CN1847231A - Process of preparing aromatic ring substituted ixooxazoline compound - Google Patents

Abstract

The present invention discloses process of preparing aromatic ring substituted isooxazoline compound. In the presence of Lewis acid or organic acid catalyst and in organic solvent, nitrone and single substituted aryl ethylene are reacted at the temperature from 80 deg.c to the reflux temperature for 4-10 hr. The preparation process of the present invention has product yield over 85 % and the product has purity over 90 %. The preparation process is environment friendly and can meet the requirement of industrial production of farm germicide.

Description

A kind of method for preparing aromatic ring substituted isoxazoline compounds

technical field

The invention relates to a method for preparing aromatic ring substituted isoxazoline compounds.

Background technique

Chinese patent CN1280767A reports heterocyclic substituted isoxazoline compounds used as fungicides. The heterocyclic substituted isoxazoline compounds disclosed in this document are prepared according to the following reaction formula:

In the formula: X is selected from N or CH, R, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl , cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, or heterocyclyl.

The reaction takes benzene, toluene or chlorobenzene as solvent, and is completed at 50°C to the reflux temperature of the reaction solution.

Further studies have found that some aromatic ring-substituted isoxazoline compounds such as the following general formula can also be prepared according to the above method:

In the formula: X is selected from hydrogen, halogen, cyano, nitro, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl or halo (C ₁ -C ₄ ) alkyl, n is An integer of 1-5; Y is selected from carbon or nitrogen; R, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, alkane Oxy, cycloalkyl or aryl.

This type of compound with bactericidal activity has applied for a Chinese patent, application number 200410020467.9.

However, this method has disadvantages such as difficult reaction, low reaction yield (only about 20%), and low product content. It is only applicable to the preparation of new compounds in the laboratory, and cannot meet the industrial scale production of heterogeneous compounds with high biological activity. The need for oxazoline compounds, thus limiting the commercial development prospects of this type of fungicides.

Contents of the invention

The purpose of the present invention is to develop a high yield, high quality and safe reaction method for the preparation of aromatic ring substituted isoxazoline compounds as shown in general formula (I).

In the formula: X is N or C, R ₁ is selected from hydrogen, C ₁ -C ₅ alkyl, halogen C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, halogen C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl or halogen C ₂ -C ₅ alkynyl, R ₂ is aryl, Y is hydrogen, halogen, cyano, nitro, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl Or halogen C ₁ -C ₄ alkyl, n is an integer of 1-5.

It has now been found that adding a suitable catalyst during the preparation of the compound of general formula (I) can promote the completion of the 1,3-dipolar cycloaddition reaction, making the reaction achieve satisfactory and unexpected outstanding effects. The catalyst added at the same time can also be used as a stabilizer of nitrone (II), so that the reaction can be completed under safe conditions, thereby solving the problems of low reaction yield, low product content and unsafe production in the prior art. .

Technical scheme of the present invention is as follows:

The invention provides a method for preparing aromatic ring-substituted isoxazoline compounds. The reaction takes nitrone (II) and monosubstituted arylethene (III) as raw materials, and the reaction formula is as follows:

A suitable catalyst for the reaction is a Lewis acid or an organic acid, and the amount of the catalyst added is 0.05-1.0 mol/mol nitrone.

The reaction is completed in an organic solvent at 80°C to the reflux temperature of the reaction solution for 4-10 hours.

More preferred catalyst is selected from aluminum trichloride, tin tetrachloride, boron trifluoride, acetic acid, acetic anhydride or propionic acid etc., and addition is 0.05-0.8 mol/mol nitrone; Further preferred catalyst is selected from acetic acid or Acetic anhydride, the addition amount is 0.1-0.5 mol/mol nitrone.

A more preferred solvent is benzene, toluene or xylene, and a further preferred solvent is xylene. The amount of solvent is preferably 1-5 liters/mole of nitrone. The preferred temperature is the reflux temperature of the reaction solution, which not only facilitates the control of the reaction, but also appropriately accelerates the reaction speed. For example, using xylene as solvent for reflux reaction and acetic acid as catalyst can effectively shorten the reaction time and greatly improve product yield and quality.

The raw materials used in the reaction are partly commercially available or can be prepared according to known methods, for example, the preparation of nitrone (II) with reference to the method reported in Chinese patent CN1280767A, with reference to Synthesis of ar-nitrostyrenes, Aust.J.Chem.197326 (9): 2067- The method reported in 2069 prepared alkenes (III).

