simple and efficient, the product yield is stable, and the purity content is high.

Description

Technical Field

[0001] The invention belongs to the field of organic chemistry and relates to a method for preparing a key intermediate of Frellana, and specifically relates to a method for efficiently preparing a key intermediate of Frellana (4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid). Background Art

[0002] Frelane intermediate 9 (i.e. 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid) is a key intermediate in the synthesis of Frelane.

[0003] The Chinese invention patent with application number 202310199150.9 discloses a method for preparing an isoxazoline pet insecticide flurana intermediate, which uses 4-((hydroxyamino)methyl)-2-methylbenzoic acid (ester) (raw material I) and 1,3-dichloro-5-(1-trifluoromethyl-vinyl) benzene (raw material II) under the action of a promoter to form an oxazole ring through a one-step reaction to obtain the target product; or uses the corresponding salt of 4-((hydroxyamino)methyl)-2-methylbenzoic acid (ester) (raw material III) and 1,3-dichloro-5-(1-trifluoromethyl-vinyl) benzene (raw material II) under the action of a promoter and a base to form an oxazole ring through a one-step reaction to obtain the target product. The raw materials and reagents of the preparation method of this application are easy to synthesize, the reaction conditions are mild, the yield is high, the reaction operability and repeatability are good, and it is suitable for large-scale industrial preparation of flurana. It can be seen that in the previous process, the reaction needs to go through three reactions of condensation, dehydration, and ring closure to synthesize intermediate nine. The conditions of the three-step post-treatment are difficult to control, the purification and refining process is complicated, many by-products are produced, the purity is low, and the yield is unstable. Summary of the invention

[0004] In order to solve the above technical problems, the object of the present invention is to provide a method for efficiently preparing a key intermediate of Frellana.

[0005] In order to achieve the above technical problem, the present invention provides a method for efficiently preparing a key intermediate of Frellana, comprising the following steps: (a) adding 2-methyl-4-acylbenzoic acid, 3,5-dichlorotrifluoroethylacetophenone, an organic solvent and triethylamine into a reaction vessel, raising the temperature to 50-60° C. and reacting for 8-24 hours to obtain a first reaction mixture; (b) cooling the first reaction mixture to 30-40° C., adding 4-dimethylaminopyridine, and then dropping acetic anhydride, and reacting for 3-5 hours to obtain a second reaction mixture; (c) The second reaction mixture is cooled to -5-0°C, alkali and hydroxylamine hydrochloride are added, and the mixture is kept warm for 1-2 hours. The organic solvent is recovered under negative pressure at 50-60°C, and the mixture is acidified and filtered to obtain the key intermediate 9 of Frelane.

[0006] Optimally, the molar ratio of the 2-methyl-4-acylbenzoic acid, 3,5-dichlorotrifluoroethylacetophenone and triethylamine is 1.0:0.9~2.5:1.2~1.8.

[0007] Furthermore, in step (a), the organic solvent is one or more selected from toluene, p-xylene, m-xylene, chlorobenzene and dichlorobenzene.

[0008] Optimally, in step (b), the molar ratio of 4-dimethylaminopyridine, acetic anhydride and 2-methyl-4-acylbenzoic acid is 0.05~0.5:1.5~3.0:1.

[0009] Optimally, in step (c), the alkali is one selected from sodium hydroxide and its aqueous solution and potassium hydroxide and its aqueous solution; when the alkali is an aqueous solution, the mass concentration of its solute is 30-60%.

[0010] Furthermore, in step (c), the molar ratio of the base, hydroxylamine hydrochloride and 2-methyl-4-acylbenzoic acid is 2-6:1.5-3.5:1.

[0011] Optimally, in step (c), equal amounts of ethanol and 10% hydrochloric acid are added to the Frellana key intermediate 9, the pH is adjusted to 1-4, cooled to -5-5°C to cool and crystallize, the filter cake is filtered out, and placed in an oven for drying.

