A method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone

Abstract

This invention discloses a method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone. The method uses compound 1, acetylacetone, as the starting material. First, compound 2, 3-isonitroso-2,4-pentanedione, is prepared. Then, compound 2 undergoes oxidation to give a 1,3-dipolar compound, which undergoes a 1,3-dipolar cycloaddition reaction with an olefin to obtain 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone. The process of this invention is simple, the raw materials are readily available, the yield is high, and it is environmentally friendly, making it very suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pesticide intermediate synthesis technology, specifically relating to a method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone. Background Technology

[0002] Fluorothiazol pyrone is a piperidinylthiazolium isoxazoline fungicide with both protective and curative activities. It has a unique target site, a novel mechanism of action, and exhibits good rapid and sustained efficacy. It is also resistant to rain washout and demonstrates good efficacy at extremely low dosages. 2,6-Difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone is a key intermediate in the synthesis of fluorothiazol pyrone. Currently, there are five main synthetic routes for 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone.

[0003] Route 1:

[0004]

[0005] The synthetic route first involves the overnight reaction of acetic anhydride 1 with imidazole in ethyl acetate to obtain compound 1-acetylimidazolium 2; then, compound 2 reacts with potassium tert-butoxide and nitromethane in tetrahydrofuran to obtain compound nitrosylacetone 3; subsequently, nitrosylacetone 3 is reacted overnight in hydrochloric acid to obtain compound N-hydroxy-2-oxo-propaneimine chloride 4; finally, compound 4 undergoes a 1,3-dipolar cycloaddition reaction with 2,6-difluorostyrene in acetonitrile solution under the action of sodium bicarbonate to obtain the target product 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone A. This synthetic route suffers from several drawbacks: the starting material nitromethane is difficult to obtain, the synthetic steps are numerous, and post-reaction processing requires column chromatography, resulting in significant time investment and low yield.

[0006] Route 2:

[0007]

[0008] Chinese patent application CN105541830A describes a synthetic route that involves reacting ethyl acetoacetate 1 with an aqueous solution of sodium hydroxide for 4-24 hours, followed by the addition of sodium nitrite to adjust the pH to 4-5, and finally adjusting the pH to 9-10. The resulting product is then extracted with ethyl acetate to obtain compound 2. Compound 2 subsequently undergoes chlorination to yield compound 3, which then undergoes cycloaddition with 2,6-difluorostyrene in the presence of potassium carbonate to give the target product A. This synthetic route is complex, requires strict control of temperature and pH, and exhibits a low yield in the chlorination step.

[0009] Route 3:

[0010]

[0011] Chinese patent application CN109516962A describes a synthetic route that involves first reacting 2,3-butanedione 1 with triethyl orthoformate to yield compound 2, then reacting compound 2 with 2,6-difluorobenzaldehyde to yield compound 3, followed by cyclization of compound 3 to yield compound 4, and finally hydrolysis of compound 4 to obtain the target product A. This synthetic route requires four steps to synthesize the target compound, which is relatively complex but economically costly.

[0012] Route 4:

[0013]

[0014] In the invention patent application with publication number WO2010065579A3, the starting compound 2-(dimethylamino)-N-hydroxy-2-oxo-ethyleneimine chloride 1 reacts with 2,6-difluorostyrene to form an isoxazoline ring, yielding compound 5-(2,6-difluorophenyl)-4,5-dihydro-N,N-dimethyl-3-isoxazolecarboxamide 2; subsequently, under Grignard reagent conditions of methyl magnesium bromide, the target product 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone A is obtained. However, the starting compound 1 required in this synthetic route is not readily available, and the second step requires the use of a Grignard reagent, placing high demands on the reaction conditions and making the reaction environment quite harsh.

[0015] Route 5:

[0016]

[0017] In the invention patent application with publication number WO2008013925A4, compound 1,3-dichloroacetone 1 is first reacted with tert-butyl nitrite in the presence of hydrochloric acid to generate compound 3-chloro-N-hydroxy-2-oxo-propaneimine chloride 2; then, it is reacted with 2,6-difluorostyrene in an alkaline environment to obtain the target product A. In this synthetic route, tert-butyl nitrite is highly toxic and flammable, requiring strict temperature control during its reaction with raw material 1 to prevent the generation of toxic gases, and it is also relatively expensive.

