A kind of preparation method of cyfluthrin

Abstract

The invention discloses a method for preparing cyflumetofen, which comprises the steps of (1) reacting raw materials p-tert-butylphenylacetonitrile and bis(2-methoxyethyl) carbonate in an aprotic solvent in the presence of an alkaline substance to obtain 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy) ethyl ester; and (2) reacting the 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy) ethyl ester obtained in the step (1) with o-trifluoromethylbenzoyl chloride in the presence of an alkaline substance to obtain cyflumetofen. The method for preparing cyflumetofen of the invention has short reaction steps, mild reaction conditions, high yield and total yield of the reaction for synthesizing 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy) ethyl ester, and high product purity, easy to obtain raw materials, simple reaction operation and post-treatment, low environmental pollution, and is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of chemical raw material preparation, and in particular to a method for preparing cyflumetofen as a novel acaricide. Background Art

[0002] Cyflumetofen is a new type of acaricide developed by Otsuka Chemical Co., Ltd. of Japan. It has a very high acaricide activity and has no cross-resistance with existing acaricides. The acaricide can effectively kill the main harmful mites parasitic on fruit trees, tea trees and other crops. It is very safe for non-target organisms, such as various plants, mammals, and natural enemies of harmful mites. It can be quickly decomposed in soil and water and is an environmentally friendly pesticide.

[0003] Cyflumetofen is synthesized by acylation reaction of two important intermediates: 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy)ethyl ester and o-trifluoromethylbenzoyl chloride. Currently, there are few reports on the synthesis of cyflumetofen, and even fewer methods suitable for industrial production.

[0004] Li Aijun et al. disclosed a method for preparing cyflumetofen using p-tert-butylbenzyl chloride as a starting material and a four-step reaction to obtain cyflumetofen, wherein the total yield of the method is 63.1%; wherein the third step, the synthesis of 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy)ethyl ester, has a long reaction time and a yield of only 88.7%, and the fourth step, the synthesis of cyflumetofen, has a yield of only 85.4%.

[0005] Wan Qin et al. disclosed a method for preparing cyflumetofen using p-tert-butylphenylacetonitrile (also known as 4-tert-butylphenylacetonitrile) as a starting material through a three-step reaction, wherein the total yield of the method is 46.8% and the content is 96%. The second step, the synthesis of 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy)ethyl ester, has a yield of only 84.3%, and the third step, the synthesis of cyflumetofen, obtains a light yellow solid with a yield of only 68.6%.

[0006] Ma Jinming et al. disclosed a method for preparing cyflumetofen using 4-tert-butylbenzeneacetonitrile and (2-methoxy)ethyl chloroformate as raw materials, and obtaining cyflumetofen through a two-step reaction in the presence of an acid-binding agent, with a total yield of 86.5% and a product purity of 98.6%. The method seems simple, but the reaction raw material (2-methoxy)ethyl chloroformate is not commercially available and is not easy to obtain; the reaction requires the use of phosgene, which is highly toxic and pollutes the environment, which is not conducive to sustainable development requirements.

[0007] Therefore, the synthesis processes of cyflumetofen disclosed in the prior art all show the characteristics of low total yield, poor product appearance and purity, among which the transesterification step shows long reaction time and low yield. The low total yield leads to high preparation cost of cyflumetofen, and the low quality affects the pest control effect. Therefore, it is urgent to develop a low-cost, high-quality preparation method of cyflumetofen. Summary of the invention

[0008] In view of the above problems, the present invention proposes a new method for preparing cyflumetofen: cyflumetofen is prepared by two-step reaction using p-tert-butylphenylacetonitrile and bis(2-methoxyethyl) carbonate as raw materials. The method has short reaction steps, mild reaction conditions, easy purchase of raw materials, low environmental pollution, high yield and high product purity.

[0009] Specifically, the method for preparing cyflumetofen of the present invention comprises steps (1) and (2), wherein

[0010] Step (1): in an aprotic solvent and in the presence of an alkaline substance, reacting the raw material p-tert-butylphenylacetonitrile and bis(2-methoxyethyl) carbonate to obtain 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy)ethyl ester;

[0011] Step (2): In a polar solvent and in the presence of an alkaline substance, the 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy)ethyl ester obtained in step (1) is reacted with o-trifluoromethylbenzoyl chloride to prepare cyfluthrin.