[0012] The method for efficiently preparing the key intermediate of Frellana of the present invention synthesizes the target product in a one-pot method with three-step reaction (without intermediate treatment), has simple and efficient post-treatment, stable product yield, high purity content, further shortens the post-treatment time, simplifies the post-treatment production process, greatly reduces production energy consumption and labor costs, ensures non-toxic operation of the production environment, and can realize large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 The reaction equation of the method for efficiently preparing the key intermediate of Frellana of the present invention; Figure 2 The present invention is a process flow chart of the method for efficiently preparing the key intermediate of Frellana. DETAILED DESCRIPTION

[0014] The invention discloses a method for efficiently preparing a Frellana key intermediate, comprising the following steps: (a) adding 2-methyl-4-acylbenzoic acid, 3,5-dichlorotrifluoroethylacetophenone, an organic solvent and triethylamine into a reaction container, heating the temperature to 50-60°C and reacting for 8-24 hours to obtain a first reaction mixture; (b) cooling the first reaction mixture to 30-40°C, adding 4-dimethylaminopyridine, then dripping acetic anhydride, and keeping the temperature for reaction for 3-5 hours to obtain a second reaction mixture; (c) cooling the second reaction mixture to -5-0°C, adding a base and hydroxylamine hydrochloride, keeping the temperature for reaction for 1-2 hours, recovering the organic solvent at 50-60°C under negative pressure, adjusting the temperature, crystallizing and filtering to obtain a Frellana key intermediate 9. The target product is synthesized in a one-pot three-step reaction (without intermediate treatment). The post-processing is simple and efficient, the product yield is stable, and the purity content is high. The post-processing time is further shortened, the post-processing production process is simplified, the production energy consumption and labor costs are greatly reduced, the non-toxic operation of the production environment is ensured, and large-scale production can be realized.

[0015] In step (a), the molar ratio of 2-methyl-4-acylbenzoic acid, 3,5-dichlorotrifluoroethylacetophenone and triethylamine is 1.0:0.9~2.5:1.2~1.8. In step (a), the organic solvent is selected from one or more of toluene, p-xylene, m-xylene, chlorobenzene and dichlorobenzene. In step (b), the molar ratio of 4-dimethylaminopyridine, acetic anhydride and 2-methyl-4-acylbenzoic acid is 0.05~0.5:1.5~3.0:1. In step (c), the base is selected from one of sodium hydroxide and its aqueous solution and potassium hydroxide and its aqueous solution; when the base is an aqueous solution, the mass concentration of its solute is 30~60%. In step (c), the molar ratio of the base, hydroxylamine hydrochloride and 2-methyl-4-acylbenzoic acid is 2~6:1.5~3.5:1. In step (c), ethanol and 10% hydrochloric acid are added to the Frellana key intermediate 9, the pH is adjusted to 1-4, the mixture is cooled to -5-5°C to crystallize, the filter cake is filtered out, and the cake is placed in an oven for drying.

[0016] The present invention will be further described below in conjunction with the embodiments shown in the accompanying drawings. Example 1

[0017] This embodiment provides a method for efficiently preparing a key intermediate of Freylan, such as Figure 1 and Figure 2 As shown, the following steps are included: (a) firstly add 27 g of 2-methyl-4-acylbenzoic acid into a reaction container, then add 55.2 g of 3,5-dichlorotrifluoroethylacetophenone, then add 150 g of toluene and 23 g of triethylamine, raise the temperature to 60° C., and react for 18 h to obtain a first reaction mixture; (b) cooling the first reaction mixture to 40° C., adding 3.7 g of 4-dimethylaminopyridine and 31 g of acetic anhydride, and reacting at this temperature for 4 h to obtain a second reaction mixture; (c) The second reaction mixture was cooled to -5°C, 24.2 g of sodium hydroxide and 24.2 g of water were added first, and then 21.1 g of hydroxylamine hydrochloride was added, and the mixture was kept warm for 2 h. After the heat preservation was completed, the mixture was heated to 60°C, and toluene was recovered by vacuum concentration to obtain a crude product. 100 g of ethanol and 100 g of 10% hydrochloric acid were added, and the pH was adjusted to 1-4. The mixture was cooled to 0°C, and the mixture was cooled for crystallization, and the filter cake was filtered and placed in an oven for drying (65°C) to obtain 46.1 g of the 9-type white crystalline powder of the intermediate Frelane. The yield of the product was 72.8%, and the content was 98% (HPLC). Example 2

[0018] This example provides a method for efficiently preparing a key intermediate of Frelana, which is basically the same as that in Example 1, except that: (a) 92.1 g of 3,5-dichlorotrifluoroethylacetophenone, 27.6 g of triethylamine, (b) 46.4 g of acetic anhydride, and (c) 36.8 g of hydroxylamine hydrochloride. The yield of the final product is 75%, and the content is 98.2% (HPLC). Example 3

[0019] This example provides a method for efficiently preparing a key intermediate of Frelana, which is basically the same as that in Example 1, except that: (a) the amount of triethylamine added is 18.4 g, (b) acetic anhydride is 23.2 g, and (c) hydroxylamine hydrochloride is 15.8 g. The yield of the final product is 71%, and the content is 98.5% (HPLC).

