Method for synthesizing cycloxaprid by using unilateral aldehyde

Abstract

The invention discloses a method for synthesizing cycloxaprid by using unilateral aldehyde, which comprises the following steps: by using 4-acetoxybutyraldehyde as an initial raw material, selectively protecting the aldehyde group of the 4-acetoxybutyraldehyde through an accurate pH value regulation strategy, oxidizing the alcoholic hydroxyl group at the other end into the aldehyde group under specific conditions, and reacting to obtain the cycloxaprid by using the unilateral aldehyde. And finally, carrying out cyclization reaction on the cycloxaprid and 2-chloro-5-((2-(nitromethylene) imidazoline-1-yl) methyl) pyridine in an acid environment, so as to prepare the cycloxaprid in one step. According to the invention, the raw material is further extended to cheap 1, 4-butanediol, and the key intermediate is prepared through selective protection and oxidation. According to the technology, separation of unstable intermediates is avoided through ingenious reaction time sequence control, high yield and high chemical purity are achieved, raw materials can be recycled, the technology has the outstanding advantages of being high in atom economy, low in cost, environmentally friendly and the like, and the problems that a traditional production technology is low in yield and difficult to scale are perfectly solved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of preparation of epoxyclothrin, in particular to a method for synthesizing epoxyclothrin by using single-side aldehyde. BACKGROUND

[0002] Epoxyclothrin is a new neonicotinoid insecticide with cis seven-membered oxygen bridge heterocyclic structure, which is successfully commercialized by East China University of Technology and Shanghai Shengnong Biochemical Products Co., Ltd. The synthesis of epoxyclothrin is generally prepared by ring-closing dehydration with epoxyclothrin intermediate 2-chloro-5-((2-(nitromethyl) imidazoline-1-yl) methyl) pyridine and butanedial aqueous solution or 2,5-dimethoxy tetrahydrofuran as main raw materials, as described in Chinese patents CN101747320 and CN112010873, etc. The main synthesis method is to use the above-mentioned synthesis method to synthesize epoxyclothrin by using butanedial or directly using 2,5-dimethoxy tetrahydrofuran as raw material. However, 2,5-dimethoxy tetrahydrofuran and butanedial are expensive, and the yield of self-made butanedial solution applied to industrial production is low, which leads to high raw material cost of epoxyclothrin. CN120118099A directly uses 1,4-butanediol as raw material for reaction, but the activity of diol is not high, and the yield of large-scale production is limited.

[0003] Therefore, it is the focus of research in this field to seek a green and safe, high atomic utilization, low cost, smooth and stable process for synthesizing epoxyclothrin. SUMMARY

[0004] The purpose of the present application is to overcome the shortcomings in the prior art and provide a method for synthesizing epoxyclothrin by using single-side aldehyde.

[0005] To achieve the above-mentioned purpose, the technical solution adopted by the present application is as follows: A method for synthesizing epoxyclothrin by using single-side aldehyde is provided, which comprises the following steps: Step one, acetyl butyraldehyde is protected by aldehyde group in the presence of aldehyde group protecting agent, the timing of protection and deprotection is controlled by adjusting pH value, and intermediate organic phase is obtained by extraction, then single-side oxidation is carried out on the intermediate by using first oxidizing agent to obtain single-side aldehyde; Step two, the single-side aldehyde obtained in step one is subjected to cyclization reaction with epoxyclothrin intermediate 2-chloro-5-((2-(nitromethyl) imidazoline-1-yl) methyl) pyridine under acidic conditions, and epoxyclothrin is obtained after post-treatment.

[0006] Further, the 4-acetyloxy butyraldehyde is prepared from 1,4-butanediol as initial raw material, which specifically comprises: taking 1,4-butanediol as initial raw material, first reacting with hydroxyl protecting agent in a solvent to protect one of the primary alcohol hydroxyl groups; then, using a second oxidizing agent to oxidize the unprotected primary alcohol hydroxyl group to obtain 4-acetyloxy butyraldehyde.

[0007] Further, the aldehyde group protecting agent is selected from acetic anhydride, ethylene glycol or trimethyl orthoformate; preferably acetic anhydride, ethylene glycol.

[0008] Further, the molar ratio of the aldehyde group protecting agent to 4-acetyloxybutyraldehyde is (0.5-1.5):1; preferably 0.67:1.

[0009] Further, the first oxidizing agent is selected from sodium hypochlorite combined with Tempo oxidant, hydrogen peroxide, potassium peroxymonosulfate, Dess-Martin oxidant or chlorinated dihydroxy-bistetramethyl-ethylene diamine copper; preferably sodium hypochlorite combined with Tempo oxidant, hydrogen peroxide.

[0010] Further, the molar ratio of the first oxidizing agent to 4-acetyloxybutyraldehyde is (0.8-1.5):1; the first oxidizing agent is preferably 10% sodium hypochlorite solution + Tempo, wherein the molar ratio of sodium hypochlorite in the 10% sodium hypochlorite solution to 4-acetyloxybutyraldehyde is 1:1, and the mass of Tempo is 0.5% of the mass of 4-acetyloxybutyraldehyde.

