Preparation method and application of [1,4,5]oxadiazepane

Abstract

The application provides a preparation method and application of [1,4,5] oxadiazepane, which comprises the following steps: 4,5-diacyl-[1,4,5]-oxadiazepine organic matter is dissolved in an organic solvent, a cyclic crown ether catalyst or a quaternary ammonium salt catalyst is added, and hydrogen halide is introduced for reaction, after the reaction is completed, a hydrogen halide salt of [1,4,5] oxadiazepane is prepared through post-treatment. It belongs to the field of pesticide chemistry and chemical technology. In summary, compared with the existing production method of [1,4,5] oxadiazepane, the method has the advantages of high reaction efficiency, short reaction time, high yield, high purity, high content, simple process, less solid waste, cost saving, good economy and suitability for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to a method for preparing [1,4,5]oxadiaheptanane and its application, belonging to the field of pesticide chemistry and chemical engineering technology. Background Technology

[0002] [1,4,5]oxadiaheptan, CAS: 746595-79-9, also known as [1,4,5]oxadiazepoxide, is an important synthetic intermediate, especially in the field of pesticide synthesis. For example, [1,4,5]oxadiaheptan is an important intermediate in the synthesis of the herbicide cyclophosphamide (WO9947525).

[0003] WO9947525 (CN1185234C) discloses a process for preparing [1,4,5]oxadiaheptan hydrobromide by reacting N,N'-di-tert-butoxycarbonyl-[1,4,5]oxadiazepine with hydrobromic acid in diethyl ether. The reaction temperature is 20°C with stirring for 22 hours, and the reaction temperature is 35°C with stirring for 27 hours. Although the reaction temperature of this process is low, the protecting group raw material Boc2O is expensive, has a large molecular weight, and generates a large amount of waste during deprotection. The solvent used, diethyl ether, has a low flash point and poses safety hazards. Moreover, the total reaction time of this process is long (48 hours) and the efficiency is low.

[0004] WO03051853A (CN1279032C) discloses a process for using an organic compound containing a 4,5-diacyl-[1,4,5]-oxodiazazepine structure as a raw material, employing a hydrohalic acid, preferably hydrogen chloride and hydrogen bromide, in a polar solvent at an elevated temperature (43-50°C), to react and remove the acyl group to generate an organic compound containing a [1,4,5]-oxodiazazepine structure. The polar solvent is preferably an alcohol with a boiling point above 100°C, such as n-butanol, n-pentanol, cyclohexanol, phenol, benzyl alcohol, ethylene glycol, diethylene glycol, glycerol, methoxyisopropanol, and ethoxyethanol. Although this process solves the problems of high price, large molecular weight, and large amount of waste during deprotection of Boc2O, there are still many problems, such as the reaction cycle is still too long (18-22 hours), the solvent boiling point requirement is high (boiling point above 100℃), and the product purity is not high due to solvent encapsulation (purity of about 90%, containing about 9% solvent).

[0005] WO2006045587 (CN101039926B) discloses a process in which an organic compound containing a 4,5-diacyl-[1,4,5]-oxodiazazepine structure is reacted with an alkali metal or alkaline earth metal hydroxide, carbonate, or alcohol base in a polar solvent selected from water, an alcohol having a boiling point above 100°C, DMSO, sulfolane, NMP, DMA, or DMF, or mixtures thereof, to remove the acyl group and generate an organic compound containing a [1,4,5]-oxodiazazepine structure. The reaction can be carried out in the presence of a salt soluble in the reaction mixture. This process requires high reaction temperatures and only achieves high yields (65-90%) when water is used as the solvent. It also requires a large amount of organic salt, easily generating a large amount of solid waste. Furthermore, the product [1,4,5]oxodiazazepine is highly soluble in water, making product separation difficult and requiring multiple extractions, which increases production costs and generates a large amount of waste liquid.

