Green preparation method of metconazole

Abstract

The invention belongs to the technical field of pesticides and chemical engineering, and particularly relates to a green preparation method of metconazole, which comprises the following steps: under the catalysis of alkali A, carrying out condensation reaction on cyclopentanone and benzaldehyde to obtain alpha, beta-unsaturated ketone; under the catalysis of alkali B, the alpha, beta-unsaturated ketone reacts with a methylation reagent to obtain double methylated alpha, beta-unsaturated ketone; under the action of a catalyst, the double-methylated alpha, beta-unsaturated ketone reacts with hydrogen to obtain 2, 2-dimethyl-5-benzyl cyclopentanone of which the double bonds are reduced; and reacting the 2, 2-dimethyl-5-benzyl cyclopentanone with a chlorination reagent under the action of a catalyst to obtain the 2, 2-dimethyl-5-(4-chlorobenzyl) cyclopentanone. According to the invention, cyclopentanone is used as a raw material to synthesize 2, 2-dimethyl-5-(4-chlorobenzyl) cyclopentanone through four-step simple reactions, metconazole is obtained through epoxidation and ring-opening substitution, and metconazole is finally obtained through recrystallization, so that the method has the advantages of cheap and easily available raw materials, simple process, environmental protection and the like, is suitable for long-term industrial development, and has wide application prospects. Good application prospects are realized.

Description

Technical Field

[0001] The invention belongs to the technical field of pesticides and chemical industry, and particularly relates to a green preparation method of metconazole. Background Art

[0002] Metconazole (common name Metconazole) is a triazole fungicide developed by Kureha Chemical Industry Co., Ltd. in Japan in 1986 and jointly developed with American Cyanamid Company (now BASF) and launched on the market in 1994. Its pure product is a mixture of cis and trans forms, a white, crystalline solid, with good thermal and hydrolytic stability, and high cis activity.

[0003] Metconazole has a very wide spectrum of fungicides and excellent activity. Field application of metconazole has excellent effects on Septoria, Alternaria and Puccinia in cereal crops. Compared with traditional fungicides, metconazole has a very low dosage and can control a wide range of cereal diseases. It is suitable for crops such as wheat, barley, oats, rye, and triticale. It has low toxicity to non-target organisms, low dosage and high fungicidal activity.

[0004] In the related technology, the synthesis of metconazole mostly goes through the compound 2,2-dimethyl-5-(4-chlorobenzyl)-cyclopentane-1-one, so it is a very important intermediate for the synthesis of metconazole. There are many methods for the synthesis of 2,2-dimethyl-5-(4-chlorobenzyl)-cyclopentane-1-one, mainly the following ideas:

[0005] First, isobutyronitrile is used as raw material, and lithium bis(trimethylsilyl)amide or lithium dimethylamide is needed in the process. Such compounds are not common and are expensive. Secondly, sodium cyanide is also needed, which is highly toxic and prone to accidents in industrial production, with a high risk factor. In addition, the purification of the intermediates requires too high equipment, which will greatly increase production costs.

[0006] Second, using 2,2-dimethylcyclopentanone as raw material, although this route is shorter, its raw materials are relatively expensive, the synthesis process is longer, and it involves the use of sodium cyanide and methyl magnesium bromide, as well as a temperature requirement of -50°C. Similarly, the production risk factor is high and the production cost is high, so it is not suitable for industrial production.

[0007] Third, using 2-ethoxycarbonylcyclopentanone as raw material, the order of unit operations such as methylation reaction, condensation reaction, hydrolysis decarboxylation reaction, reduction reaction, and epoxidation reaction in the preparation of metconazole has a great influence on the yield and purification of the final product. In particular, there are two-step methylation reactions in the process, which are highly toxic and difficult to operate. Therefore, the preparation method of metconazole still has difficulties.

[0008] As the demand for pesticides is growing, it is expected that the demand for pesticides will continue to expand in the future. Metconazole has low toxicity to non-target organisms, low dosage and high fungicidal activity, and is widely used in the field of pesticides. Therefore, how to synthesize metconazole under the premise of meeting the requirements of green control has become one of the research hotspots in the field of pesticides in recent years. Summary of the invention

[0009] The invention aims to provide a green preparation method of metconazole, which uses cyclopentanone as a raw material to firstly synthesize 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone through four simple reactions, then obtains metconazole through two-step reactions of epoxidation and ring-opening substitution, and finally obtains metconazole through recrystallization. The method has the advantages of cheap and readily available raw materials, simple process, green and environmental protection, etc., is suitable for long-term industrial development, and has good application prospects.

