Preparation method of isoxazole herbicide intermediates

Abstract

This invention relates to the field of chemical synthesis, specifically to a method for preparing an intermediate of isoxazole herbicides. The isoxazole herbicide intermediate is a compound as shown in formula (III), prepared by reacting compound (I), compound (II), and a base in the presence of a solvent. This method is simple, safe, and has a high conversion rate, and its use in the preparation of isoxazole herbicides can reduce costs and is more economical and environmentally friendly. The synthetic route is as follows:

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, specifically to a method for preparing intermediates of isoxazole herbicides. Background Technology

[0002] Rhône-Plunkett Agricultural GmbH (now Bayer AG) first reported the use of isoxazole compounds as herbicides in its 1990 patent application EP0418175. The company further mentioned isoxazolidinone as a broad-spectrum herbicide in its 1992 patent application EP0527036. From then on, the synthesis of isoxazole compounds, especially benzoyl isoxazole compounds, received widespread attention. EP0527036 also described the synthesis of benzoyl isoxazole compounds, specifically a method for synthesizing isoxazole compounds by reacting the following compounds with hydroxylamine, as shown in the following reaction formula:

[0003]

[0004] In the formula, R represents leaving groups such as ethoxy and dimethylamino groups.

[0005] Currently, patent documents WO2002078447, CN104529924, CN104817510, CN105712944, and CN107162995 also report methods for preparing 5-cyclopropyl-4-[2-methylthio-4-(trifluoromethyl)benzoyl] isoxazole. For example, the disclosed reaction formula is as follows:

[0006]

[0007] The existing method uses 1-cyclopropyl-3-(2-methylthio-4-trifluoromethylphenyl)prop-1,3-dione or similar, triethyl or methyl orthoformate, and acetic anhydride to react with hydroxylamine to obtain isoxazolidinone intermediate. This method has the problem that acetic anhydride and its byproducts are highly corrosive and difficult to recover. In addition, the amount of triethyl orthoformate (or methyl orthoformate) used is large and the price is expensive, which is not conducive to industrial production. Summary of the Invention

[0008] This invention provides a method for preparing an isoxazole herbicide intermediate, namely the compound shown in formula (III) (i.e., 1-cyclopropyl-2-[(dimethylamino)methylene]-3-[2-(methylthio)-4-(trifluoromethyl)]phenylpropane-1,3-dione). This method is simple, safe, and has a high conversion rate. It can reduce costs and is more economical and environmentally friendly when used to prepare isoxazole herbicides.

[0009] Specifically, the present invention provides a method for preparing the compound shown in formula (III) below, and the synthetic route is as follows:

[0010]

[0011] Specifically, the above preparation method involves reacting the compounds shown in formula (I) and formula (II) in the presence of an organic solvent and a base. The reaction temperature is preferably 50-100°C, more preferably 65-70°C.

[0012] In the method of this invention, there is no particular limitation on the reaction time. Those skilled in the art can use conventional methods such as HPLC for detection and analysis. The reaction can be stopped when the conversion rate of the compound represented by formula (III) reaches 99.0% or more. Preferably, the reaction time of this invention is 2-3 hours.

[0013] Furthermore, the base is selected from DMF (N,N-dimethylformamide), pyridine, triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, or sodium acetate, and more preferably triethylamine or pyridine. Studies have found that using the above-mentioned organic bases, especially triethylamine, for the reaction can achieve a yield of over 95% and facilitates recycling and reuse, as well as environmentally friendly production.

[0014] Furthermore, the molar ratio of the compound shown in formula (II) to the compound shown in formula (I) is 1:(1.05-1.2), more preferably 1:1.1. Under these conditions, the conversion rate can reach over 99%, and the yield over 95%.

[0015] Furthermore, the molar ratio of the compound shown in formula (II) to the base is 1:(1.2-1.5), more preferably 1:1.2. Under these conditions, the conversion rate of the compound shown in formula (II) can reach over 99%.

[0016] In the method of the present invention, there is no particular limitation on the type of organic solvent. Those skilled in the art can select from various commonly used solvents, as long as the organic solvent used can dissolve the compounds shown in formula (II) and formula (I). In the method of the present invention, in order to obtain a higher purity and yield of the compound shown in formula (III) obtained by the reaction, it is preferred that the organic solvent used is at least one of toluene, chlorobenzene, cyclohexane, dichloroethane, tetrahydrofuran, propylene oxide, ethyl acetate and 1,2-epoxybutane, more preferably toluene or dichloroethane.

