Method for synthesizing diaveridine intermediate

Abstract

The invention relates to a method for synthesizing a diaveridine intermediate, which comprises the following steps: (a) adding dimethyl sulfoxide, potassium hydroxide and 3-dimethylaminopropionitrile into a reaction container, and heating to 65-75 DEG C; then adding veratraldehyde, and stirring to react for 2-3 hours to obtain a first reaction solution; and (b) adding ethanol and aniline into the first reaction solution, then dropwise adding an acid-containing solution, carrying out heat preservation reaction at 75-85 DEG C for 2-3 hours, cooling, crystallizing, and drying to obtain the diaveridine intermediate. Therefore, the side reaction for synthesizing the diaveridine intermediate can be inhibited, so that the reaction conditions are simplified, and the yield of the product is improved.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical product technology, specifically relating to a method for synthesizing a dimethoxybenzidine intermediate. Background Technology

[0002] Diaveridine is a dihydrofolate reductase inhibitor with an inhibition constant Ki of 11.5 nM against wild-type DHFR, exhibiting antibacterial activity. As a potentiator for sulfonamide drugs, it primarily enhances antibacterial effects when used in combination with sulfonamides, and is used to prevent and treat bacterial infections such as coccidiosis in poultry, white diarrhea in piglets, and fowl cholera.

[0003] Chinese invention patent application number 201310589520.6 discloses a method for preparing tritium-labeled dimethoxybenzidine. It uses 3,4-dimethoxy-5-bromobenzaldehyde as a raw material, and synthesizes 5-bromo-dimethoxybenzidine through a Knoevenagel reaction and a cyclization reaction. This patent uses a sodium methoxide / methanol solution, requiring a reaction at 25°C for 1 hour before reacting with 3,4-dimethoxy-5-bromobenzaldehyde at 50°C. This yields approximately 85%, leaving room for improvement. Summary of the Invention

[0004] To address the aforementioned technical problems, the present invention aims to provide a method for synthesizing dimethoxybenzidine intermediates.

[0005] To achieve the above objectives, the technical solution adopted by this invention is: a method for synthesizing a dimethoxybenzidine intermediate, comprising the following steps: (a) Add dimethyl sulfoxide, potassium hydroxide and 3-dimethylaminopropionitrile to the reaction vessel and heat to 65~75℃; then add veratral and stir the reaction for 2~3h to obtain the first reaction solution; (b) Water and aniline are added to the first reaction solution, followed by the addition of an acidic solution. The mixture is kept at 75-85°C for 2-3 hours, then cooled to allow crystallization. The crystals are dried to obtain a dimethoxybenzidine intermediate. The chemical structural formula of the dimethoxybenzidine intermediate is as follows: .

[0006] Ideally, the mass ratio of veratral to dimethyl sulfoxide is 1:3~4.

[0007] Furthermore, the molar ratio of veratral, potassium hydroxide and 3-dimethylaminopropionitrile is 1:0.3~0.5:1.3~1.5.

[0008] Ideally, in step (b), the molar ratio of aniline to veratral is 1:1.1~1.2.

[0009] Further, in step (b), the first reaction solution is cooled to 40-50°C, and then ethanol and aniline are added.

[0010] Furthermore, in step (b), the acidic solution is a sulfuric acid solution with a mass concentration of 30%.

[0011] Furthermore, in step (b), after cooling and crystallization, the solid is filtered, washed, and dried to obtain a dimethoxybenzidine intermediate.

[0012] Further, in step (a), the veratral is first dissolved in dimethyl sulfoxide, added dropwise, and then stirred to react.

[0013] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art: The method of the present invention for synthesizing dimethoxybenzidine intermediates first reacts veratral and 3-dimethylaminopropionitrile, and then reacts with aniline. This can suppress the side reactions in the synthesis of dimethoxybenzidine intermediates, thereby simplifying the reaction conditions and improving the yield of the product. Attached Figure Description

[0014] Figure 1 This is a route diagram for the synthesis of the dimethoxybenzidine intermediate in this invention; Figure 2 This is a process flow diagram for synthesizing the dimethoxybenzidine intermediate of the present invention. Detailed Implementation

[0015] like Figure 1 and Figure 2 The method for synthesizing the dimethoxybenzidine intermediate shown includes the following steps: (a) adding dimethyl sulfoxide, potassium hydroxide, and 3-dimethylaminopropionitrile to a reaction vessel and heating to 65-75°C; then adding veratral and stirring for 2-3 hours to obtain a first reaction solution; (b) adding water and aniline to the first reaction solution, then adding an acidic solution dropwise, maintaining the temperature at 75-85°C for 2-3 hours, cooling to allow crystallization, and drying to obtain the dimethoxybenzidine intermediate; the chemical structural formula of the dimethoxybenzidine intermediate is as follows: This method involves reacting veratral with 3-dimethylaminopropionitrile first, followed by reaction with aniline. This process suppresses side reactions in the synthesis of the dimethoxybenzidine intermediate, thereby simplifying the reaction conditions and increasing the product yield.

[0016] The mass ratio of veratraldehyde to dimethyl sulfoxide is 1:3~4. The molar ratio of veratraldehyde, potassium hydroxide, and 3-dimethylaminopropionitrile is 1:0.3~0.5:1.3~1.5. In step (a), veratraldehyde is first dissolved in dimethyl sulfoxide, added dropwise, and then the reaction is stirred.