[0012] The synthetic route is as follows:

[0013]

[0014] The present invention provides a method for preparing cyflumetofen from raw materials p-tert-butylphenylacetonitrile and bis(2-methoxyethyl) carbonate via steps (1) and (2). The method achieves high product yield and high purity in each step by strictly controlling reaction parameters. The embodiments provide a variety of specific operation steps for preparing cyflumetofen from raw materials p-tert-butylphenylacetonitrile and bis(2-methoxyethyl) carbonate via steps (1) and (2).

[0015] Specifically, by optimizing various parameters, the product yield of step (1), i.e., the mass ratio of 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy)ethyl ester to p-tert-butylphenylacetonitrile, can reach 99.51%, and the purity can reach 98.55%.

[0016] Furthermore, in the step (1), the molar ratio of bis(2-methoxyethyl) carbonate, p-tert-butylphenylacetonitrile, alkaline substance and aprotic solvent is 1:1:1-6:10-50, preferably 1:1:1-1.5:24, and more preferably 1:1:1.1:24.

[0017] Furthermore, the alkaline substance used in step (1) is one or more of sodium methoxide, sodium isopropoxide, lithium hexamethyldisilazide, potassium hydroxide, and potassium carbonate, preferably one or both of lithium hexamethyldisilazide and sodium methoxide, and more preferably lithium hexamethyldisilazide.

[0018] Furthermore, the aprotic solvent used in step (1) is one of tetrahydrofuran, acetonitrile, dichloromethane or acetone, preferably acetonitrile.

[0019] Furthermore, the reaction temperature of step (1) is 30-60°C, preferably 50-55°C.

[0020] Specifically, by optimizing various parameters, the product yield of step (2), i.e., the mass ratio of cyfluthrin to 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy)ethyl ester, can reach 96.11%, and the purity can reach 99.66%.

[0021] Furthermore, in the step (2), the molar ratio of 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy)ethyl ester, o-trifluoromethylbenzoyl chloride, alkaline substance and polar solvent is 1:1:1-6:10-50, preferably 1:1:1-1.1:15, and more preferably 1:1:1.1:15.

[0022] Furthermore, the alkaline substance used in step (2) is one or more of diethylamine, tetramethylethylenediamine, N,N-diisopropylethylamine, N,N-xylidine, quinoline, pyridine, and potassium carbonate, more preferably one or more of diethylamine, N,N-diisopropylethylamine, tetramethylethylenediamine, pyridine, and potassium carbonate, and even more preferably tetramethylethylenediamine.

[0023] Furthermore, the polar solvent used in step (2) is one of ethyl acetate, acetonitrile, chloroform, dichloroethane or acetone, preferably ethyl acetate.

[0024] Furthermore, the reaction temperature of step (2) is 30-60°C, preferably 50-55°C.

[0025] The present invention uses p-tert-butylphenylacetonitrile and bis(2-methoxyethyl) carbonate as raw materials to prepare cyflumetofen through two-step reaction. Compared with the four-step method and the three-step method in the prior art, the present invention has short reaction steps, mild reaction conditions, high yield, total yield and product purity of the synthesis reaction of 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy)ethyl ester; compared with the two-step method in the prior art, the present invention has easy-to-obtain raw materials, simple reaction operation and post-treatment, low environmental pollution, and higher total yield and product purity. Therefore, the preparation method of cyflumetofen according to the present invention is low-cost, high-quality and suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The drawings constituting a part of the present application are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0027] Figure 1 The high performance liquid chromatogram of cyflumetofen prepared in Example 1-2.1 is shown. DETAILED DESCRIPTION

[0028] In order to facilitate the understanding of the present invention, the present invention will be described more comprehensively below, and preferred embodiments of the present invention are given. However, it should be understood that these embodiments are only used for more detailed description, and should not be understood as limiting the present invention in any form, that is, they are not intended to limit the scope of protection of the present invention. Unless otherwise defined, the technical terms used in the following examples have the same meanings as those generally understood by technicians in the field to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods, unless otherwise specified, are all conventional methods.