[0006] CN108264492B and CN108264493B disclose a method for using an organic compound containing a 4,5-diacyl-[1,4,5]-oxodiazazolide structure as a raw material, using potassium hydroxide as a base, and reacting in a non-polar solvent (toluene or xylene) at a temperature of 100-130°C to remove the acyl group and generate a compound containing [1,4,5]-oxodiazazolide. The reported yield of this process is high, and the reported reaction time is short, but the reaction temperature is high, exceeding 100°C. The examples all use a toluene reflux temperature of 130°C. We found that the reaction does not occur at lower temperatures, but only when the temperature reaches a high reaction temperature, such as 130°C, will the reaction proceed rapidly and release heat in a concentrated manner. This poses a significant safety risk to industrial scale-up, and there is a problem of generating a large amount of waste during deprotection, especially a large amount of mixed waste salt containing toluene or xylene of potassium hydroxide and potassium acetate. This waste salt has a complex composition and requires hazardous waste treatment, which is costly. At the same time, the non-polar solvent (toluene or xylene) has a high boiling point, which will also lead to high energy consumption in the solvent removal process in subsequent reaction steps.

[0007] IN201821039267A discloses a method for generating [1,4,5]-oxadiazepine from 4,5-diacetyl-[1,4,5]-oxadiazepine using hydrogen chloride in a polar solvent at elevated temperatures (45-60°C) by deacetylation. However, the reaction cycle remains too long (47 hours), and the product yield is low (approximately 38-47%).

[0008] Therefore, there is a need to develop methods for preparing one or more improved [1,4,5]oxadiaheptananes. Summary of the Invention

[0009] The purpose of this invention is to solve the problems existing in the preparation methods of [1,4,5]oxadiaheptanane in the prior art.

[0010] To address the aforementioned problems, the present invention provides a method for preparing [1,4,5]oxadiaheptanane, comprising the following steps: dissolving an organic compound with the 4,5-diacyl-[1,4,5]oxadiaheptanane structure shown in formula (A) in an organic solvent, adding a cyclic crown ether catalyst or a quaternary ammonium salt catalyst, and introducing hydrogen halide (HX) to carry out the reaction. After the reaction is completed, the hydrogen halide of [1,4,5]oxadiaheptanane shown in formula (B) is prepared by post-treatment.

[0011]

[0012] Preferably, the organic solvent is a polar solvent with a boiling point below 100°C; the polar solvent is further preferably an alcohol, more preferably at least one of tert-butanol, n-propanol, isopropanol, ethanol and methanol, and the organic solvent can be recycled.

[0013] Preferably, the mass ratio of the compound of formula (A) to the organic solvent is 1:1.0-9.0, and more preferably 1:3.0-7.0.

[0014] Preferably, the cyclic crown ether catalyst is 18-crown 6, and the quaternary ammonium salt catalyst is tetrabutylammonium hydrogen sulfate.

[0015] Preferably, the mass ratio of the compound of formula (A) to the catalyst is 1:0.005-0.3, more preferably 1:0.01-0.2.

[0016] Preferably, the molar ratio of the compound of formula (A) to the hydrogen halide is 1:2.0-9.0, and more preferably 1:3.0-8.0.

[0017] Preferably, the reaction temperature is 35–80°C; more preferably, it is 40–60°C.

[0018] Preferably, the total reaction time is 2 to 12 hours; more preferably, it is 4 to 8 hours.

[0019] Preferably, the post-processing step includes precipitating the product from the reaction system by cooling, and obtaining the product by filtering it in a nitrogen-protected filter.

[0020] The present invention also experimentally verified that the hydrogen halide of [1,4,5]oxadiazepine obtained by this preparation method can be converted into herbicides such as cyclohexane through further reaction.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] 1. The preparation method of the present invention significantly increases the reaction rate and shortens the reaction time at a relatively mild reaction temperature. At the same time, the reaction has a good conversion rate and a high yield, with the highest yield reaching 96.4%.