[0017] Specifically, the preparation method includes:

[0018] 1) In the presence of an organic solvent, first mix the compound shown in formula (I) and the compound shown in formula (II), and then stir and heat.

[0019] 2) When the reaction temperature reaches 50-60℃, add the alkali (dropwise) and continue to keep the temperature at 65-70℃ until the reaction is complete (about 2 hours).

[0020] Studies have found that when the above preparation method is followed by (dropwise) addition of alkali and then heated to 65-70°C for 2 hours, the concentration of compound (II) is less than 0.5%, the conversion rate is over 99%, and the yield can reach over 95%.

[0021] The method of the present invention may further include various post-processing methods commonly used by those skilled in the art to post-process the reaction product system (including the target product compound represented by formula III) prepared by the above method of the present invention. Preferably, the post-processing method of the present invention can be as follows:

[0022] When the reaction conversion rate reaches 99.0% or higher, the reaction is stopped, the temperature is lowered to 0-5℃, hydrochloric acid solution is added dropwise to quench the reaction, organic solvent is used for extraction, the organic phase is separated, dried, and the solvent is removed to obtain the compound shown in formula (III). The organic solvent used here can be the same as that described above. The concentration of the hydrochloric acid solution is usually around 30%. The pH of the reaction system can usually be adjusted to around 4-5 using hydrochloric acid solution.

[0023] The present invention has found that the moisture content of the recovered solvent and the recovered organic alkali must be below 0.1%, otherwise the product yield will be lower than 90%.

[0024] In this invention, the compound shown in formula (I), namely [(dimethylamino)methylene]cyclopropylmethyl ketone, can be prepared using existing techniques, for example, see patent document US20040186292.

[0025] In this invention, the compound shown in formula (II) can be prepared by existing techniques or purchased commercially.

[0026] In a preferred embodiment of the present invention, the method for preparing the compound represented by formula (III) is as follows:

[0027] An organic solvent (preferably dichloroethane or toluene), an appropriate proportion of compound (I) and compound (II) are added to a reactor. When the system temperature reaches 50-60℃, an appropriate amount of triethylamine is added dropwise. After the addition is complete, the temperature is maintained at 65-70℃ for 2 hours to complete the reaction. After the reaction is stopped, the temperature is lowered to 0-5℃, and hydrochloric acid solution is added dropwise to the reaction system to adjust the pH value to 4-5 or weakly acidic, so that the reaction system is separated into layers. The aqueous phase is extracted with dichloroethane, and the organic phases are combined, dried, and desolventized to obtain the product of compound (III).

[0028] The present invention further provides a method for preparing the compound shown in formula (IV), comprising:

[0029] The compound of formula (III) was prepared by the method described above; then the compound of formula (IV) was prepared by the following route;

[0030]

[0031] The compound shown in formula (IV) can be prepared from the compound shown in formula (III) using existing technical methods, such as those mentioned in the background art. Specifically, the method is as follows:

[0032] An organic solvent (such as ethanol) and the compound of formula (III) above were added to a reactor. The mixture was stirred and the temperature was controlled between 40-45°C. A suitable amount of hydroxylamine hydrochloride was added in batches. After the addition was complete, the temperature was maintained at 40-45°C until the reaction was complete (about 5 hours) to obtain the compound shown in formula (IV). The ethanol was recovered under reduced pressure to obtain 5-cyclopropyl-4-[2-methylthio-4-(trifluoromethyl)benzoyl] isoxazole.

[0033] Because this invention uses a novel method to prepare the compound shown in formula (III), and then further prepares the compound shown in formula (IV), it effectively solves the problem that acetic anhydride and its byproducts are highly corrosive and difficult to recycle. The preparation method is safer and more efficient, and more importantly, it can reduce costs and is more economical and environmentally friendly.

[0034] Experiments have shown that the method of this invention can achieve a conversion rate of up to 99%, a product purity of up to 95%, and a cost saving of 10% when preparing the compound shown in formula (IV).

[0035] All raw materials used in this invention are commercially available or prepared using conventional methods in the field.