[0011] Further, the molar ratio of the cycloxypyrifalixent intermediate to monobromine aldehyde is 1:(1.1-1.8); preferably 1:1.2.

[0012] Further, the acid used in the acidic condition is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or trichloroacetic acid; preferably hydrochloric acid, trifluoroacetic acid.

[0013] Further, the mass ratio of the cycloxypyrifalixent intermediate to the acid is 1:(0.1-0.5); preferably 1:0.29.

[0014] Further, the reaction temperature of the aldehyde group protection in step one is 0-5°C, and the reaction time is 0.5-1 hour; the reaction temperature of the monobromine oxidation in step one is 0-5°C, and the reaction time is 0.5-1 hour; the reaction temperature of the cyclization reaction in step two is 25-30°C, and the reaction time is 2-3 hours.

[0015] Further, the solvent used in the process is selected from one or more of water, dichloromethane, dichloroethane or acetonitrile; preferably dichloromethane.

[0016] The above technical scheme is adopted in the present application, and compared with the prior art, the present application has the following technical effects: The application designs a novel synthesis path taking "single aldehyde" as a key intermediate for efficiently preparing ethopropis. The path takes 4-acetyloxybutyraldehyde as a starting material, first protects the aldehyde group under acidic conditions; then adjusts the system to weak alkaline, and specifically oxidizes the alcohol hydroxyl group at the other end to a second aldehyde group; finally, after mixing with ethopropis intermediate CMNI, the reaction is switched back to acidic conditions, and the acetal deprotection and ring closing reaction are completed synchronously, and the target product is generated in one step. This strategy of controlling the reaction timing by pH switching avoids the separation of unstable dialdehyde intermediates, ensuring the smoothness, stability and high yield of the process.

[0017] To further improve the industrial value, the above synthesis strategy is extended to the bulk chemical 1,4-butanediol, which is a cheap and readily available starting material. By selectively differentiating the treatment of the two identical primary alcohol hydroxyl groups of 1,4-butanediol, i.e. selectively protecting one of the hydroxyl groups with acetic anhydride, and then oxidizing the other exposed hydroxyl group, the key intermediate 4-acetyloxybutyraldehyde is successfully prepared. This not only builds a complete and economic technical chain from basic chemical raw materials to high value products, but also the various raw materials involved in the process can be recycled and used, ultimately forming an advantage process with the characteristics of atom economy, low cost and environmental friendliness, perfectly solving the pain points of traditional methods with unsatisfactory yield and difficult to scale up. DETAILED DESCRIPTION

[0018] The application will be further described below in conjunction with specific examples, but not as a limitation of the application. It should be noted that the examples in the application and the features in the examples can be combined with each other without conflict.

[0019] Example 1 Preparation of ethopropis with 4-acetyloxybutyraldehyde as a starting material: A three-necked flask was added 4-acetyloxybutyraldehyde 6.1 g (1.2 eq), dichloromethane 50 g, and ethylene glycol 2.4 g (0.8 eq) in sequence, wherein the calculation of the equivalent was based on CMNI. The temperature of the reaction system was controlled at 0-5℃, and the reaction was stirred at this temperature for 1 hour, and the reaction progress was monitored by gas chromatography (GC). After the reaction was completed, the pH of the reaction liquid was adjusted to weak alkaline (7-8), and the organic phase was collected after standing and separating. 10% sodium hypochlorite aqueous solution 35.1 g (1.2 eq) and TEMPO catalyst (0.06 g) were added to the obtained organic phase, and the temperature was maintained at 0-5℃ to continue stirring for 1 hour. After the reaction was completed, the organic phase was separated again and reserved.

[0020] The epoxy cyhalothrin intermediate CMNI (2-chloro-5-((2-(nitrosylmethyl) imidazoline-1-yl) methyl) pyridine, 10 g, 0.04 mol) was dissolved in a small amount of dichloromethane to prepare a CMNI solution, which was added to the above-mentioned organic phase, and then 10% hydrochloric acid solution 2.9 g (0.2 eq) was added dropwise. The reaction system was gradually warmed to 25-30°C, and the reaction was stirred at this temperature for 2 hours.

[0021] After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was crystallized, filtered, and dried under appropriate conditions to obtain white solid product epoxy cyhalothrin 11.4 g, with a yield of 88.9%, and the chemical purity was analyzed to be 98.7%.

[0022] The structure identification data are as follows: 1 H-NMR (400MHz): δ 8.36 (d, J = 2.4Hz, 1H), 7.80 (dd, J1 = 2.4Hz, J2= 8.4Hz, 1H), 7.52 (d, J = 8.4Hz, 1H), 5.35-8.38 (s, 2H), 5.01 (d, J = 15.6Hz, 1H), 4.69 (d, J = 15.6Hz, 1H), 3.56-3.74 (m, 4H), 1.93-2.05 (m, 4H).