[0018] In summary, existing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketones either suffer from complex synthetic routes, cumbersome operating steps, and harsh reaction conditions; or they suffer from high raw material costs, high toxicity of raw materials, and the generation of large amounts of waste during synthesis. Summary of the Invention

[0019] In view of this, the primary objective of the present invention is to provide a method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone. This synthetic method has simple process steps, requires only two steps to obtain the target product, and has a high yield and is environmentally friendly. In addition, the raw materials used are inexpensive and readily available, resulting in low production costs and suitability for industrial production.

[0020] To achieve the above objectives, the present invention adopts the following technical solution:

[0021] This invention first provides a method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone, the synthetic route of which is as follows:

[0022]

[0023] A further embodiment of the method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone includes the following steps:

[0024] Step 1: Compound 1, acetylacetone, is reacted with sodium nitrite and a hydrogen ion donor to prepare compound 2, 3-isonitroso-2,4-pentanedione;

[0025] Step 2: React compound 2,3-isonitroso-2,4-pentanedione, 2,6-difluorostyrene, a high-valent iodine compound, an alcohol solvent, and a catalyst to prepare the target compound A, 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone.

[0026] The present invention first prepares compound 2, then oxidizes compound 2 with a high-valent iodine compound to obtain a 1,3-dipolar, and the 1,3-dipolar reacts with an alkene in a [3+2] cycloaddition reaction to obtain the target compound A.

[0027] In a further embodiment, in step one, the hydrogen ion supplier is a strong acid, such as sulfuric acid, hydrochloric acid, or acetic acid. Its function is to provide hydrogen ions for the reaction.

[0028] In a further embodiment, the reaction temperature in step one is 0–20°C.

[0029] A further proposed solution is as follows: Step one specifically involves:

[0030] Compound 1, acetylacetone, was dissolved in an aqueous solution of a hydrogen ion donor, followed by the addition of an aqueous solution of sodium nitrite. The mixture was stirred at 0–20 °C for 1–2 h.

[0031] In a further embodiment, the mass fraction of the hydrogen ion feeder is 6-8%, preferably 7%.

[0032] In a further embodiment, the concentration of the aqueous solution of sodium nitrite is 3–4 mol / L.

[0033] In a further embodiment, the molar ratio of compound 1 acetylacetone to sodium nitrite is 1:(1.2-1.5).

[0034] In a further embodiment, step one further includes a post-processing step after the reaction is complete, the post-processing including the following steps:

[0035] After the reaction was complete, an extractant was added to the system to extract the aqueous phase at least once, and the organic phases were combined. The organic phases were washed with water, dried, and concentrated under reduced pressure to obtain compound 2,3-isonitroso-2,4-pentanedione.

[0036] Compound 2 is purified and refined through the above post-processing steps. Specific examples of the extractants used include ethyl acetate, diethyl ether, or methyl tert-butyl ether, but are not limited to these. The number of extractions is selected as needed, with at least one extraction, and preferably multiple extractions. In some specific embodiments of the present invention, extraction is performed 1-3 times.

[0037] The combined organic phases are washed with water, dried, and then concentrated under reduced pressure. The washing can be done using saturated salt, which is common in the art, and the drying is done using a desiccant, such as anhydrous sodium sulfate or anhydrous magnesium sulfate, but not limited to these.

[0038] In a further embodiment, in step two, the catalyst is trifluoroacetic acid;

[0039] And / or, the alcohol solvent is methanol or ethanol;

[0040] And / or, the high-valent iodine compound is a trivalent iodine compound, and the trivalent iodine compound is iodobenzene acetate.

[0041] In a further embodiment, the reaction temperature in step two is 15–30°C.

[0042] In a further proposed solution, step two specifically involves:

[0043] A catalyst and an alcohol solvent are added to a reaction vessel, followed by the addition of 2,6-difluorostyrene and a high-valent iodine compound. An alcohol solution of compound 2,3-isonitroso-2,4-pentanedione is slowly (preferably 2-3 drops / second) added dropwise to the reaction system, and the reaction is stirred at 15-30°C.

[0044] Preferably, the volume ratio of the catalyst to the total alcohol solvent is 1:100; the molar ratio of compound 2,3-isonitroso-2,4-pentanedione to 2,6-difluorostyrene is 1:(1.2-1.5); and the molar ratio of compound 2,3-isonitroso-2,4-pentanedione to iodobenzene acetate is 1:(1.2-1.5).

