Synthesis method of 5, 5-dimethyl-4, 5-dihydroisoxazole

Abstract

The invention discloses a synthesis method of 5, 5-dimethyl-4, 5-dihydroisoxazole, which is characterized in that isopentenal and acetoxime or diacetylmonoxime react in the presence of a catalyst and water to obtain the 5, 5-dimethyl-4, 5-dihydroisoxazole. Compared with the prior art, the method has the advantages that the 5, 5-dimethyl-4, 5-dihydroisoxazole is directly obtained by reacting isopentenal with acetoxime or diacetylmonoxime in the presence of the catalyst and water, and the method can be carried out without participation of an organic solvent in the whole synthesis process and the post-treatment process, so that the use of the organic solvent is avoided; and moreover, the purposes of high yield and simple and safe post-treatment can still be achieved, and industrial implementation is facilitated.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and particularly to a method for synthesizing 5,5-dimethyl-4,5-dihydroisoxazole. Background Art

[0002] Isoxazolines are commonly found in natural products. The compound 5,5-dimethyl-4,5-dihydroisoxazole shown in the following formula III is an important building block for pyroxasulfone (CAS: 447399-55-5) and fenoxasulfone (CAS: 639826-16-7).

[0003]

[0004] Compounds containing isoxazoline fragments mostly have good biological activities, so this fragment is widely used in new drug research and development. However, the existing synthesis schemes for this compound usually have defects such as unsatisfactory yields or large safety risks due to violent reactions.

[0005] For example, International Patent WO2011063842A1 discloses a method for synthesizing 5,5-dimethyl-4,5-dihydroisoxazole. The method is as follows.

[0006]

[0007] In an optional organic solvent, acetone oxime is mixed with isopentenal, and a catalyst is added and reacted at 0-30 °C for 16-60 hours to obtain the target product. However, this method has a long feeding time, a long operation time, and a low yield.

[0008] Again, for example, International Patent WO2020251006A1 discloses another method, which synthesizes the target product through two steps of oximation and cyclization. The reaction process is as follows.

[0009]

[0010] The highest yield of this scheme can reach 90%, but the two-step process is cumbersome. At the same time, phase separation will generate nitrogen-containing wastewater, resulting in relatively large pollution, and the subsequent treatment of hazardous waste is difficult and costly.

[0011] For another example, International Patent WO2019208643A1 discloses another method that uses isopentenal and hydroxylamine as starting materials for the reaction, and uses an acid or an acid-base catalyst to synthesize 5,5-dimethyl-4,5-dihydroisoxazole. Although the synthesis steps are simplified, the contact between isopentenal and hydroxylamine will generate a large amount of heat and is not easy to control, there are certain safety risks, and organic solvents still need to be added to the system during the reaction process. The post-treatment process involves phase separation to produce nitrogen-containing wastewater that is difficult to treat.

[0012] In addition, in the above-mentioned scheme, using an aqueous solution of hydroxylamine (45% - 55%) as the oximation reagent has relatively large safety risks in industrial storage and transportation (hydroxylamine compounds are unstable and prone to decomposition); using hydroxylamine hydrochloride and hydroxylamine sulfate as the oximation reagent can solve the problem of safety risks, but it needs to be neutralized with an alkali solution before oximation, and this process will generate a large amount of saline wastewater.

[0013] In summary, there is a lack of a synthesis method for 5,5-dimethyl-4,5-dihydroisoxazole that is safer, simpler, more economical and environmentally friendly in the prior art. Summary of the Invention

[0014] The technical problem to be solved by the present invention is how to synthesize 5,5-dimethyl-4,5-dihydroisoxazole more safely and efficiently. In view of the above technical problem to be solved, a synthesis method for 5,5-dimethyl-4,5-dihydroisoxazole is now proposed.

[0015] To achieve the above object, the present invention provides the following technical solution: A synthesis method for 5,5-dimethyl-4,5-dihydroisoxazole, which reacts isopentenal with acetone oxime or butanone oxime in the presence of a catalyst and water to obtain 5,5-dimethyl-4,5-dihydroisoxazole. The reaction formula is as follows.