[0036] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined with each other to obtain various preferred embodiments of the present invention. Detailed Implementation

[0037] The following examples are for illustrative purposes only and are not intended to limit the scope of the invention. Where specific techniques or conditions are not specified in the examples, they should be performed according to the techniques or conditions described in the literature in this field, or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased from legitimate channels.

[0038] The structures of compounds of formulas I, II, III, and IV mentioned below are as follows:

[0039]

[0040] The compound represented by formula (I) used below can be prepared as follows: 17.14 g (0.2 mol) of cyclopropylmethyl ketone and 26.71 g (0.22 mol) of N,N-dimethylamide dimethyl acetal were added to a 250 ml four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. The mixture was stirred, and 100 ml of DMF was added dropwise. The temperature was raised to 110 °C and maintained for 24 h to obtain compound (I). DMF and excess N,N-dimethylamide dimethyl acetal were removed by vacuum distillation to obtain 27.24 g of compound (I), with a yield of 98%.

[0041] Example 1

[0042] In a 250ml four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 15.4g of compound (I) (99% purity, 0.11mol), 60g of toluene, and 26.0g of compound (II) (98% purity, 0.1mol) were added. The mixture was stirred and heated to 60℃. Then, 12.2g of triethylamine (0.12mol) was added dropwise over 0.5h. The mixture was kept at 65-70℃ for 2 hours to obtain compound (III). 30ml of water was added to the reaction mixture, and 30% hydrochloric acid was added dropwise to adjust the pH of the reaction system to a weakly acidic state (around pH 5). The organic phases separated, and the solvent was removed to obtain 36.1g of the product; purity 95%, yield 96%.

[0043] Example 2

[0044] In a 250ml four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 15.4g of the compound of formula (I) prepared above (purity 99%, 0.11mol), 80g of dichloroethane, and 26.0g of the compound of formula (II) (purity 98%, 0.1mol) were added. The mixture was stirred and heated to 65-70℃. 12.2g (0.12mol) of triethylamine was added dropwise over 0.5h. The mixture was kept at 65-70℃ for 3h to obtain the compound of formula (III). 30ml of water was added to the reaction mixture, and 30% hydrochloric acid was added dropwise to adjust the pH to a weakly acidic level (around pH 5). The organic phases separated, and the solvent was removed to obtain 35.8g of the product with a purity of 95% and a yield of 95%.

[0045] Example 3

[0046] In a 250ml four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 15.4g of the compound of formula (I) prepared above (purity 99%, 0.11mol), 80g of dichloroethane, and 26.0g of the compound of formula (II) (purity 98%, 0.1mol) were added. The mixture was stirred and heated to 70-75℃. 9.6g of pyridine (0.12mol) was added dropwise over 0.5h. The mixture was kept at 70-75℃ for 3h to obtain the compound of formula (III). 30ml of water was added to the reaction mixture, and 30% hydrochloric acid was added dropwise to adjust the pH to a weakly acidic level (around pH 5). The organic phases separated, and the solvent was removed to obtain 34.6g of the product with a purity of 94.8% and a yield of 92%.

[0047] Example 4

[0048] Compound (III) was prepared using the same method as in Example 2.

[0049] In a 250ml four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 37.6g of the prepared compound (III) (95% purity, 0.1mol) and 100g of 95% ethanol were added. The reaction temperature was controlled between 40-45℃ by stirring. 8.4g of hydroxylamine hydrochloride (98% purity, 0.12mol) was added in batches, and the addition was completed in 1 hour. The reaction was maintained at 40-45℃ for 4 hours to obtain the compound shown in formula (IV). The ethanol was recovered under reduced pressure and reused. The obtained 5-cyclopropyl-4-[2-methylthio-4-(trifluoromethyl)benzoyl]isoxazole had a purity of over 93% and a yield of over 92%.