[0045] In a further embodiment, step two includes a post-processing step after the reaction is complete. The post-processing includes the following steps: concentrating the reaction system under reduced pressure and then purifying it using rapid column chromatography.

[0046] The beneficial effects of this invention are:

[0047] The synthetic route of this invention is concise, requiring only two reaction steps to obtain the target product, thus shortening the reaction steps and time, reducing the production cycle, and improving the synthesis efficiency. Furthermore, this synthetic route yields a high overall product yield and is environmentally friendly. In addition, the raw materials used in this synthetic route are all commercially available, inexpensive, and readily available, resulting in low overall synthesis costs. In summary, the synthetic route of this invention is highly suitable for industrial production. Attached Figure Description

[0048] Figure 1 The nuclear magnetic resonance spectrum of 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone synthesized in a preferred embodiment of the present invention is shown. Detailed Implementation

[0049] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of this invention is for the purpose of describing particular embodiments only and is not intended to limit the invention. Furthermore, unless otherwise specified, methods not specifically describing conditions or steps are conventional methods, and the reagents and materials used are commercially available.

[0051] Example 1

[0052] This embodiment provides a method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone, the specific route of which is shown below:

[0053]

[0054] The specific steps are as follows:

[0055] Step 1: Add 25 mL of 7% sulfuric acid and compound 1 (2.5 g, 25.0 mmol) to a reaction flask. Slowly add sodium nitrite solution (2.0 g sodium nitrite dissolved in 7.5 mL of water, 30.0 mmol) at 10 °C and stir at room temperature for 1-2 h. After the reaction is complete, add ethyl acetate to the system, stir thoroughly, and allow to stand for separation. Extract the aqueous phase with ethyl acetate 1-3 times, and combine the organic phases. Wash the organic phase once with saturated brine, then dry it with anhydrous sodium sulfate. Concentrate under reduced pressure to obtain compound 2, a pale yellow solid, with a yield of 86.8%, which can be used directly in the next step.

[0056] Step 2: Compound 2 (1.9 g, 15 mmol) was dissolved in methanol (35 mL) and added dropwise to a methanol (25 mL) solution containing iodobenzene acetate (5.8 g, 18 mmol), 2,6-difluorostyrene (2.5 g, 18 mmol), and trifluoroacetic acid (0.6 mL). The mixture was stirred at 20 °C for 4 h. After the reaction was complete, the reaction system was concentrated under reduced pressure and purified by column chromatography to obtain compound A2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone as a white solid, with a yield of 73.6%.

[0057] The NMR results of the target product 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone obtained in this embodiment are shown in Figure 1. 1 H NMR (400MHz, CDCl3) δ7.45–7.29(m,1H),6.96(t,J=8.2Hz,2H),6.25–6.04(m,1H),3.54(dd,J =17.5, 12.6Hz, 1H), 3.33 (dd, J = 17.6, 9.1Hz, 1H), 2.60 (s, 3H).

[0058] Example 2

[0059] This embodiment provides another method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone, which adopts the same implementation method as in Example 1, except that the hydrogen ion donor used in step one is nitric acid.

[0060] Example 3

[0061] This embodiment provides another method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone, which adopts the same implementation method as in Example 1, except that the extractant used in the post-processing step in step one is methyl tert-butyl ether and the drying agent is anhydrous magnesium sulfate.

[0062] Example 4

[0063] This embodiment provides another method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone, which adopts the same implementation method as in Example 1, except that the reaction temperature in step one is 0°C.

[0064] Example 5

[0065] The examples provide another method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone, which adopts the same implementation method as in Example 1, except that the reaction temperature in step one is 20°C.

[0066] Example 6

[0067] The examples provide another method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone, which adopts the same implementation method as in Example 1, except that the molar amount of sodium nitrite in step one is 35 mmol.

[0068] Example 7

[0069] The examples provide another method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone, which adopts the same implementation method as in Example 1, except that the molar amount of sodium nitrite in step one is 37.5 mmol.

[0070] Example 8

[0071] The examples provide another method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone, which adopts the same implementation method as in Example 1, except that the reaction temperature in step two is 15°C.

[0072] Example 9

[0073] The examples provide another method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone, which adopts the same implementation method as in Example 1, except that the reaction temperature in step two is 30°C.

[0074] Example 10

[0075] The examples provide another method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone, which adopts the same implementation method as in Example 1, except that the molar amounts of iodobenzene acetate and 2,6-difluorostyrene in step two are 19.5 mmol each.