[0016]

[0017] Preferably, the molar ratio of water to isopentenal is greater than 0.5.

[0018] More preferably, the molar ratio of water to isopentenal is 0.5 - 1.

[0019] Preferably, the molar ratio of acetone oxime or butanone oxime to isopentenal is 1 - 1.5.

[0020] More preferably, the molar ratio of acetone oxime or butanone oxime to isopentenal is 1.0 - 1.1.

[0021] Preferably, the catalyst is one or more of trifluoroacetic acid, nitric acid, chlorosulfonic acid, methanesulfonic acid, maleic acid, maleic anhydride.

[0022] Preferably, the molar ratio of the catalyst to isopentenal is 0.05 - 0.1.

[0023] Preferably, the reaction temperature is 25 - 80 °C.

[0024] More preferably, the reaction temperature is 30 - 50 °C.

[0025] Feasibly, the reaction time is not particularly limited. From the perspectives of saving time and energy, it is preferably in the range of 1 hour - 50 hours, and more preferably in the range of 15 hours - 30 hours.

[0026] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0027] In the present invention, 5,5 - dimethyl - 4,5 - dihydroisoxazole is directly obtained by reacting isopentenal with acetone oxime or butanone oxime in the presence of a catalyst and water. This method can be carried out without the participation of organic solvents throughout the synthesis process and the post - treatment process, avoiding the use of organic solvents in the entire synthesis process and post - treatment process, and still being able to achieve high yields and simple and safe post - treatment, which is convenient for industrial implementation. Specific Embodiments

[0028] Next, the technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0029] According to a feasible reaction formula shown below, the synthesis invention of 5,5 - dimethyl - 4,5 - dihydroisoxazole in the present invention is illustrated through multiple embodiments. The structural formula of 5,5 - dimethyl - 4,5 - dihydroisoxazole is as shown by Ⅲ in the reaction formula, Ⅰ in the reaction formula is isopentenal, when R1 is methyl, Ⅱ and Ⅳ are acetone oxime and acetone respectively, and when R1 is ethyl, Ⅱ and Ⅳ are butanone oxime and butanone respectively.

[0030]

[0031] Example 1

[0032] In a 250 mL round-bottom flask, 42.92 g (98%, 0.5 mol, 100 mol%) of isopentenal, 39.16 g (98%, 0.525 mol, 105 mol%) of acetone oxime, 4.5 g (0.25 mol, 50 mol%) of water, and 2.87 g (99.5%, 25 mmol, 5 mol%) of trifluoroacetic acid were added. The temperature of the system decreased during the contact of acetone oxime and isopentenal. After the addition was completed, the mixture was kept at 30 °C for 30 h and then sampled for analysis. The HPLC content of isopentenal was monitored to be less than 0.1%, and the target product was 95% (calculated as the area percentage by HPLC). The reaction could be completed without adding organic solvents during the process.

[0033] Example 2

[0034] In a 250 mL round-bottom flask, 44.27 g (98%, 0.5 mol, 100 mol%) of isopentenal, 46.68 g (98%, 0.525 mol, 105 mol%) of butanone oxime, 4.5 g (0.25 mol, 50 mol%) of water, and 2.87 g (99.5%, 25 mmol, 5 mol%) of trifluoroacetic acid were added. The temperature of the system decreased during the contact of butanone oxime and isopentenal. After the addition was completed, the mixture was kept at 30 °C for 30 h and then sampled for analysis. The HPLC content of isopentenal was monitored to be less than 0.1%, and the target product was 94% (area percentage by HPLC).

[0035] Examples 3 - 14 and Comparative Examples 1 - 6 are shown in Table 1. Among them, except for changing the amount of water, the amount of oxime, the type of catalyst, the amount of catalyst, and the reaction temperature, 5,5-dimethyl-4,5-dihydroisoxazole was prepared using the same method as in Example 1 or 2. Therefore, the reaction process will not be described again. The reaction conditions and experimental results of the examples and comparative examples are listed in detail in the table.