[0023] 2. In the preparation method of the present invention, alcohol solvents with relatively low boiling points are used. These solvents are easy to recover, and the recovery energy consumption is low. The solvent residue in the product is significantly reduced, and the purity and mass content of the product are significantly improved. At the same time, the problem of poor stirring effect of viscous crystals mentioned in the prior art is improved.

[0024] 3. In the preparation method of this invention, the catalysts used are commonly used and relatively inexpensive catalysts, and the amount of catalyst used is small, resulting in good catalytic effect on the reaction, significantly improving the reaction rate, reducing the generation of reaction impurities, and improving product quality. It also significantly improves the problem mentioned in the prior art that the [1,4,5]-oxodiazazoline hydrohalates have poor stability and are inconvenient to store.

[0025] 4. The post-processing technology used in this invention is simple and efficient, reduces crystal viscosity, and improves filtration effect, thus addressing the problem of poor separation effect of [1,4,5]-oxodiazazoline hydrohalides mentioned in the prior art. At the same time, it has good stability when stored in a sealed container, the mother liquor can be recycled and reused, there is less solid waste, and it is cost-effective and economical.

[0026] In summary, compared with existing methods for producing [1,4,5]oxadiaheptan, the method of the present invention has higher reaction efficiency, shorter reaction time, higher yield, higher purity, higher content of the product, simpler process, less solid waste, lower cost, better economic performance, and is more suitable for large-scale industrial production. Detailed Implementation

[0027] To make the present invention more apparent and understandable, preferred embodiments are described in detail below:

[0028] This embodiment is implemented based on the technical solution of the present invention, and provides detailed implementation methods and specific operation processes. However, the scope of protection of the present invention is not limited to the following embodiment.

[0029] Unless otherwise specified, percentages in this invention refer to mass concentration or mass percentage.

[0030] In this embodiment of the invention, the content of hydrohalate of [1,4,5]oxadiazepane was determined by high performance liquid chromatography with external standard quantification.

[0031] Example 1: Preparation of [1,4,5]oxazaheptan hydrochloride

[0032] In a 500 mL reaction flask, add 37.24 g of 4,5-diacetyl-[1,4,5]oxadiazepine (0.2 mol) and 149 g (192.2 mL) of tert-butanol, along with 0.8 g of 18crown6. Heat to an internal temperature of 40-45 °C. Slowly introduce 29.2 g (0.8 mol) of dry hydrogen chloride gas into the reaction system through a bottom-inserted glass tube. The hydrogen chloride gas should be introduced completely over approximately 2 hours. After the gas introduction is complete, maintain the reaction mixture under nitrogen protection at 50-55 °C for 4 hours. After the reaction is complete, degas the reaction suspension at 35-45 °C to remove the hydrogen chloride gas. Cool to 0-5 °C and filter through a nitrogen-protected filter to obtain the product. Collect the tert-butanol mother liquor (approximately 156 g) for use in the next batch. The filtered solid was washed three times with ethyl acetate at 0-5°C under nitrogen protection, using 20.0 g of ethyl acetate each time. The ethyl acetate mother liquor was collected separately. After drying the obtained solid under nitrogen protection, 33.22 g of [1,4,5]oxodiazaheptane hydrochloride was obtained, with a purity of 97.2%, a mass content of 96.1%, and a molar yield of 91.2%.