[0010] The technical solution adopted by the present invention is as follows: A green preparation method of metconazole comprises the following steps: Step 1: Under the catalysis of base A, cyclopentanone and benzaldehyde are subjected to condensation reaction to obtain α,β-unsaturated ketone (compound II); Step 2: Under the catalysis of base B, the α,β-unsaturated ketone (compound II) reacts with a methylating agent to obtain a dimethylated α,β-unsaturated ketone (compound III); Step 3: Under the action of a catalyst, the dimethylated α,β-unsaturated ketone (Compound III) reacts with hydrogen to obtain 2,2-dimethyl-5-benzylcyclopentanone (Compound IV) with a reduced double bond; Step 4: The 2,2-dimethyl-5-benzylcyclopentanone (Compound IV) reacts with a chlorination reagent under the action of a catalyst to obtain 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone (Compound V); Step 5: The 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone (Compound V) undergoes a Johnson-Cory-Chaykovsky reaction and then reacts with 1,2,4-triazole to obtain metconazole (Compound I) after recrystallization.

[0011] In a preferred embodiment, the step 1 is specifically: Cyclopentanone, benzaldehyde and base A are mixed and stirred for condensation reaction at a reaction temperature of 0°C to 150°C for 1h to 10h to obtain a mixed solution a, and the mixed solution a is sequentially extracted, separated and dehydrated to obtain an α,β-unsaturated ketone (Compound II), wherein the molar ratio of the cyclopentanone, benzaldehyde and base A is 1:(0.8-1.2):(0.05-0.4).

[0012] In a preferred embodiment, in the step 1, the condensation reaction is carried out in the presence of an organic solvent A or in the absence of a solvent, wherein the organic solvent A is toluene.

[0013] In a preferred embodiment, the base A is one of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium hydride and tert-butyl lithium.

[0014] In a preferred embodiment, the step 2 is specifically as follows: Adding base B and methylating agent to α,B-unsaturated ketone (compound II) in batches, reacting at 0°C to 150°C for 1 to 15 hours in the presence of organic solvent B to obtain dimethylated α,β-unsaturated ketone (compound III), wherein the molar ratio of the α,β-unsaturated ketone, base B and methylating agent is 1:(2.0 to 4.0):(2.5 to 5.0).

[0015] In a preferred embodiment, the base B is one of sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate and sodium carbonate.

[0016] In a preferred embodiment, the methylating agent is dimethyl carbonate.

[0017] In a preferred embodiment, the organic solvent B is toluene.

[0018] In a preferred embodiment, the step three is specifically as follows: In the presence of an organic solvent C, the dimethylated α, β-unsaturated ketone (compound III) is reacted with a catalyst at room temperature under a hydrogen pressure of 1 to 100 atm for 1 h to 15 h to obtain 2,2-dimethyl-5-benzylcyclopentanone (compound IV) with reduced double bonds, wherein the molar ratio of the dimethylated α, β-unsaturated ketone (compound III) to the catalyst A is 1: (0.0001 to 0.05).

[0019] In a preferred embodiment, the catalyst A is palladium carbon or Raney nickel.

[0020] In a preferred embodiment, the organic solvent C is methanol.

[0021] In a preferred embodiment, the step 4 is specifically as follows: Catalyst B is added to 2,2-dimethyl-5-benzylcyclopentanone (Compound IV), and chlorine gas is introduced into the mixture at 0°C for 5 hours in the presence of an organic solvent D.

[0022] In a preferred embodiment, the catalyst B is ferric chloride or aluminum chloride.

[0023] In a preferred embodiment, the organic solvent D is toluene.

[0024] In a preferred embodiment, in step 5, the recrystallization process is specifically as follows: dissolving the cis-trans isomer mixture of metconazole obtained by the reaction in an organic solvent E at 40°C to 189°C, then cooling to 0°C to 30°C, washing the precipitated crystals with a cold recrystallization solvent and then drying to obtain metconazole.