[0017] In step (b), the molar ratio of aniline to veratral is 1:1.1~1.2. In step (b), the first reaction solution is cooled to 40~50°C, and then ethanol and aniline are added. In step (b), the acidic solution is a 30% (w / w) sulfuric acid solution. In step (b), after cooling and crystallization, the mixture is filtered, washed, and the solid is dried to obtain the dimethoxybenzidine intermediate.

[0018] The present invention will be further described below with reference to the embodiments shown. Example 1

[0019] This embodiment provides a method for synthesizing a dimethoxybenzidine intermediate, comprising the following steps: (a) At room temperature, add 200g of dimethyl sulfoxide, 15.0g of 90% KOH and 82.7g of 3-dimethylaminopropionitrile to the reaction vessel. After heating to 70°C, add dropwise 100g of veratraldehyde (i.e., a dimethyl sulfoxide solution of veratraldehyde) dissolved in 200g of dimethyl sulfoxide (at this time, the total mass ratio of veratraldehyde to dimethyl sulfoxide is 1:4). Keep warm and stir for 2-3 hours to obtain the first reaction solution (i.e., reaction solution 1).

[0020] (b) Cool reaction solution 1 to 40-50℃, add 200g of water and 61.6g of aniline to reaction solution 1, then add 210g of 30% (mass concentration) sulfuric acid dropwise, controlling the pH of the solution to 2-3; after the addition is complete, raise the temperature to 80℃ and stir for 2-3 hours. After the reaction is complete, cool to allow crystals to precipitate, filter, wash, and dry the solid to obtain 159.9g of dimethoxybenzidine intermediate. Yield: 90.3%, purity: 95.5% (HPLC). Example 2

[0021] This embodiment provides a method for synthesizing a dimethoprim intermediate, which is basically the same as that in Example 1, except for the amount of reactants used. Specifically, in step (a), 88.6 g of 3-dimethylaminopropionitrile and 18.75 g of 90% KOH are used; in step (b), 67.3 g of aniline is used; 157.6 g of dimethoprim intermediate is obtained. The yield of the final product is 89.0%, and the purity is 95.1% (HPLC). Example 3

[0022] This embodiment provides a method for synthesizing a dimethoxybenzidine intermediate, which is basically the same as that in Example 1, except for the amount of reactants. Specifically, in step (a), 76.8 g of 3-dimethylaminopropionitrile and 11.2 g of 90% KOH are used; in step (b), 64.4 g of aniline is used; 156.9 g of dimethoxybenzidine intermediate is obtained. The yield of the final product is 88.6%, and the purity is 95.0% (HPLC).

[0023] Comparative Example 1 This example provides a method for synthesizing a dimethoprim intermediate, which is basically the same as that in Example 1, except that in step (b), water is not used, but ethanol of the corresponding mass is used instead; 142.6 g of dimethoprim intermediate is obtained. The yield of the final product is 80.5%, and the purity is 92.6% (HPLC).

[0024] Comparative Example 2 This example provides a method for synthesizing a dimethoxybenzidine intermediate, which is basically the same as that in Example 1, except that in step (a), 90% KOH is not added, and the dimethoxybenzidine intermediate cannot be obtained.

[0025] Comparative Example 3 This example provides a method for synthesizing a dimethoxybenzidine intermediate, which is basically the same as that in Example 1, except that in step (a), 50 g of 3-dimethylaminopropionitrile and 10.0 g of 90% KOH are used to obtain 128.4 g of the dimethoxybenzidine intermediate. The yield of the final product is 72.5%, and the purity is 89.2% (HPLC).

[0026] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A method for synthesizing a dimethoxybenzidine intermediate, characterized in that, Includes the following steps: (a) Add dimethyl sulfoxide, potassium hydroxide and 3-dimethylaminopropionitrile to the reaction vessel and heat to 65~75℃; then add veratral and stir the reaction for 2~3h to obtain the first reaction solution; (b) Water and aniline are added to the first reaction solution, followed by the addition of an acidic solution. The mixture is kept at 75-85°C for 2-3 hours, then cooled to allow crystallization. The crystals are dried to obtain a dimethoxybenzidine intermediate. The chemical structural formula of the dimethoxybenzidine intermediate is as follows: .

2. The method for synthesizing the dimethoxybenzidine intermediate according to claim 1, characterized in that: The mass ratio of veratral to dimethyl sulfoxide is 1:3~4.

3. The method for synthesizing the dimethoxybenzidine intermediate according to claim 1 or 2, characterized in that: The molar ratio of veratral, potassium hydroxide and 3-dimethylaminopropionitrile is 1:0.3~0.5:1.3~1.

5.

4. The method for synthesizing the dimethoxybenzidine intermediate according to claim 1, characterized in that: In step (b), the molar ratio of aniline to veratral is 1:1.1~1.

2.

5. The method for synthesizing the dimethoxybenzidine intermediate according to claim 4, characterized in that: In step (b), the first reaction solution is cooled to 40-50°C, and then ethanol and aniline are added.

6. The method for synthesizing the dimethoxybenzidine intermediate according to claim 4 or 5, characterized in that: In step (b), the acidic solution is a sulfuric acid solution with a mass concentration of 30%.

7. The method for synthesizing the dimethoxybenzidine intermediate according to claim 4 or 5, characterized in that: In step (b), after cooling and crystallization, the product is filtered, washed, and dried to obtain a dimethoxybenzidine intermediate.

8. The method for synthesizing the dimethoxybenzidine intermediate according to claim 1 or 2, characterized in that: In step (a), the veratral is first dissolved in dimethyl sulfoxide, added dropwise, and then stirred to react.

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