[0033] Example 2: Preparation of [1,4,5]oxazaheptan hydrochloride

[0034] In a 500 mL reaction flask, 37.24 g of 4,5-diacetyl-[1,4,5]-oxadiazon (0.2 mol) and 156 g of the tert-butanol mother liquor from Example 1 were added, along with 0.8 g of 18crown 6. The mixture was heated to an internal temperature of 40-45 °C. 29.2 g (0.8 mol) of dry hydrogen chloride gas was slowly introduced into the reaction system through a bottom-inserted glass tube, with the hydrogen chloride gas being introduced completely over approximately 2 hours. After the gas introduction was complete, the reaction mixture was maintained at 50-55 °C for 4 hours under nitrogen protection. After the reaction was complete, the reaction suspension was degassed at 35-45 °C to remove the hydrogen chloride gas. After cooling to 0-5 °C, the product was obtained by filtration through a nitrogen-protected filter. The filtered solid was washed three times with 20.0 g of ethyl acetate at 0-5 °C under nitrogen protection. The ethyl acetate mother liquor was collected separately. The obtained solid was dried under nitrogen protection to obtain 35.49 g of [1,4,5]oxodiazaheptane hydrochloride with a purity of 96.1%, a mass content of 95.1%, and a molar yield of 96.4%.

[0035] Example 3: Preparation of [1,4,5]oxazaheptan hydrochloride

[0036] In a 500 mL reaction flask, add 37.24 g of 4,5-diacetyl-[1,4,5]-oxadazole (0.2 mol) and 186.2 g (237.2 mL) of isopropanol, along with 0.4 g of tetrabutylammonium hydrogen sulfate. Heat to an internal temperature of 45-50 °C. Slowly introduce 36.5 g (1.0 mol) of dry hydrogen chloride gas into the reaction system through a bottom-inserted glass tube. The hydrogen chloride gas should be introduced completely over approximately 2 hours. After the gas introduction is complete, maintain the reaction mixture under nitrogen protection at 55-60 °C for 5 hours. After the reaction is complete, degas the reaction suspension at 35-45 °C to remove the hydrogen chloride gas. Cool to 0-5 °C and filter through a nitrogen-protected filter to obtain the product. The isopropanol mother liquor can be collected for reuse. The filtered solid was washed three times with ethyl acetate at 0-5°C under nitrogen protection, using 20.0 g of ethyl acetate each time. The ethyl acetate mother liquor was collected separately. The obtained solid was dried under nitrogen protection to obtain 33.73 g of [1,4,5]oxodiazaheptane hydrochloride with a purity of 96.9%, a mass content of 95.6%, and a molar yield of 92.1%.

[0037] Example 4: Preparation of [1,4,5]oxazaheptan hydrochloride

[0038] In a 500 mL reaction flask, 37.24 g of 4,5-diacetyl-[1,4,5]-oxadiazon (0.2 mol) and 223.44 g (283.2 mL) of ethanol were added, along with 0.8 g of tetrabutylammonium hydrogen sulfate. The mixture was heated to an internal temperature of 40-45 °C. 51.1 g (1.4 mol) of dry hydrogen chloride gas was slowly introduced into the reaction system through a bottom-inserted glass tube, with the hydrogen chloride gas being introduced completely over approximately 3 hours. After the gas introduction was complete, the reaction mixture was maintained at 55-60 °C for 5 hours under nitrogen protection. After the reaction was complete, the reaction suspension was degassed at 35-45 °C to remove the hydrogen chloride gas. After cooling to 0-5 °C, the product was obtained by filtration through a nitrogen-protected filter. The ethanol mother liquor was collected for reuse. The filtered solid was washed three times with ethyl acetate at 0-5 °C under nitrogen protection, using 20.0 g of ethyl acetate each time. The ethyl acetate mother liquor was collected separately. The obtained solid was dried under nitrogen protection to obtain 33.4 g of [1,4,5]oxodiazaheptane hydrochloride with a purity of 96.7%, a mass content of 95.9%, and a molar yield of 91.5%.