[0029] Example 1

[0030] This example shows a method for preparing cyflumetofen under specific working conditions. The method comprises steps (1) and (2), wherein

[0031] Step (1):

[0032] Add 356.36g (2.0mol) bis(2-methoxyethyl) carbonate, 368.13g (2.2mol) lithium hexamethyldisilazide and 1500.00g (36.54mol) acetonitrile to the reaction bottle, and then add 346.50g (2.0mol) p-tert-butylbenzeneacetonitrile and 500.00g (12.18mol) acetonitrile in a mixed solution after heating to 50°C, and control the temperature to 50-55°C; after the addition is completed and the raw materials react completely, quench the reaction solution with water; add hydrochloric acid to adjust to acidity, separate the liquids, and extract the aqueous phase with ethyl acetate; concentrate the above two organic phases and evaporate the solvent to obtain 547.98g of orange-yellow oil, with a yield of 99.51% and a purity of 98.55%. The orange-yellow oil is 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy) ethyl ester.

[0033] In the above reaction step (1), in order to promote the reaction to proceed fully, the solvent used is an aprotic solvent, so acetonitrile can be replaced by tetrahydrofuran, dichloromethane or acetone.

[0034] In this embodiment, the type of alkaline substance used in step (1) is optimized. Specifically, the alkaline substance lithium hexamethyldisilazide used in step (1) (set as Example 1-1.1) is replaced with sodium methoxide, sodium isopropoxide, potassium hydroxide and potassium carbonate with the same molar number for reaction (respectively, Example 1-1.2 to Example 1-1.5, other parameters and reaction conditions remain unchanged), and the reaction yield is shown in Table 1.

[0035] Table 1

[0036] Serial number Alkaline substance used in step (1) Yield (%) Example 1-1.1 Lithium Hexamethyldisilazide 99.51 Example 1-1.2 Sodium Methanol 98.21 Example 1-1.3 Sodium isopropoxide 97.62 Example 1-1.4 Potassium hydroxide 97.11 Example 1-1.5 Potassium carbonate 96.25

[0037] It can be verified from Table 1 that the use of different alkaline substances in step (1) of the method for preparing cyflumetofen in this embodiment can result in a yield as high as 99.51%, wherein the yields of Examples 1-1.1 and 1-1.2 are higher than the average yield (97.74%).

[0038] In this embodiment, the amount of the alkaline substance used in step (1) is optimized. Specifically, in step (1), different molar ratios of p-tert-butylphenylacetonitrile and lithium hexamethyldisilazide are set for reaction, and other parameters and reaction conditions are kept unchanged. The reaction yield is shown in Table 2.

[0039] Table 2

[0040]

[0041] It can be verified from Table 2 that in step (1) of the method for preparing cyflumetofen in this embodiment, setting the molar ratio of p-tert-butylphenylacetonitrile to lithium hexamethyldisilazide to 1:1-1:3 can make the yield as high as 99.51%, among which the yields of Examples 1-1.1, 1-1.6 and 1-1.7 are higher than the average yield (98.32%).

[0042] Step (2):

[0043] 413.01 g (1.5 mol) of 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy)ethyl ester obtained in step (1), 191.75 g (1.65 mol) of tetramethylethylenediamine and 1500 g (17.02 mol) of ethyl acetate were added to the reaction flask, and the temperature was raised to 50° C. and then a mixed solution of 312.75 g (1.5 mol) of o-trifluoromethylbenzoyl chloride and 500.00 g (5.67 mol) of ethyl acetate was added dropwise, and the temperature was controlled at 50-55° C. After the addition was completed and the reaction of the raw materials was complete, the reaction solution was quenched with water, hydrochloric acid was added to adjust it to acidity, the liquids were separated, and the aqueous phase was extracted with ethyl acetate; the organic phase was concentrated and ethyl acetate was removed by evaporation, n-heptane was added for recrystallization, the temperature was lowered for crystallization, suction filtered, and dried to obtain 645.07 g of cyflumetofen as a white powder, with a yield of 96.11% and a purity of 99.66%. The high performance liquid chromatogram of the obtained cyflumetofen was as shown in FIG. Figure 1 .