Usually the order of addition is: add solvent, nitrone (II) and catalyst first, then add olefin (III) dropwise under reflux state. In order to prevent olefin polymerization during the reaction, generally 0.05%-1% polymerization inhibitor (based on the weight of olefin added) is added. Commonly used polymerization inhibitors for preventing olefin polymerization can be used. Tests have found that the most suitable inhibitor for this reaction is p-tert-butylcatechol. The polymerization inhibitor can be added during the reaction, or can be added to the raw material olefin (III) in advance.

According to the preparation method provided by the present invention, the product yield of the aromatic ring-substituted isoxazoline compounds represented by the general formula (I) can be greatly improved (from about 20% in the prior art to more than 85%). The content of the product can reach more than 90%, and can meet the needs of industrial scale production of agricultural fungicides without further refining. At the same time, the production process is safe and environmentally friendly, which can be called a very meaningful green synthesis method.

Detailed ways

The following examples serve to further illustrate the invention. However, the present invention is not limited to the following examples.

Example 1

Synthesis of 2-methyl-3-(4-methoxyphenyl)-5-(3-methoxyphenyl)isoxazoline:

100 milliliters of there-necked flasks feed 3.4 grams (0.02 mole) of N-methyl-C-p-methoxyphenylnitrone, xylene (30 milliliters), stir, add dropwise 10% acetic anhydride xylene solution (10 grams), Solution pH = 6-7, add p-tert-butylcatechol (1.5 mg), slowly warm up to reflux, drop m-methoxystyrene 2.8 g (0.0202 moles), add about 15 minutes, continue to reflux reaction, liquid Phase chromatography tracking analysis controls the reaction end point, and the total reaction time is about 4-5 hours. The temperature was lowered, and the reaction solution was washed twice with 50 ml of 2% sodium bicarbonate aqueous solution, and the toluene was removed to obtain 5.8 g of a yellow oil (content 93.8%), yield 90.9%. The analysis results are as follows:

NMR:

¹ H-NMR (CDCI ₃ , 300MHz) δ2.68(S 3H) 3.81(S 3H), 3.83(S 3H), 2.36-2.44, 2.99-3.08(2m1H), 2.54-2.59, 2.60-2.72(2m 1H ), 5.21 (t J = 7.8Hz 1H), 3.78 (m 1H), 6.84 (m 1H), 6.90 (m 1H), 7.00 (m 1H), 7.04 (m 1H), 7.29 (m 3H).

¹³ C-NMR (CDCI ₃ , 300MHz) δ42.96 (43.46), 48.38, 55.05, 72.59 (73.20), 77.85 (78.43), 111.3, 112.9, 114.2, 118.7, 128.6, 129.3, 130.7, 142.7 (144.9), 159.1, 159.6.

Infrared: IR (NaCI) 2980, 2920, 1620, 1520, 1250, 1040, 840 ^{cm -1} .

Mass spectrum: MS (m/z) 300 ([M ⁺ +1], 100), 253(6), 166(6), 150(8).

Elemental analysis: C ₁₈ H ₂₁ NO ₃ theoretical value: C 72.24, H 7.02, O 16.05, N 4.68;

Found values: C 72.00, H 7.26, O 16.08, N 4.64.

Example 2

Synthesis of 2,3-dimethyl-3-(3-pyridyl)-5-(4-chlorophenyl)isoxazoline:

100 ml three-necked flask was charged with C, 3.1 g (0.02 moles) of N-dimethyl-C-(3-pyridyl) nitrone, xylene (30 ml), stirred, and added dropwise 10% xylene acetic acid solution (8.5 g ), the solution pH=6.8, add p-tert-butylcatechol (1.5 mg), slowly warm up to reflux, drop 2.9 grams (0.0202 moles) of p-chlorostyrene, add it in about 20 minutes, continue the reflux reaction, liquid chromatography Follow-up analysis controls the reaction end point, and the total reaction time is about 4-5 hours. Cool down, add 10% hydrochloric acid aqueous solution (20 ml), separate the water phase, neutralize with 30% sodium hydroxide to a pH value of 9, extract with toluene three times (20 ml/time), remove toluene to obtain 5.6 g of a brown solid-liquid mixture (content 92.8%), yield 90.1%. The analysis results are as follows:

NMR:

¹ H-NMR (CDCI ₃ , 300MHz): δ1.58(S 3H), 2.64(S 3H), 2.36, 2.97, 2.89, 2.56(4dd 2H), 5.01, 5.25(t,dd 1H), 7.96(d1H ), 8.53 (d1H), 8.82 (d1H), 7.14-7.34 (m5H).