[0039] Example 5: Preparation of [1,4,5]oxazaheptan hydrobromide

[0040] In a 500 mL reaction flask, add 42.85 g of 4,5-dipropionyl-[1,4,5]-oxadazole (0.2 mol) and 257.1 g (331.7 mL) of tert-butanol, along with 0.6 g of tetrabutylammonium bisulfate. Heat to an internal temperature of 40-45 °C. Slowly introduce 64.73 g (0.8 mol) of dry hydrogen bromide gas into the reaction system through a bottom-inserted glass tube. The hydrogen bromide gas should be completely introduced over approximately 3 hours. After the gas introduction is complete, maintain the reaction mixture under nitrogen protection at 50-55 °C for 4 hours. After the reaction is complete, degas the reaction suspension at 45-50 °C to remove the hydrogen bromide gas. Cool to 0-5 °C and filter through a nitrogen-protected filter to obtain the product. The tert-butanol mother liquor can be collected for reuse. The filtered solid was washed three times with ethyl acetate at 0-5°C under nitrogen protection, using 20.0 g of ethyl acetate each time. The ethyl acetate mother liquor was collected separately. The solid was dried under nitrogen protection to obtain 50.01 g of [1,4,5]oxadiazeptane hydrobromide with a purity of 95.9%, a mass content of 95.0%, and a molar yield of 90.0%.

[0041] Example 6: Preparation of 8-(2,6-diethyl-4-methylbenzene)-1,2,4,5-tetrahydropyrazole[1,2-d][1,4,5]oxodiazepine-7,9-dione

[0042] In a reaction flask, 6.93 g (0.05 mol) of [1,4,5]oxadiazepoxide hydrochloride prepared in Example 1 was added, followed by 13.9 g (0.05 mol) of dimethyl 2,6-diethyl-4-methylphenylmalonate and 7.6 g (0.075 mol) of triethylamine. The reaction solution was heated to reflux. After the reaction was complete, it was cooled to room temperature, and the reaction solution was washed successively with 2 mol / L hydrochloric acid solvent and water, dried, and concentrated to obtain 14.3 g of solid 8-(2,6-diethyl-4-methylbenzene)-1,2,4,5-tetrahydropyrazole[1,2-d][1,4,5]oxadiazepoxide-7,9-dione, with a yield of 90.7%.

[0043] Example 7: Preparation of clopyralid

[0044] 9.5 g (0.03 mol) of 8-(2,6-diethyl-4-methylbenzene)-1,2,4,5-tetrahydropyrazole[1,2-d][1,4,5]oxodiazepine-7,9-dione prepared in Example 5 was added to 60 mL of tetrahydrofuran and stirred to dissolve. 6.1 g (0.06 mol) of triethylamine and 0.2 g of DMAP catalyst were added. The mixture was cooled to -5 to 0 °C, and 4.8 g (0.04 mol) of pentanoyl chloride was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 4 h. The reaction solution was poured into 120 mL of saturated sodium chloride solution, extracted three times with ethyl acetate, the organic layer was washed with water and dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the mixture was recrystallized using tert-butyl methyl ether to give 10.2 g of off-white solid, with a yield of 84.9% and a mass content greater than 97%.

[0045] Comparative Example 1: Preparation of [1,4,5]oxadiazepoxide hydrochloride without catalyst

[0046] In a 500 mL reaction flask, add 37.24 g of 4,5-diacetyl-[1,4,5]oxadiazepine (0.2 mol) and 149 g (192.2 mL) of tert-butanol. Heat to an internal temperature of 40-45 °C. Slowly introduce 29.2 g (0.8 mol) of dry hydrogen chloride gas into the reaction system through a bottom-inserted glass tube. The hydrogen chloride gas should be introduced completely over approximately 2 hours. After the gas introduction is complete, maintain the reaction mixture under nitrogen protection at 50-55 °C for 4 hours. After the reaction is complete, degas the reaction suspension at 35-45 °C to remove the hydrogen chloride gas. Cool to 0-5 °C and filter through a nitrogen-protected filter to obtain the product. The tert-butanol mother liquor can be collected for reuse. The filtered solid is washed three times with 20.0 g of ethyl acetate at 0-5 °C under nitrogen protection. The ethyl acetate mother liquor is collected separately. The obtained solid was dried under nitrogen protection to obtain 20.83 g of [1,4,5]oxodiazaheptane hydrochloride with a purity of 89.9%, a mass content of 88.4%, and a molar yield of 52.6%.