[0076] Example 11

[0077] The examples provide another method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone, which adopts the same implementation method as in Example 1, except that the molar amounts of iodobenzene acetate and 2,6-difluorostyrene in step two are 22.5 mmol each.

[0078] Testing showed that the yields of 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone prepared in the above examples were all above 70%. The synthesis method provided in this invention has simple process steps, high yield, and uses commercially available and inexpensive raw materials, which can greatly reduce costs and has great potential for industrial production.

[0079] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0080] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone, characterized in that, The synthesis route is as follows: 。 2. The method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone as described in claim 1, characterized in that, Includes the following steps: Step 1: Compound 1, acetylacetone, is reacted with sodium nitrite and a hydrogen ion donor to prepare compound 2, 3-isonitroso-2,4-pentanedione; Step 2: React compound 2,3-isonitroso-2,4-pentanedione, 2,6-difluorostyrene, a high-valent iodine compound, an alcohol solvent, and a catalyst to prepare the target compound A, 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone.

3. The method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone as described in claim 2, characterized in that, In step one, the hydrogen ion supplier is sulfuric acid, hydrochloric acid, or acetic acid.

4. The method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone as described in claim 2, characterized in that, The reaction temperature in step one is 0~20℃.

5. The method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone as described in claim 2, characterized in that, Step one specifically involves: Compound 1, acetylacetone, was dissolved in an aqueous solution of a hydrogen ion donor, followed by the addition of an aqueous solution of sodium nitrite. The mixture was stirred at 0–20 °C for 1–2 h.

6. The method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone as described in claim 5, characterized in that, The aqueous solution of the hydrogen ion feeder has a mass fraction of 6-8%.

7. The method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone as described in claim 5, characterized in that, The concentration of the aqueous solution of sodium nitrite is 3~4 mol / L.

8. The method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone as described in claim 5, characterized in that, The molar ratio of compound 1, acetylacetone, to sodium nitrite is 1:(1.2-1.5).

9. The method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone according to any one of claims 2-8, characterized in that, Step one further includes a post-processing step after the reaction is complete. Includes the following steps: After the reaction was complete, an extractant was added to the system to extract the aqueous phase at least once, and the organic phases were combined. The organic phases were washed with water, dried, and concentrated under reduced pressure to obtain compound 2,3-isonitroso-2,4-pentanedione.

10. The method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone as described in claim 9, characterized in that, The extractant is ethyl acetate, diethyl ether, or methyl tert-butyl ether.

11. The method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone as described in claim 9, characterized in that, The organic phase washing uses saturated salt.

12. The method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone as described in claim 9, characterized in that, The organic phase drying is carried out using a desiccant.

13. The method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone as described in claim 12, characterized in that, The desiccant is anhydrous sodium sulfate or anhydrous magnesium sulfate.

14. The method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone as described in claim 2, characterized in that, In step two, the catalyst is trifluoroacetic acid; And / or, the alcohol solvent is methanol or ethanol; And / or, the high-valent iodine compound is a trivalent iodine compound, and the trivalent iodine compound is iodobenzene acetate.

15. The method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone as described in claim 2, characterized in that, The reaction temperature in step two is 15~30℃.

16. The method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone as described in claim 2, characterized in that, Step two specifically involves: A catalyst and an alcohol solvent were added to the reaction vessel, followed by the addition of 2,6-difluorostyrene and a high-valent iodine compound. An alcohol solution of compound 2,3-isonitroso-2,4-pentanedione was slowly added dropwise to the reaction system, and the reaction was stirred at 15-30°C.

17. The method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone as described in claim 16, characterized in that, The volume ratio of the catalyst to the total alcohol solvent is 1:100; the molar ratio of compound 2,3-isonitroso-2,4-pentanedione to 2,6-difluorostyrene is 1:(1.2-1.5); the molar ratio of compound 2,3-isonitroso-2,4-pentanedione to iodobenzene acetate is 1:(1.2-1.5).

18. The method for synthesizing 2,6-difluorophenyl-1-(4,5-dihydroisoxazole)-3-ethyl ketone according to any one of claims 14-17, characterized in that, Step two further includes a post-processing step after the reaction is complete. The process includes the following steps: concentrating the reaction system under reduced pressure and then purifying it using rapid column chromatography.

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