[0036] Among them, the proportion (%) of the mixture in the reaction solution refers to the area percentage by HPLC, including the target product, raw materials, and by-products other than them. In addition, the results of Example 1 and Example 2 are shown in Table 1.

[0037] In addition, the meanings of the respective chemical formulas in the table in this example are as follows:

[0038] TFA is trifluoroacetic acid;

[0039] HNO3 is 69% nitric acid;

[0040] TsOH·H2O is p-toluenesulfonic acid monohydrate;

[0041] HCl is 36% hydrochloric acid;

[0042] HAc is acetic acid.

[0043] Table 1

[0044]

[0045] The above results show that the results of Examples 1 - 2 and Comparative Examples 1 - 4 show that in the absence of organic solvents, isopentenal can react completely with acetone oxime or butanone oxime in the presence of TFA and water, and the target product can be obtained in a relatively high yield.

[0046] Compared with Example 1, in Examples 3 - 6, the reaction conditions: the amount of water added, the amount of acetone oxime, the amount of catalyst, and the reaction temperature were adjusted. In Example 3, adding 100 mol% of water could also obtain good experimental results, but excessive water was not conducive to the post-treatment. In Comparative Example 5, the amount of water was reduced to 40 mol%, and under this condition, isopentenal did not react completely. Therefore, 50 mol% of water was most preferably used for the reaction to ensure the lowest water consumption under the condition of complete reaction. In Example 4, using excessive acetone oxime also had a high yield, but there was no further improvement in the reaction. In Example 5, increasing the amount of catalyst used could obtain a good yield, but there was no further improvement in the reaction. In Comparative Example 6, using 4 mol% of the catalyst amount, the reaction was not complete within 30 h. Therefore, the lowest catalyst amount that could make the reaction complete - 5 mol% was selected. In Example 6, raising the reaction temperature had a high yield, but did not reach the level of Example 1. Although increasing the temperature shortened the reaction time, from the perspective of economy and suppressing by-products, a reaction temperature of 30 °C was more appropriate.

[0047] Examples 7 - 14 demonstrate the effects of various catalysts. In addition to TFA, nitric acid, methanesulfonic acid, maleic acid, and maleic anhydride showed good catalytic performance, and the target product was obtained in a relatively high yield. While p-toluenesulfonic acid monohydrate, hydrochloric acid, and acetic acid had poor catalytic effects.

[0048] The preparation method described in the present invention is also beneficial to the post-treatment process, which will be described in detail through examples below.

[0049] Example 15

[0050] In a 500 mL round-bottom flask, 85.84 g (98%, 1.0 mol, 100 mol%) of isopentenal, 78.32 g (98%, 1.05 mol, 105 mol%) of acetone oxime, 9.01 g (0.5 mol, 50 mol%) of water, and 5.73 g (99.5%, 50 mmol, 5 mol%) of trifluoroacetic acid were added. After the addition was completed, the mixture was kept at 30 °C for 30 h and then sampled for analysis. The HPLC content of isopentenal was monitored to be less than 0.1%, and the target product was 95% (analyzed by area percentage). The yield of the target product in the reaction solution was 94.8% (the content of 5,5-dimethyl-4,5-dihydroisoxazole in the reaction solution was tested by the external standard method to calculate the yield).

[0051] The reaction solution was directly subjected to vacuum distillation to separate the product, and 94.55 g of a colorless transparent liquid was obtained. The mass fraction of 5,5-dimethyl-4,5-dihydroisoxazole was 94.3% (external standard method), and the yield of the target product was 89.94%.