[0050] Comparative Example 1

[0051] Example of the original process for synthesizing 5-cyclopropyl-4-[2-methylthio-4-(trifluoromethyl)benzoyl]isoxazole:

[0052] In a 250ml four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 31.8 g (95% purity, 0.1 mol) of 1-cyclopropyl-3-(2-methylthio-4-trifluoromethylphenyl)prop-1,3-dione compound, 31.2 g (98% purity, 0.3 mol) of acetic anhydride, and 36.2 g (98% purity, 0.24 mol) of triethyl orthoformate were added. The mixture was refluxed at 125℃ for 2 hours, and the reflux temperature was later reduced to 104℃. HPLC analysis showed that 1-cyclopropyl-3-(2-methylthio-4-trifluoromethylphenyl)propane was the final product. The content of 5-cyclopropyl-4-[2-methylthio-4-(trifluoromethyl)benzoyl]isoxazole is less than 1%. Acetic acid mixture is distilled off under reduced pressure to 110℃, cooled to 50℃, and 100g of 95% ethanol is added. The reaction temperature is controlled between 40-45℃ with stirring. 8.4g of hydroxylamine hydrochloride (98% purity, 0.12mol) is added in batches, completing the addition in 1 hour. The reaction is maintained at 40-45℃ for 4 hours to obtain the compound shown in formula (IV). The ethanol recovered under reduced pressure can be reused. The obtained 5-cyclopropyl-4-[2-methylthio-4-(trifluoromethyl)benzoyl]isoxazole has a content of over 92%, and the yield can reach over 90%. This process uses acetic anhydride, which generates a large amount of acetic acid byproducts that are difficult to treat and not conducive to environmentally friendly production. In addition, the price of triethyl orthoformate used is relatively high, increasing production costs.

[0053] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. The preparation method of the compound shown in formula (III) is as follows, and its synthetic route is as follows: in, The preparation method involves reacting the compound shown in formula (I) and the compound shown in formula (II) in the presence of an organic solvent and a base. The reaction temperature is 50-100℃; The base is selected from triethylamine or pyridine; The molar ratio of the compound shown in formula (II) to the compound shown in formula (I) is 1:(1.05-1.2); The molar ratio of the compound shown in formula (II) to the base is 1:(1.2-1.5).

2. The preparation method according to claim 1, characterized in that, The reaction temperature is 65-70℃.

3. The preparation method according to claim 1 or 2, characterized in that, The molar ratio of the compound shown in formula (II) to the compound shown in formula (I) is 1:1.

1.

4. The preparation method according to claim 3, characterized in that, The molar ratio of the compound shown in formula (II) to the base is 1:1.

2.

5. The preparation method according to any one of claims 1-2, 4, characterized in that, include: 1) In the presence of an organic solvent, first mix the compound shown in formula (I) and the compound shown in formula (II), and then stir and heat. 2) When the reaction temperature reaches 50-60℃, add the alkali and continue the reaction at 65-70℃ until the reaction is complete.

6. The preparation method according to claim 5, characterized in that, It also includes a post-processing step for the prepared reaction product system, the specific method of which is as follows: When the reaction conversion rate reaches 99.0% or higher, the reaction is stopped, the temperature is lowered to 0-5℃, hydrochloric acid solution is added dropwise to quench the reaction, organic solvent is used for extraction, the organic phase is separated, dried, and the solvent is removed to obtain the compound shown in formula (III).

7. The preparation method according to claim 6, characterized in that, include: An organic solvent, a suitable proportion of compound (I) and compound (II) are added to a reactor. When the system temperature reaches 50-60℃, an appropriate amount of triethylamine is added dropwise. After the addition is complete, the temperature is maintained at 65-70℃ for 2 hours to complete the reaction. After the reaction is stopped, the temperature is lowered to 0-5℃, and hydrochloric acid solution is added dropwise to the reaction system to adjust the pH value to 4-5 or weakly acidic, so that the reaction system is separated into layers. The aqueous phase is extracted with dichloroethane, and the organic phases are combined, dried, and desolventized to obtain the product of compound (III). The organic solvent is dichloroethane or toluene.

8. A method for preparing the compound shown in formula (IV), characterized in that, include: The compound of formula (III) is prepared by the method according to any one of claims 1-7; then the compound of formula (IV) is prepared by the following route; 9. The preparation method according to claim 8, characterized in that, include: An organic solvent and the compound of formula (III) were added to a reactor, and an appropriate amount of hydroxylamine hydrochloride was added in batches while stirring and controlling the temperature between 40-45°C. After the addition was complete, the temperature was maintained at 40-45°C until the reaction was complete, and the compound of formula (IV) was obtained.

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