¹³ C-NMR (CDCI ₃ , 300MHz) 22.02, 39.01, 51.58, 67.88, 77.00 (76.57, 77.42), 123.3, 127.5, 128.4, 133.4, 134.4, 139.5 (140.2), 148.2 (148.0), 142.97) (14 159.1, 159.6.

Infrared: IR (NaCI) 2990, 2940, 1570, 1420, 1090, 820, 720 ^{cm -1} .

Elemental analysis: C ₁₆ H ₁₇ CIN ₂ O theoretical value: C 66.55, H 5.89, O 5.55, N 9.71;

Found values: C 66.56, H 5.86, O 5.58, N 9.73.

Comparative example:

According to the method reported in Chinese patent CN1280767A, the compound described in Example 2 was prepared: 2,3-dimethyl-3-(3-pyridyl)-5-(4-chlorophenyl) isoxazoline

Add 31 grams of nitrone (0.2 moles), 29 grams of p-chlorostyrene (0.202 moles) and 200 milliliters of toluene into a 500 milliliter three-necked flask, heat to reflux, and control the end point of the reaction by liquid chromatography. The total reaction time is about 9.5 hours. After the reaction was completed, the temperature was lowered, and the product solution was extracted twice with 200 ml of 10% hydrochloric acid, and the pH value was adjusted to 9 with 10% sodium hydroxide. Extract 3 times with 200 ml of toluene. The combined organic phases were precipitated to obtain 32 grams of brown oil, with a product content of 43.6%, a reaction yield of 24.2%, and a 3-acetylpyridine content of 51.4%.

32 grams of crude product, 80 milliliters of methanol in a 250 milliliter three-necked flask, add 12 grams of N-methylhydroxylamine sulfate and 21 grams of anhydrous sodium acetate, stir at room temperature, follow-up analysis of liquid chromatography to control the reaction end point, the total reaction time is about 24 Hour. Cool down and filter. Add 500 milliliters of water and 100 milliliters of toluene to the filtrate, separate the phases, and wash the organic phase with water. After precipitation, 15 g of a brown solid-liquid mixture (content 88.5%) was obtained, with a yield of 23%. After analysis, it was the target product.

Example 3

2, the synthesis of 3-dimethyl-3-(3-pyridyl)-5-(4-chlorophenyl) isoxazoline: (reaction is the same as Example 2)

3000 liters of enamel kettle feed C, 156 kilograms (1000 moles) of N-dimethyl-C-(3-pyridyl) nitrone, xylene (1000 kilograms), stir, add dropwise 10% xylene acetic acid solution (100 kilograms ), solution pH=6.8, add p-tert-butylcatechol (80 grams), slowly heat up to reflux, drop 147 kilograms (1020 moles) of p-chlorostyrene, add in 30 minutes, continue the reflux reaction, liquid chromatography tracking The analysis controls the reaction end point, and the total reaction time is 4.8 hours. The reaction solution was cooled to room temperature, added 10% hydrochloric acid aqueous solution (450 kg), separated the water phase, neutralized with 30% sodium hydroxide until the pH value of the solution was 9, extracted with toluene (200 kg three times), and the toluene was removed to obtain a brown solid-liquid mixture 291 kg (90.6% content), yield 91.4%. Analysis result is with embodiment 2.

Example 4

Synthesis of 2-methyl-3-(4-methoxyphenyl)-5-(4-pyridyl)isoxazoline:

100 milliliters of there-necked flasks were dropped into 3.4 grams (0.02 moles) of N-methyl-C-(4-methoxyphenyl) nitrone, toluene (20 milliliters), stirred, and 10% toluene acetate solution (6.5 grams) was added dropwise to Solution pH = 7.0, add p-tert-butylcatechol (2.0 mg), slowly warm up to reflux, drop 2.2 g (0.0202 mol) of 4-pyridylethylene, add about 20 minutes, continue to reflux reaction, liquid chromatography tracking The analysis controls the reaction end point, and the total reaction time is about 9-10 hours. The reaction solution was washed twice with 50 ml of 2% aqueous sodium bicarbonate solution. Add 10% aqueous hydrochloric acid (20 milliliters), separate the aqueous phase, neutralize with 30% sodium hydroxide to a pH value of 9, extract with toluene (20 milliliters three times), remove toluene, and obtain 5.2 grams of yellow oil (content 91.2%) ), yield 87.8%. The analysis results are as follows:

NMR:

¹ H-NMR (CDCI ₃ , 300MHz): δ2.66, 2.70(2S 3H), 3.78, 3.81(2S 3H), 2.26-2.35, 3.11-3.21(2m1H), 2.48-2.54, 2.70-2.84(2m 1H ), 3.65(m 1H), 5.20(q J=6.6Hz, 8.4Hz 1H), 6.84, 6.90(2dd J=8.7Hz2H), 7.20, 7.30(2dd J=8.7Hz 2H), 7.26-7.39(m 2H ), 8.58-8.61 (m 2H).