[0025] In a preferred embodiment, the organic solvent E is one or a mixture of dichloromethane, acetone, methanol, tetrahydrofuran, ethyl acetate, acetonitrile, ethanol, isopropanol, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, N,N-dimethylformamide.

[0026] The technical effects achieved by the present invention are: The invention uses cyclopentanone as a raw material, firstly synthesizes 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone through four simple steps of reaction, then obtains metconazole through two steps of epoxidation and ring-opening substitution, and finally obtains metconazole through recrystallization. The invention has the advantages of cheap and readily available raw materials, simple process, green environmental protection, etc., is suitable for long-term industrial development, and has good application prospects. DETAILED DESCRIPTION

[0027] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific embodiments of the present invention are described in detail below.

[0028] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0029] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure or characteristic that may be included in at least one implementation of the present invention. The phrase "in a preferred embodiment" that appears in different places in this specification does not refer to the same embodiment, nor is it a separate or selective embodiment that is mutually exclusive with other embodiments.

[0030] This embodiment provides a green preparation method of metconazole, and its synthesis path is as follows:

[0031] The preparation method comprises the following steps: Step 1: In the presence of an organic solvent A or in the absence of a solvent, cyclopentanone, benzaldehyde and base A are mixed and stirred for condensation reaction at a reaction temperature of 0°C to 150°C for 1h to 10h to obtain a mixed solution a, and the mixed solution a is sequentially extracted, separated and dehydrated to obtain an α,β-unsaturated ketone (compound II); Wherein, the organic solvent A is toluene, the base A is one of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium hydride, and tert-butyl lithium, and the molar ratio of the cyclopentanone, benzaldehyde, and base A is 1:(0.8-1.2):(0.05-0.4); Step 2: adding base B and methylating agent to α, B-unsaturated ketone (compound II) in batches, reacting at 0°C to 150°C for 1 to 15 hours in the presence of organic solvent B to obtain dimethylated α, β-unsaturated ketone (compound III); Wherein, the organic solvent B is toluene, the methylating agent is dimethyl carbonate, the base B is one of sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, and sodium carbonate, and the molar ratio of the α,β-unsaturated ketone, the base B, and the methylating agent is 1:(2.0-4.0):(2.5-5.0); Step 3: In the presence of an organic solvent C, reacting the dimethylated α,β-unsaturated ketone (Compound III) with a catalyst at room temperature under a hydrogen pressure of 1 to 100 atm for 1 h to 15 h to obtain 2,2-dimethyl-5-benzylcyclopentanone (Compound IV) with a reduced double bond; Wherein, the organic solvent C is methanol, the catalyst A is palladium carbon or Raney nickel, and the molar ratio of the dimethylated α,β-unsaturated ketone (compound III) to the catalyst A is 1:(0.0001-0.05); Step 4: The 2,2-dimethyl-5-benzylcyclopentanone (Compound IV) reacts with a chlorination reagent under the action of a catalyst to obtain 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone (Compound V); The 2,2-dimethyl-5-benzylcyclopentanone (Compound IV) and the organic solvent D are mixed and stirred, and a chlorination reagent is added to react at a reaction temperature of 0°C to 5°C for 0.5h to 1h. After the reaction is completed, ice water is added to quench the reaction to obtain 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone (Compound V); Wherein, the catalyst B is ferric chloride or aluminum chloride, the organic solvent D is toluene, and the chlorination agent is chlorine; Step 5: The 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone (Compound V) undergoes a Johnson-Cory-Chaykovsky reaction and then reacts with 1,2,4-triazole, and then recrystallizes to obtain metconazole (Compound I); Wherein, the organic solvent E is one or a mixture of dichloromethane, acetone, methanol, tetrahydrofuran, ethyl acetate, acetonitrile, ethanol, isopropanol, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, N,N-dimethylformamide.

[0032] Example 1 Preparation of 2-benzylidenecyclopentanone (Compound II) Cyclopentanone (36 g, 0.428 mol), benzaldehyde (45 g, 0.424 mol), potassium hydroxide (24 g, 0.428 mol) and 300 ml of toluene were added into a 500 mL dry four-necked flask, stirred at 25 °C for 6 hours, extracted with ethyl acetate, separated the liquids, and dried by rotation to obtain α, β-unsaturated ketone (Compound II, i.e., 2-benzylidenecyclopentanone) with a yield of 90%.