[0044] The solvent used in the above step (2) is a polar solvent, and ethyl acetate can be replaced by acetonitrile, chloroform, dichloroethane or acetone.

[0045] In this embodiment, the type of alkaline substance used in step (2) is optimized. Specifically, the alkaline substance tetramethylethylenediamine used in step (2) (set as Example 1-2.1) is replaced with diethylamine, N, N-diisopropylethylamine, pyridine, potassium carbonate, N, N-dimethylaniline and quinoline with the same mole number to react (respectively, Example 1-2.2 to Example 1-2.7, other parameters and reaction conditions remain unchanged), and the reaction yield is shown in Table 3.

[0046] Table 3

[0047] Serial number Alkaline substance used in step (2) Yield (%) Example 1-2.1 Tetramethylethylenediamine 96.11 Example 1-2.2 Diethylamine 95.21 Example 1-2.3 N,N-Diisopropylethylamine 93.62 Example 1-2.4 Pyridine 93.34 Example 1-2.5 Potassium carbonate 91.22 Example 1-2.6 N,N-Dimethylaniline 87.31 Example 1-2.7 Quinoline 73.16

[0048] It can be verified from Table 3 that the use of different alkaline substances in step (2) of the method for preparing cyflumetofen in this embodiment can result in a yield as high as 96.11%, wherein the yields of Examples 1-2.1 to 1-2.5 are higher than the average yield (90%).

[0049] In this embodiment, the amount of the alkaline substance used in step (2) is optimized. Specifically, in step (2), different molar ratios of o-trifluoromethylbenzoyl chloride and tetramethylethylenediamine are set for reaction, and other parameters and reaction conditions are kept unchanged. The reaction yields are shown in Table 4.

[0050] Table 4

[0051]

[0052] It can be verified from Table 4 that in step (2) of the method for preparing cyflumetofen in this embodiment, setting the molar ratio of p-tert-butylphenylacetonitrile to tetramethylethylenediamine to 1:1-1:3 can make the yield as high as 96.11%, among which the yields of Examples 1-2.1 and 1-2.8 are higher than the average yield (94.57%).

[0053] Example 2

[0054] This example shows a method for preparing cyflumetofen under another working condition, which comprises steps (1) and (2), wherein

[0055] Step (1): add 356.36g (2.0mol) bis(2-methoxyethyl) carbonate, 560.10g (10.0mol) potassium hydroxide and 1442.20g (20.0mol) tetrahydrofuran to a reaction bottle, and then add a mixed solution of 346.50g (2.0mol) p-tert-butylbenzene acetonitrile and 721.10g (10.0mol) tetrahydrofuran dropwise after the temperature is raised to 40°C, and the temperature is controlled at 40-45°C; after the addition is completed and the raw materials react completely, the reaction solution is quenched with water, hydrochloric acid is added to adjust it to acidity, the liquids are separated, and the aqueous phase is extracted with ethyl acetate; the above two organic phases are concentrated and evaporated to remove the solvent, and 530.97g of an orange-yellow oily substance is obtained, with a yield of 96.42% and a purity of 97.11%. The orange-yellow oily substance is 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy) ethyl ester.

[0056] Step (2): add 413.01 g (1.5 mol) of the above oil, 711.09 g (9.0 mol) of pyridine and 2463.00 g (60.0 mol) of acetonitrile to a reaction bottle, raise the temperature to 40°C and then start to dropwise add a mixed solution of 312.75 g (1.5 mol) of o-trifluoromethylbenzoyl chloride and 615.75 g (15.0 mol) of acetonitrile, and control the temperature at 40-45°C; after the dropwise addition is completed and the raw materials react completely, quench the reaction solution with water, add hydrochloric acid to adjust to acidity, separate the liquids, and extract the aqueous phase with ethyl acetate; concentrate the organic phase to remove ethyl acetate, add n-heptane for recrystallization, cool and crystallize, filter and dry to obtain 626.48 g of cyfluthrin as a white powder, with a yield of 93.34% and a purity of 99.01%.