¹³ C-NMR (CDCI ₃ , 300 MHz) 43.06, 47.3 (48.0), 55.18, 72.23 (73.35), 76.17 (76.91), 114.1, 120.7, 122.7, 129.9, 130.3, 150.0, 159.3.

Infrared: IR (NaCI) 2980, 2920, 1600, 1520, 1250, 1040, 840 ^{cm -1} .

Mass spectrum: MS m/z (%) 271 ([M ⁺ +l], 64), 166 (100), 106 (8), 240 (4).

Example 5

Synthesis of 2-methyl-3-p-methoxyphenyl-5-p-chlorophenylisoxazoline:

3.4 grams (0.02 mole) of N-methyl-C-p-methoxyphenylnitrone and toluene (20 milliliters) were fed into a 100 milliliter three-necked flask, stirred, and 10% acetic anhydride toluene solution (11 grams) was added dropwise, and the pH of the solution was =6.8, add p-tert-butylcatechol (2.0 mg), slowly heat up to reflux, drop 2.9 grams (0.0202 moles) of p-chlorostyrene, add it in about 15 minutes, continue the reflux reaction, and follow the analysis of liquid chromatography to control the reaction End point, total reaction time about 9-10 hours. The temperature was lowered, and the reaction solution was washed three times with 50 ml of 2% sodium bicarbonate aqueous solution, and the toluene was removed to obtain 5.8 g (content: 92.8%) of a light yellow solid, with a yield of 88.7% and a melting point of 80-90°C. The analysis results are as follows:

NMR:

¹ H-NMR (CDCI ₃ , 300MHz): δ2.3-2.36, 3.04-3.13(2m 1H), 2.47-2.56, 2.65-2.77(2m 1H), 2.66, 2.67(2S 3H), 3.65-3.7(m 1H), 3.78, 3.81 (2S 3H), 5.22 (t J = 8.41H), 6.86, 6.90 (2dd J = 8.7Hz2H), 7.24-7.30 (m 2H), 7.30-7.43 (m 4H).

¹³ C-NMR (CDCI ₃ , 300MHz) 42.99(43.35), 47.50(48.52), 55.15, 72.68(73.35), 77.25(77.90), 114.00, 127.23, 127.84, 128.46, 128.53, 128.70, 128.37, 128.70, 128.79, 132.77, 133.41.

Infrared: IR (KBr) 2980, 2920, 1620, 1520, 1300, 1260, 1180, 1040, 830 cm ^-1 .

Mass spectrum: MS m/z (%) 304 ([M ⁺ +1], 100), 286(3), 257(7), 170(10).

Elemental analysis: C ₁₇ H ₁₈ CINO ₂ theoretical value: C 67.22, H 5.93, O 10.54, N 4.61;

Found values: C 67.19, H 5.96, O 10.58, N 4.57.

Claims (2)

1. A method for preparing an aromatic ring-substituted isoxazoline compound. The reaction takes nitrone (II) and monosubstituted arylethene (III) as raw materials, in the presence of a Lewis acid or an organic acid catalyst, in an organic solvent Medium, 80°C to reflux temperature for 4-10 hours to complete, the reaction formula is as follows:

In the formula: X is N or C, R ₁ is selected from hydrogen, C ₁ -C ₅ alkyl, halogen C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, halogen C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl or halogen C ₂ -C ₅ alkynyl, R ₂ is aryl, Y is hydrogen, halogen, cyano, nitro, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl Or halogen C ₁ -C ₄ alkyl, n is an integer of 1-5; The addition amount of the catalyst is 0.05-1.0 mol/mol nitrone. 2. The preparation method according to claim 1, characterized in that: the catalyst is selected from acetic acid or acetic anhydride, and the addition amount is 0.1-0.5 mol/mol nitrone; the solvent is selected from toluene or xylene.