[0023] LC-MS (ESI): 323 (M+H).

[0024] Example 2 Epoxy cyhalothrin was prepared using 1,4-butanediol as a starting material: A three-necked flask was sequentially added with 1,4-butanediol 7.1 g (0.08 mol), dichloromethane 50 g, and acetic anhydride 6.4 g (0.8 eq). The temperature of the reaction system was controlled at 0-5°C, and the reaction was stirred for 1 hour, during which the reaction progress was monitored by gas chromatography (GC).

[0025] After the reaction was completed, the reaction solution was adjusted to weak alkaline (pH 7-8), and the liquid was allowed to stand and separate, and the organic phase was collected. To the organic phase was added 15% hydrogen peroxide solution 17.9 g (1.0 eq), and the reaction was continued to stir for 1 hour at 0-5°C. After the reaction was completed, the liquid was again separated, and the organic phase was retained.

[0026] To the organic phase was added ethylene glycol 2.6 g (0.8 eq), and the mixture was stirred for 30 minutes at 0-5°C, followed by sequentially adding 10% sodium hypochlorite aqueous solution 48.4 g (1.2 eq) and TEMPO catalyst (0.07 g), and the reaction was continued to stir for 1 hour at the same temperature. After the reaction was completed, the liquid was separated, and the organic phase was collected.

[0027] The epoxy cyhalothrin intermediate CMNI (2-chloro-5-((2-(nitrosylmethyl) imidazoline-1-yl) methyl) pyridine, 10 g, 0.04 mol) was dissolved in a small amount of dichloromethane to prepare a CMNI solution, which was added to the above organic phase, and then 10% hydrochloric acid solution 2.9 g (0.2 eq) was added dropwise. The reaction system was gradually warmed to 25-30°C, and the reaction was stirred for 2 hours.

[0028] After the reaction was completed, the reaction liquid was concentrated under reduced pressure to remove the solvent, and the obtained solid was crystallized, filtered and dried to obtain white solid product epoxy cyhalothrin 11.8 g, with a yield of 91.6%, and the chemical purity was analyzed to be 98.3%.

[0029] The above only describes the preferred embodiments of the present application, and does not limit the implementation and protection scope of the present application. It should be realized by those skilled in the art that any equivalent replacement and obvious changes made according to the content of the present application should be included in the protection scope of the present application.

Claims

1. A process for the synthesis of epoxydienofenide using monobasic aldehyde, characterized by, The method comprises the following steps: Step one, the aldehyde group of 4-acetoxybutyraldehyde is protected in the presence of an aldehyde group protection agent, the timing of protection and deprotection is controlled by adjusting the pH value, an intermediate organic phase is obtained by extraction, and then the intermediate is subjected to one-side oxidation using a first oxidizing agent to obtain a one-side aldehyde; Step two, the one-side aldehyde obtained in step one is subjected to a cyclization reaction with an epoxy cyhalothrin intermediate 2-chloro-5-((2-(nitrosylmethylene) imidazoline-1-yl) methyl) pyridine under acidic conditions, and the epoxy cyhalothrin is obtained after post-treatment.

2. The method of claim 1, wherein, The 4-acetoxybutyraldehyde is prepared from 1,4-butanediol as an initial raw material, and specifically comprises the following steps: 1,4-butanediol as an initial raw material is first reacted with a hydroxyl protection agent in a solvent to protect one primary alcohol hydroxyl group; then, a second oxidizing agent is used to oxidize the unprotected primary alcohol hydroxyl group to obtain 4-acetoxybutyraldehyde.

3. The method of claim 1, wherein, The aldehyde group protection agent is selected from acetic anhydride, ethylene glycol or trimethyl orthoformate.

4. The method of claim 3, wherein, The molar ratio of the aldehyde group protection agent to 4-acetoxybutyraldehyde is (0.5-1.5):

1.

5. The method of claim 1, wherein, The first oxidizing agent is selected from a combination of sodium hypochlorite and Tempo oxidizing agent, hydrogen peroxide, potassium monopersulfate, des-martin oxidizing agent or chlorinated dihydroxy-bistetramethyl ethylene diamine copper.

6. The method of claim 5, wherein, The molar ratio of the first oxidizing agent to 4-acetoxybutyraldehyde is (0.8-1.5):

1.

7. The method of claim 1, wherein, The molar ratio of the epoxy cyhalothrin intermediate to the one-side aldehyde is 1:(1.1-1.8).

8. The method of claim 1, wherein, The acid used in the acidic conditions is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or trichloroacetic acid.

9. The method of claim 8, wherein, The mass ratio of the epoxy cyhalothrin intermediate to the acid is 1:(0.1-0.5).

10. The method of claim 1, wherein, The reaction temperature of the aldehyde group protection in step one is 0-5°C, and the reaction time is 0.5-1 hour; the reaction temperature of the one-side oxidation in step one is 0-5°C, and the reaction time is 0.5-1 hour; the reaction temperature of the cyclization reaction in step two is 25-30°C, and the reaction time is 2-3 hours.