[0020] Comparative Example 1 This example provides a method for preparing a key intermediate of Frelane, which is basically the same as that in Example 1, except that in step (a), triethylamine is not added and the product cannot be obtained.

[0021] Comparative Example 2 This example provides a method for preparing a key intermediate of Frelane, which is basically the same as that in Example 1, except that in step (b), acetic anhydride is not added and the product cannot be obtained.

[0022] Comparative Example 3 This example provides a method for preparing a key intermediate of Frellana, which adopts the existing conventional method, as follows: (a) First, 27 g of 2-methyl-4-acylbenzoic acid was added to a reaction vessel, followed by 55.2 g of 3,5-dichlorotrifluoroethylacetophenone, and then 150 g of toluene and 27.6 g of triethylamine. The temperature was raised to 60° C. and the reaction was carried out for 24 h to obtain a first reaction mixture. The reaction mixture was cooled to 0-10° C., filtered and dried to obtain 67 g of intermediate 1.

[0023] (b) Add 67 g of intermediate 1 and 150 g of toluene to a reaction vessel, then add 3.7 g of 4-dimethylaminopyridine and dropwise add 31 g of acetic anhydride, keep the reaction warm for 5 h, add 55 g of triethylamine, adjust the pH to 7-8, cool and filter to obtain about 55 g of intermediate 2; (c) Add 55g of intermediate 2 to 400ml of toluene, then add 24.2g of sodium hydroxide and 24.2g of water, then add 21.1g of hydroxylamine hydrochloride, and keep warm for 2h; after the insulation is completed, heat to 60°C, vacuum concentrate to recover toluene to obtain a crude product; add 100g of ethanol and 100g of 10% hydrochloric acid, adjust the pH to 1-4, cool to 0°C, cool to crystallize, filter and take the filter cake, place in an oven for drying (65°C) to obtain 36.5g of Frellana intermediate IX as a white crystalline powder. Total yield of three steps: 57%, content: 97.7% (HPLC).

[0024] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for efficiently preparing a key intermediate of Frellana, characterized in that: The following steps are involved: (a) adding 2-methyl-4-acylbenzoic acid, 3,5-dichlorotrifluoroethylacetophenone, an organic solvent and triethylamine into a reaction vessel, raising the temperature to 50-60° C. and reacting for 8-12 hours to obtain a first reaction mixture; (b) cooling the first reaction mixture to 30-40° C., adding 4-dimethylaminopyridine, and then dropping acetic anhydride, and reacting for 3-4 hours to obtain a second reaction mixture; (c) The second reaction mixture is cooled to -5-0°C, a base and hydroxylamine hydrochloride are added, and the mixture is kept warm for 1-2 hours. The organic solvent is recovered under negative pressure at 50-60°C, and the key intermediate 9 of Frelane is obtained by crystallization and filtration.

2. The method for efficiently preparing a key intermediate of Frellana according to claim 1, characterized in that: In step (a), the molar ratio of 2-methyl-4-acylbenzoic acid, 3,5-dichlorotrifluoroethylacetophenone and triethylamine is 1.0:0.9-2.5:1.2-1.

8.

3. The method for efficiently preparing a key intermediate of Frellana according to claim 1 or 2, characterized in that: In step (a), the organic solvent is one or more selected from toluene, p-xylene, m-xylene, chlorobenzene and dichlorobenzene.

4. The method for efficiently preparing a key intermediate of Frellana according to claim 1, characterized in that: In step (b), the molar ratio of 4-dimethylaminopyridine, acetic anhydride and 2-methyl-4-acylbenzoic acid is 0.05-0.5:1.5-3.0:

1.

5. The method for efficiently preparing a key intermediate of Frellana according to claim 1, characterized in that: In step (c), the alkali is one selected from sodium hydroxide and its aqueous solution and potassium hydroxide and its aqueous solution; when the alkali is an aqueous solution, the mass concentration of the solute is 30-60%.

6. The method for efficiently preparing a key intermediate of Frellana according to claim 1 or 5, characterized in that: In step (c), the molar ratio of the base, hydroxylamine hydrochloride and 2-methyl-4-acylbenzoic acid is 2-6:1.5-3.5:

1.

7. The method for efficiently preparing a key intermediate of Frellana according to claim 1, characterized in that: In step (c), ethanol and 10% hydrochloric acid are added to the Frellana key intermediate 9, the pH is adjusted to 1-4, the mixture is cooled to -5-5°C to crystallize, the filter cake is filtered out, and the cake is placed in an oven for drying.

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