[0033] Example 2 Preparation of 2,2-dimethyl-5-benzylidenecyclopentanone (Compound III) Under nitrogen protection, 2-benzylidenecyclopentanone (20 g, 0.116 mol), potassium tert-butoxide (39 g, 0.348 mol), and 300 ml of toluene were added to a dry 500 ml four-necked flask. After stirring at -5°C for one hour, dimethyl carbonate (52.2 g, 0.58 mol) was added dropwise. After the addition was completed, the mixture was reacted at 60°C for six hours. After the reaction was completed, water and ethyl acetate were added for separation. The organic layer was washed with water and dried. After the solvent was removed by rotation, the dimethylated α, β-unsaturated ketone (Compound III, i.e., 2,2-dimethyl-5-benzylidenecyclopentanone) was obtained with a yield of 90%.

[0034] Example 3 Preparation of 2,2-dimethyl-5-benzylcyclopentanone (Compound IV) In a dry 500mL reactor, 2,2-dimethyl-5-benzylidenecyclopentanone (10 g, 0.058 mol) and Pd / C (5%) (0.122 g, 0.0058 mol) were added. The reaction mixture was evacuated and replaced with H2 two or three times. 200 mL of methanol solvent was added under H2 atmosphere. H2 was introduced to 1.5 atm and stirred at room temperature for 8 hours. After removing the solvent, 2,2-dimethyl-5-benzylcyclopentanone (Compound IV, i.e., 2,2-dimethyl-5-benzylcyclopentanone) with reduced double bonds was obtained in a yield of 86%.

[0035] Example 4 Preparation of 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone (Compound V) 2,2-Dimethyl-5-benzylcyclopentanone (20 g, 0.1 mol) and 200 ml of toluene were added into a 500 mL four-necked bottle, cooled to 0°C, and chlorine gas (7.1 g, 0.1 mol) was slowly introduced. The temperature was controlled below 5°C, and the tail gas was absorbed by three stages. After the ventilation was completed, it was stirred for one hour. After the reaction was completed, ice water was added to quench. The organic phase was washed with saturated sodium carbonate aqueous solution until neutral. The organic phase was distilled under reduced pressure to obtain 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone (Compound V) with a yield of 85%.

[0036] Example 5 Preparation of metconazole (compound Ⅰ) In a 250ml four-necked bottle, trimethyl sulfoxide iodide (25.4g, 0.115mol), 1,2,4-triazole (8.8g, 0.127 mol), 60% sodium hydride (7.18g, 0.299mol) were added, vacuumed, replaced with nitrogen three times, and then 150ml of dimethyl sulfoxide was added. After the reaction was free of bubbles, 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone (25g, 0.106mol) was added, and then reacted at 90°C for 24h. After the reaction was completed, water and toluene were added, and the layers were extracted. The aqueous phase was extracted with toluene twice, and the toluene phase was washed with water and desolventized. After toluene was removed, the oil pump was decompressed to remove the high-boiling impurities, and recrystallized with 5 times methanol to obtain metconazole (Compound I), which was dried with a yield of 90.5%.

[0037] In summary, the present invention uses cyclopentanone as a raw material to firstly synthesize 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone through four simple steps of reaction, then obtains metconazole through two steps of epoxidation and ring-opening substitution, and finally obtains metconazole through recrystallization. Compared with the prior art, the preparation process has the advantages of cheap and easy-to-obtain raw materials, simple process, green and environmental protection, etc., is suitable for long-term industrial development, and has good application prospects.

[0038] The above is only a preferred embodiment of the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made without departing from the principles of the present invention, and these improvements and modifications should also be considered as the protection scope of the present invention. The structures, devices and operating methods not specifically described and explained in the present invention shall be implemented according to the conventional means in the art unless otherwise specified and limited.