[0052] Example 16

[0053] In a 500 mL round-bottom flask, 85.84 g (98%, 1.0 mol, 100 mol%) of isopentenal, 93.35 g (98%, 1.05 mol, 105 mol%) of butanone oxime, 9.01 g (0.5 mol, 50 mol%) of water, and 5.73 g (99.5%, 50 mmol, 5 mol%) of trifluoroacetic acid were added. After the addition was completed, the mixture was kept at 30 °C for 30 h and then sampled for analysis. The HPLC content of isopentenal was monitored to be less than 0.1%, and the target product was 94% (analyzed by area percentage). The yield of the target product in the reaction solution was 92.9% (external standard method).

[0054] The reaction solution was directly subjected to vacuum distillation to separate the product, and 90.90 g of a colorless transparent liquid was obtained. The mass fraction of 5,5-dimethyl-4,5-dihydroisoxazole was 93.1% (external standard method), and the yield of the target product was 85.37%.

[0055] Examples 15 and 16 verified the post-treatment method. A relatively pure product could be obtained with a high separation yield directly through vacuum distillation, with less generation of three wastes and almost no wastewater generated. The process method is economical, green, and safe. The process described in the present invention is not only more convenient in operation but also has irreplaceable advantages in the post-treatment process, which is conducive to industrial production.

[0056] It should be noted that if the scheme is applied to industrialization, the process such as round-bottom flasks and feeding methods only needs to be transformed into industrial processes, which will not be elaborated here.

[0057] In the method of the present invention, 5,5-dimethyl-4,5-dihydroisoxazole is directly obtained by reacting prenal with acetone oxime or butanone oxime in the presence of a catalyst and water. This method can proceed without the participation of organic solvents in the whole synthesis process and post-treatment process, avoiding the use of organic solvents in the whole synthesis process and post-treatment process, and still being able to achieve the purposes of high yield, simple and safe post-treatment, and being convenient for industrial implementation.

[0058] The above embodiments are only examples for better expressing the content of the present invention by elaborating on the solution of the present invention through a laboratory synthesis route, and do not limit the content of the present invention. Industrial improvements and process implementations carried out without departing from the synthesis idea of the present invention are not beyond the protection scope of the present invention. The present invention is not limited to the above-described embodiments. For those skilled in the art, various changes, modifications, substitutions, and variations of these embodiments still fall within the protection scope of the present invention without departing from the principle and spirit of the present invention.

Claims

1. A method for synthesizing 5,5-dimethyl-4,5-dihydroisoxazole, characterized in that, Reaction of isopentenal with acetone oxime or butanone oxime in the presence of a catalyst and water gives 5,5-dimethyl-4,5-dihydroisoxazole.

2. The synthesis method of 5,5-dimethyl-4,5-dihydroisoxazole according to claim 1, characterized in that, The molar ratio of water to isopentenal is greater than 0.

5.

3. The synthesis method of 5,5-dimethyl-4,5-dihydroisoxazole according to claim 2, characterized in that, The molar ratio of water to isopentenal is 0.5 - 1.

4. The synthesis method of 5,5-dimethyl-4,5-dihydroisoxazole according to claim 1, wherein, The molar ratio of acetone oxime or butanone oxime to isopentenal is 1 - 1.

5.

5. The synthesis method of 5,5-dimethyl-4,5-dihydroisoxazole according to claim 4, characterized in that, The molar ratio of acetone oxime or butanone oxime to isopentenal is 1.0 - 1.

1.

6. The synthesis method of 5,5-dimethyl-4,5-dihydroisoxazole according to claim 1, characterized in that, The catalyst is one or more of trifluoroacetic acid, nitric acid, chlorosulfonic acid, methanesulfonic acid, maleic acid, maleic anhydride.

7. A method for synthesizing 5,5-dimethyl-4,5-dihydroisoxazole according to claim 1, characterized in that, The molar ratio of the catalyst to isopentenal is 0.05 - 0.

1.

8. A method for synthesizing 5,5-dimethyl-4,5-dihydroisoxazole according to claim 1, characterized in that, The reaction temperature is 25 - 80 °C.

9. The synthesis method of 5,5-dimethyl-4,5-dihydroisoxazole according to claim 1, characterized in that, The reaction temperature is 30 - 50 °C.

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