[0057] Example 3

[0058] This example shows a method for preparing cyflumetofen under another working condition, which comprises steps (1) and (2), wherein

[0059] Step (1): add 356.36g (2.0mol) bis(2-methoxyethyl) carbonate, 691.05g (5.0mol) potassium carbonate and 4065.60g (70.0mol) acetone to a reaction bottle, and then add a mixed solution of 346.50g (2.0mol) p-tert-butylbenzene acetonitrile and 1161.60g (20.0mol) acetone dropwise after the temperature is raised to 30°C, and the temperature is controlled at 30-35°C; after the addition is completed and the raw materials react completely, the reaction solution is quenched with water, hydrochloric acid is added to adjust it to acidity, the liquids are separated, and the aqueous phase is extracted with ethyl acetate; the above two organic phases are concentrated and evaporated to remove the solvent, and 496.22g of an orange-yellow oily substance is obtained, with a yield of 90.11% and a purity of 96.35%. The orange-yellow oily substance is 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy) ethyl ester.

[0060] Step (2): add 413.01 g (1.5 mol) of the above oil, 621.95 g (4.5 mol) of potassium carbonate and 2969.10 g (30.0 mol) of dichloroethane to a reaction bottle, and then add a mixed solution of 312.75 g (1.5 mol) of o-trifluoromethylbenzoyl chloride and 1484.55 g (15.0 mol) of dichloroethane dropwise after heating to 30°C, and control the temperature to 30-35°C; after the addition is completed and the raw materials react completely, quench the reaction solution with water, add hydrochloric acid to adjust to acidity, separate the liquids, and extract the aqueous phase with ethyl acetate; concentrate the organic phase to remove ethyl acetate, add n-heptane for recrystallization, cool and crystallize, filter with suction, and dry to obtain 612.25 g of cyfluthrin as a white powder, with a yield of 91.22% and a purity of 98.46%.

[0061] The above contents are further detailed descriptions of the present invention in combination with specific implementation methods, and it cannot be determined that the specific implementation of the present invention is limited to these descriptions. For ordinary technicians in the technical field to which the present invention belongs, several simple improvements and modifications can be made without departing from the concept of the present invention, which should be regarded as falling within the scope of protection of the present invention.

Claims

1. A method for preparing cyflumetofen, characterized in that: The method comprises the following steps Step (1): in acetonitrile and in the presence of lithium hexamethyldisilazide, the raw material p-tert-butylphenylacetonitrile and bis(2-methoxyethyl) carbonate are reacted to obtain 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy)ethyl ester; Step (2): in ethyl acetate and in the presence of tetramethylethylenediamine, reacting the 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy)ethyl ester obtained in step (1) with o-trifluoromethylbenzoyl chloride to prepare cyfluthrin; In the step (1), the molar ratio of bis(2-methoxyethyl) carbonate, p-tert-butylphenylacetonitrile, lithium hexamethyldisilazide, and acetonitrile is 1:1:1-6:10-50; the reaction temperature of the step (1) is 30-60°C; In the step (2), the molar ratio of 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy)ethyl ester, o-trifluoromethylbenzoyl chloride, tetramethylethylenediamine, and ethyl acetate is 1:1:1-6:10-50; and the reaction temperature of the step (2) is 30-60°C.

2. The method for preparing cyflumetofen according to claim 1, characterized in that: In the step (1), the molar ratio of bis(2-methoxyethyl) carbonate, p-tert-butylphenylacetonitrile, lithium hexamethyldisilazide and acetonitrile is 1:1:1.1:

24.

3. The method for preparing cyflumetofen according to claim 1, characterized in that: The reaction temperature of step (1) is 50-55°C.

4. The method for preparing cyflumetofen according to claim 1, characterized in that: In the step (2), the molar ratio of 2-(4-tert-butylphenyl)-2-cyanoacetic acid (2-methoxy)ethyl ester, o-trifluoromethylbenzoyl chloride, tetramethylethylenediamine and ethyl acetate is 1:1:1.1:

15.

5. The method for preparing cyflumetofen according to claim 1, characterized in that: The reaction temperature of step (2) is 50-55°C.

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