Claims

1. A green preparation method of metconazole, characterized in that: The following steps are involved: Step 1: Under the catalysis of base A, cyclopentanone and benzaldehyde are subjected to condensation reaction to obtain α,β-unsaturated ketone (compound II); Step 2: Under the catalysis of base B, the α,β-unsaturated ketone (compound II) reacts with a methylating agent to obtain a dimethylated α,β-unsaturated ketone (compound III); Step 3: Under the action of a catalyst, the dimethylated α,β-unsaturated ketone (Compound III) reacts with hydrogen to obtain 2,2-dimethyl-5-benzylcyclopentanone (Compound IV) with a reduced double bond; Step 4: The 2,2-dimethyl-5-benzylcyclopentanone (Compound IV) reacts with a chlorination reagent under the action of a catalyst to obtain 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone (Compound V); Step 5: The 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone (Compound V) undergoes a Johnson-Cory-Chaykovsky reaction and then reacts with 1,2,4-triazole to obtain metconazole (Compound I) after recrystallization.

2. A green preparation method of metconazole according to claim 1, characterized in that: The step 1 is specifically as follows: Cyclopentanone, benzaldehyde and base A are mixed and stirred for condensation reaction at a reaction temperature of 0°C to 150°C for 1h to 10h to obtain a mixed solution a, and the mixed solution a is sequentially extracted, separated and dehydrated to obtain an α,β-unsaturated ketone (Compound II), wherein the molar ratio of the cyclopentanone, benzaldehyde and base A is 1:(0.8-1.2):(0.05-0.4).

3. A green preparation method of metconazole according to claim 2, characterized in that: In the step 1, the condensation reaction is carried out in the presence of an organic solvent A or in the absence of a solvent, wherein the organic solvent A is toluene.

4. A green preparation method of metconazole according to claim 2, characterized in that: The base A is one of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium hydride and tert-butyl lithium.

5. A green preparation method of metconazole according to claim 1, characterized in that: The step 2 is specifically as follows: Adding base B and methylating agent to α,B-unsaturated ketone (compound II) in batches, reacting at 0°C to 150°C for 1 to 15 hours in the presence of organic solvent B to obtain dimethylated α,β-unsaturated ketone (compound III), wherein the molar ratio of the α,β-unsaturated ketone, base B and methylating agent is 1:(2.0 to 4.0):(2.5 to 5.0).

6. A green preparation method of metconazole according to claim 5, characterized in that: The base B is one of sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate and sodium carbonate.

7. A green preparation method of metconazole according to claim 5, characterized in that: The methylating agent is dimethyl carbonate.

8. A green preparation method of metconazole according to claim 5, characterized in that: The organic solvent B is toluene.

9. A green preparation method of metconazole according to claim 1, characterized in that: The step three is specifically as follows: In the presence of an organic solvent C, the dimethylated α, β-unsaturated ketone (compound III) is reacted with a catalyst at room temperature under a hydrogen pressure of 1 to 100 atm for 1 h to 15 h to obtain 2,2-dimethyl-5-benzylcyclopentanone (compound IV) with reduced double bonds, wherein the molar ratio of the dimethylated α, β-unsaturated ketone (compound III) to the catalyst A is 1: (0.0001 to 0.05).

10. A green preparation method of metconazole according to claim 9, characterized in that: The catalyst A is palladium carbon or Raney nickel.

11. The green preparation method of metconazole according to claim 9, characterized in that: The organic solvent C is methanol.

12. The green preparation method of metconazole according to claim 1, characterized in that: The step 4 is specifically as follows: Catalyst B is added to 2,2-dimethyl-5-benzylcyclopentanone (Compound IV), and chlorine gas is introduced into the mixture at 0°C for 5 hours in the presence of an organic solvent D.

13. A green preparation method of metconazole according to claim 12, characterized in that: The catalyst B is ferric chloride or aluminum chloride.

14. The green preparation method of metconazole according to claim 12, characterized in that: The organic solvent D is toluene.

15. The green preparation method of metconazole according to claim 1, characterized in that: In the step 5, the recrystallization process is specifically as follows: dissolving the cis-trans isomer mixture of metconazole obtained by the reaction in an organic solvent E at 40°C to 189°C, then cooling to 0°C to 30°C, washing the precipitated crystals with a cold recrystallization solvent and then drying to obtain metconazole.

16. A green preparation method of metconazole according to claim 16, characterized in that: The organic solvent E is one or a mixture of dichloromethane, acetone, methanol, tetrahydrofuran, ethyl acetate, acetonitrile, ethanol, isopropanol, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, and N,N-dimethylformamide.

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