[0047] Comparative Example 2: Preparation of [1,4,5]oxadiazepoxide hydrochloride using high-boiling-point alcohol solvents without a catalyst

[0048] In a 500 mL reaction flask, add 37.24 g of 4,5-diacetyl-[1,4,5]-oxadiazonium (0.2 mol) and 149 g (133.9 mL) of ethylene glycol. Heat to an internal temperature of 40-45 °C. Slowly introduce 29.2 g (0.8 mol) of dry hydrogen chloride gas into the reaction system through a bottom-inserted glass tube. The hydrogen chloride gas should be introduced completely over approximately 2 hours. After the gas introduction is complete, maintain the reaction mixture under nitrogen protection at 50-55 °C for 4 hours. After the reaction is complete, degas the reaction suspension at 35-45 °C to remove the hydrogen chloride gas. Cool to 0-5 °C and filter through a nitrogen-protected filter to obtain the product. The ethylene glycol mother liquor can be collected for reuse. The filtered solid is washed three times with ethyl acetate at 0-5 °C under nitrogen protection, using 20.0 g of ethyl acetate each time. The ethyl acetate mother liquor is collected separately. The obtained solid was dried under nitrogen protection to obtain 17.05 g of [1,4,5]oxodiazaheptane hydrochloride with a purity of 87.2%, a mass content of 84.2%, and a molar yield of 41.0%.

[0049] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any form or substance. It should be noted that those skilled in the art can make various improvements and additions without departing from the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention. Any modifications, alterations, and equivalent changes made by those skilled in the art based on the above-disclosed technical content without departing from the spirit and scope of the present invention are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and evolutions made to the above embodiments based on the essential technology of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A method for preparing a hydrohalate of [1,4,5]oxazaheptanane, characterized in that, The process includes the following steps: dissolving 4,5-diacyl-[1,4,5]-oxodiazazepine organic compounds in an organic solvent, adding a cyclic crown ether catalyst or a quaternary ammonium salt catalyst, passing hydrogen halide acid through the catalyst to carry out the reaction, and after the reaction is completed, preparing the hydrogen halide of [1,4,5]oxodiazazepine by post-treatment. The organic solvent is at least one selected from tert-butanol, n-propanol, isopropanol, ethanol, and methanol. The cyclic crown ether catalyst is 18-crown 6, and the quaternary ammonium salt catalyst is tetrabutylammonium hydrogen sulfate; The 4,5-diacyl-[1,4,5]-oxodiazazolide organic compounds are 4,5-diacetyl-[1,4,5]-oxodiazazolide or 4,5-dipropionyl-[1,4,5]-oxodiazazolide.

2. The method for preparing the hydrohalate of [1,4,5]oxadiazeptane as described in claim 1, characterized in that, The mass ratio of the 4,5-diacyl-[1,4,5]-oxadiazonium organic compound to the catalyst is 1:0.005-0.

3.

3. The method for preparing the hydrohalate of [1,4,5]oxadiaheptanane as described in claim 1, characterized in that, The molar ratio of the 4,5-diacyl-[1,4,5]-oxadiazonium organic compound to the hydrogen halide is 1:2.0-9.

0.

4. The method for preparing the hydrohalate of [1,4,5]oxadiaheptanane as described in claim 1, characterized in that, The hydrogen halide acid mentioned is hydrogen chloride or hydrogen bromide.

5. The method for preparing the hydrohalate of [1,4,5]oxadiaheptanane as described in claim 1, characterized in that, The reaction temperature is 35–80°C; the total reaction time is 2–12 hours.

6. The method for preparing the hydrohalate of [1,4,5]oxadiazeptane as described in claim 1, characterized in that, The post-processing steps include precipitating the product from the reaction system by cooling and obtaining the product by filtering it through a nitrogen-protected filter.

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