A process for the preparation of cycloxaprid

Abstract

The present application relates to a kind of preparation cycloxapridone method.The method of the present application is prepared by cyclization reaction with amide compound or cyclic urea compound as catalyst, the amide compound or cyclic urea compound is preferably N',N-dimethylformamide or N',N-dimethylimidazolinone.Cycloxapridone can be greatly reduced by using the method of the present application The generation of ethoxy impurities improves the purity of the product, and the price of catalyst is cheap, easy to synthesize, and the reaction condition is mild, can significantly reduce production cost, has good industrial application value.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing cycloazinones. Background Technology

[0002] Cycloazolinone, also known as Wilbur, Lincaojing, Feicaojing, and Sentai, has the chemical name 3-cyclohexyl-6-dimethylamino-1-methyl-1,3,5-triazine-2,4-dione. It is a colorless, odorless crystalline solid, belonging to the systemic, selective, post-emergence contact triazine herbicide class. This herbicide is extremely effective against forest weeds, shrubs, and vines. It can be absorbed by the stems and leaves of plants and transported within the plant via the xylem, directly interfering with photosynthesis, causing metabolic disorders and leading to plant death. It can also be absorbed by the roots and transported to the stems and leaves, interfering with photosynthesis and causing metabolic disorders, ultimately leading to plant death. In addition to its herbicidal and stubble-killing activities, cycloazolinone also has the effect of killing fungi and bacteria in plants; for example, it can effectively control wheat infections caused by *Stripetracus rust*.

[0003] Currently, the synthesis methods of cycloazinone both domestically and internationally mainly refer to US patents US4178448 and US4150225. The synthesis of triazine rings in these methods all use strong bases as cyclization catalysts. In this way, the alcohol generated by cyclization exchanges with the dimethylamine group of cycloazinone, generating cyclization side products, which affects the yield.

[0004] The following is a common synthetic route for cycloazinones:

[0005]

[0006] Common catalysts for cyclization reactions include strong inorganic bases and strong metal bases of organic alcohols. The ethanol produced in this reaction undergoes a reversible exchange reaction with the cyclization product cycloazinone in the presence of a strong base catalyst, resulting in the removal of a dimethylamine group. The reaction equation is as follows:

[0007]

[0008] In existing technologies, there are generally two methods to suppress this side reaction: one is to introduce an equivalent amount or more of dimethylamine to inhibit its release; the other is to remove the alcohol produced in the reaction in a timely manner to prevent the side reaction from occurring. Both of these methods have drawbacks: in the first method, the introduced gaseous dimethylamine needs to be removed with water, and the resulting wastewater increases environmental pressure, and the use of dimethylamine poses safety hazards. In addition, this method cannot completely suppress the side reaction, with about 10% of the side reaction still occurring; the second method has stricter equipment requirements, a very narrow range of operational flexibility, and also increases production costs.

[0009] To avoid cyclization side reactions, CN104402837A discloses a novel synthetic route for cycloazinones, comprising two steps: first, guanidine reacts with cyclohexylamine to generate a guanidinylurea intermediate and an alcohol; after the reaction, the alcohol is removed; then, a photochemical cyclization reaction is carried out. However, this route requires phosgene, posing safety hazards in industrial production and easily causing pollution.

[0010] In view of the above-mentioned defects in the existing technology, the inventors have provided a new method for preparing cycloazinone, which can greatly reduce the generation of ethoxy impurities, improve the purity of the product, and the catalyst is inexpensive, easy to synthesize, and the reaction conditions are mild, which can significantly reduce production costs and has great industrial application value. Summary of the Invention

[0011] The purpose of this invention is to provide a method for preparing cycloazinone, so as to solve the technical problems of high impurity content and high production cost in the existing technology.

[0012] In a first aspect, the present invention provides a method for preparing cycloazinones, comprising the following steps: in the presence of an organic solvent, a base, and a catalyst, compound II undergoes a cyclization reaction at a certain temperature to obtain cycloazinone I, the reaction route being as follows:

[0013]

[0014] Wherein: the catalyst is selected from one or a combination of Formula 1, Formula 2, and Formula 3;

[0015]

[0016] Wherein: R1 is selected from H or CH3; R2 is selected from CH3 or CH2CH3;

[0017] n is selected from 1 or 2.

[0018] Preferably, the catalyst is selected from one or a combination of N',N-dimethylformamide or N',N-dimethylimidazolinone.

[0019] Preferably, the alkali is selected from inorganic alkalis or organic alkalis;

[0020] Preferably, the inorganic base is selected from alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydroxides, and alkaline earth metal hydroxides, including but not limited to potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide; the organic base includes but is not limited to alkali metal salts of aliphatic amines, aromatic amines, alcohols, or alkyl lithiums, such as triethylamine, tripropylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, sodium methoxide, sodium ethoxide, phenyl lithium, diisopropylaminolithium, and hexamethyldisilazine lithium; most preferably, the base is selected from sodium methoxide, sodium ethoxide, and sodium tert-butoxide.

[0021] Preferably, the organic solvent is selected from one or more aliphatic, alicyclic, and aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, toluene, and xylene; ethers, such as diethyl ether, dimethyl ether, tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, and dioxane; alcohols, such as methanol and ethanol; and esters, such as ethyl acetate and tert-butyl acetate. More preferably, the organic solvent is selected from one or more of toluene, xylene, methanol, ethanol, and ethyl acetate.

[0022] Preferably, the amount of catalyst used is 0.01 mol% to 20 mol% of the compound of formula II, more preferably 0.05 mol% to 10 mol%.

[0023] Preferably, the reaction temperature is -10 to 30°C, more preferably -5 to 20°C, and even more preferably -5 to 5°C.

[0024] Preferably, the reaction time is 1 minute to 12 hours, more preferably 5 minutes to 3 hours, and most preferably 15 to 30 minutes.

[0025] Preferably, the preparation method of the present invention further includes a post-processing step: after the reaction is completed, water is added to the reaction mixture, the mixture is separated into layers, the organic phase is washed with water, the organic phase is concentrated to remove the solvent, then n-hexane is added, the mixture is kept warm for 30 min, the temperature is slowly lowered, the mixture is filtered, and the filter cake is washed and dried to obtain the product cycloazinone.

[0026] Preferably, the ethoxy impurity content in the product obtained by the preparation method of the present invention is significantly reduced. Preferably, the ethoxy impurity content is less than 5%, more preferably, less than 2%, and even more preferably, less than 0.4%. The structural formula of the ethoxy impurity is as follows:

[0027]

[0028] Preferably, dimethylamine is not required in the reaction system.

[0029] In another aspect of the present invention, there is a use of a catalyst, characterized in that the catalyst is used to prepare cycloazinones represented by Formula I;

[0030]

[0031] The catalyst is selected from one or a combination of Formula 1, Formula 2, and Formula 3;

[0032]

[0033] Wherein: R1 is selected from H or CH3; R2 is selected from CH3 or CH2CH3;

[0034] n is selected from 1 or 2.

[0035] Preferably, the catalyst is selected from one or a combination of N',N-dimethylformamide or N',N-dimethylimidazolinone.

[0036] Preferably, the use of the catalyst is characterized in that, in the presence of an organic solvent, a base, and a catalyst, compound II undergoes a cyclization reaction at a certain temperature to produce cycloazinone I, as shown in the following reaction route:

[0037]

[0038] Preferably, the alkali is selected from inorganic alkalis or organic alkalis;

[0039] Preferably, the inorganic base is selected from alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydroxides, and alkaline earth metal hydroxides, including but not limited to potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide; the organic base includes but is not limited to alkali metal salts of aliphatic amines, aromatic amines, alcohols, or alkyl lithiums, such as triethylamine, tripropylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, sodium methoxide, sodium ethoxide, phenyl lithium, diisopropylaminolithium, and hexamethyldisilazine lithium; most preferably, the base is selected from sodium methoxide, sodium ethoxide, and sodium tert-butoxide.

[0040] Preferably, the organic solvent is selected from one or more aliphatic, alicyclic, and aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, toluene, and xylene; ethers, such as diethyl ether, dimethyl ether, tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, and dioxane; alcohols, such as methanol and ethanol; and esters, such as ethyl acetate and tert-butyl acetate. More preferably, the organic solvent is selected from one or more of toluene, xylene, methanol, ethanol, and ethyl acetate.

[0041] Preferably, the amount of catalyst used is 0.01 mol% to 20 mol% of the compound of formula II, more preferably 0.05 mol% to 10 mol%.

[0042] Preferably, the reaction temperature is -10 to 30°C, more preferably -5 to 20°C, and even more preferably -5 to 5°C.

[0043] Preferably, the reaction time is 1 minute to 12 hours, more preferably 5 minutes to 3 hours, and most preferably 15 to 30 minutes.

[0044] Preferably, the preparation method of the present invention further includes a post-processing step: after the reaction is completed, water is added to the reaction mixture, the mixture is separated into layers, the organic phase is washed with water, the organic phase is concentrated to remove the solvent, then n-hexane is added, the mixture is kept warm for 30 min, the temperature is slowly lowered, the mixture is filtered, and the filter cake is washed and dried to obtain the product cycloazinone.

[0045] Preferably, the ethoxy impurity content in the product obtained by the preparation method of the present invention is significantly reduced. Preferably, the ethoxy impurity content is less than 5%, more preferably, less than 2%, and even more preferably, less than 0.4%. The structural formula of the ethoxy impurity is as follows:

[0046]

[0047] Preferably, dimethylamine is not required in the reaction system.

[0048] By adopting the above technical solution, the present invention has the following beneficial effects:

[0049] 1) By adding a catalyst, the selectivity of the reaction is improved, dimethylamine is not required, the generation of ethoxy impurities is suppressed, the reaction yield and product purity are improved, and the production cost is reduced.

[0050] 2) The catalyst of the present invention can effectively reduce the activation energy of the cyclization reaction, enabling the reaction to proceed at low temperature and shortening the reaction time.

[0051] 3) The catalyst of the present invention is inexpensive and readily available, which can effectively reduce production costs. Detailed Implementation

[0052] The technical solution of the present invention will be clearly and completely described below with specific embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0053] Example 1: Preparation of cycloazinone (I) using N',N-dimethylformamide as a catalyst

[0054] 220 g of the adduct (0.74 mol) was added to a reaction flask, followed by 1000 g of toluene and 5.4 g of N',N-dimethylformamide (0.074 mol). The mixture was stirred and cooled to 0 °C, then 3.2 g of solid sodium methoxide (0.059 mol) was added. The mixture was kept warm and stirred for 15–30 min, then 300 g of process water was added. The mixture was allowed to separate into layers, and the toluene phase was washed with 300 g of water. The mixture was concentrated by adding 300 g of n-hexane and kept warm for 30 min. The mixture was then slowly cooled to 20 °C and filtered. The product was washed and dried to obtain 158 g of product, with a yield of 85%. HPLC analysis showed that the product purity was 99.3% and the ethoxy impurity content was 0.3%.

[0055] Example 2: Preparation of cycloazinone (I) using N',N-dimethylimidazolinone as a catalyst

[0056] 220 g of the adduct (0.74 mol) was added to a reaction flask, followed by 1000 g of toluene and 8.4 g of N'N-dimethylimidazolinone (0.074 mol). The mixture was stirred and cooled to 0 °C, then 3.2 g of solid sodium methoxide (0.056 mol) was added. The mixture was kept warm and stirred for 15–30 min, then 300 g of process water was added. The mixture was allowed to separate into layers, and the toluene phase was washed with 300 g of water. The mixture was concentrated by adding 300 g of n-hexane and kept warm for 30 min. The mixture was then slowly cooled to 20 °C and filtered. The product was washed and dried to obtain 164 g of product, with a yield of 88%. HPLC analysis showed that the product purity was 99.2% and the ethoxy impurity content was 0.4%.

[0057] Comparative Example 1

[0058] Preparation of cycloazinone (I) with the addition of dimethylamine in the absence of a catalyst

[0059] 220 g of the adduct (0.74 mol) was added to a reaction flask, followed by 1000 g of toluene and 39 g (0.87 mol) of liquid dimethylamine. The mixture was stirred and heated to 40–50 °C. 11 g (0.059 mol) of 29% sodium methoxide methanol solution was added dropwise. The mixture was kept warm and stirred for 30 min. 300 g of water was added, and the mixture was allowed to separate into layers. The toluene phase was washed with 300 g of water, concentrated, and then 300 g of n-hexane was added. The mixture was kept warm for 30 min, then slowly cooled to 20 °C and filtered. The filter cake was washed and dried to obtain 149 g of cycloazinone (I), with a yield of 80%. HPLC analysis showed that the product purity was 98.3% and the ethoxy impurity content was 1.2%.

[0060] As can be seen from Examples 1-2 and the comparative examples above, by adding a small amount of catalyst to replace excess dimethylamine, the yield and purity of the cyclization reaction not only do not decrease, but are slightly improved, which has great application value in process production.

Claims

1. A method for preparing cycloazinone, comprising the following steps: in the presence of an organic solvent, a base, and a catalyst, compound II undergoes a cyclization reaction at a certain temperature to obtain cycloazinone I, the reaction route being as follows: ； in: The catalyst is selected from one or a combination of N',N-dimethylformamide or N',N-dimethylimidazolinone.

2. The method according to claim 1, characterized in that, The base is selected from potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, tripropylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, sodium methoxide, sodium ethoxide, phenyllithium, diisopropylaminolithium, and hexamethyldisilazine lithium.

3. The method according to claim 2, characterized in that, The alkali is selected from sodium methoxide, sodium ethoxide, and sodium tert-butoxide.

4. The method according to any one of claims 1-3, characterized in that, The organic solvent is selected from petroleum ether, hexane, heptane, cyclohexane, toluene, xylene, diethyl ether, tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, methanol, ethanol, ethyl acetate, and tert-butyl acetate.

5. The method according to claim 4, characterized in that, The organic solvent is selected from one or more of toluene, xylene, methanol, ethanol, and ethyl acetate.

6. The method according to any one of claims 1-3, characterized in that, The amount of catalyst used is 0.01 mol% to 20 mol of the compound of formula II.

7. The method according to claim 6, characterized in that, The amount of catalyst used is 0.05 mol% to 10 mol of the compound of formula II.

8. The method according to claim 1 or 2, characterized in that, The reaction temperature is -10~30℃, and the reaction time is 1 minute to 12 hours.

9. The method according to claim 1 or 2, characterized in that, The obtained cycloazinone product contains less than 2% ethoxylated impurities, and the structural formula of the ethoxylated impurities is as follows: 。

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