CN101250173B - A kind of preparation method of spiromethin - Google Patents

Abstract

。本发明的螺甲螨酯的制备方法，适合产业化批量生产。The invention discloses a preparation method of spiromethin, which uses 1-carboxycyclopentanol, 2,4,6-trimethylphenylacetyl chloride and 3,3-dimethylbutyryl chloride as main raw materials, comprising the following Steps: 1) generate compound II: react 1-carboxycyclopentanol with 2,4,6-trimethylphenylacetyl chloride in a catalyst and an organic solvent; 2) generate compound III: react compound II with a strong base Heating in an alcohol solution or an aprotic strong polar solvent for reflux reaction; 3) generating spiromethicone: react compound III with 3,3-dimethylbutyryl chloride in a catalyst and an organic solvent, and the resulting spiromethicone The structural formula of mite is as follows:

. The preparation method of spiromethin of the present invention is suitable for industrialized mass production.

Description

A kind of preparation method of spiromethimen

technical field

The present invention relates to a preparation method of spiromethimen, namely a kind of 3-(2,4,6-trimethylphenyl)-2-oxo-1-oxaspiro[4.4]-nonan- Process for the preparation of 3-en-4-yl-3,3-dimethylbutyl ester.

Background technique

Spiromethin is a second-generation spirotetronic acid insecticide and acaricide developed by Bayer. It is mainly used for the control of whitefly and spider mites in cotton, vegetables and ornamental plants. The mechanism of action of spiromethin is to affect the development of whiteflies and mites, interfere with the biosynthesis of their liposomes, especially have good activity on the larval stage, and at the same time, it can also produce ovariectal closure, reducing the incidence of mites and whitefly adults. reproductive capacity, greatly reducing the number of eggs laid. Spiromethin can effectively control whiteflies that are resistant to pyriproxyfen, and it can effectively control resistant whiteflies when used in combination with methiocarb. Spiromethin has no cross-resistance with any commonly used insecticides and acaricides. Indoor and field tests have proved that spiromethin is safe for beneficial organisms, suitable for integrated pest control, excellent in residual effect, good in plant compatibility, and safe for the environment. Suitable for industrial production.

The currently reported preparation method of spiromethimen is: 3-(2,4,6-trimethylphenyl)-2-oxo-1-oxaspiro[4.4]-non-3-ene 4-ol A ring-forming reaction occurs under alkaline and reduced pressure conditions. After the product is hydrolyzed under acidic conditions, it is reacted with 3,3-dimethylbutyryl chloride. The resulting product is spiromethin. The two-step reaction yield is 60 %above. It has the following disadvantages: firstly, the product obtained in each step of the reaction needs to be separated and purified by silica gel column, the process is complicated and time-consuming; secondly, the reaction yield is relatively low, which does not meet the requirements of current green chemistry; finally, the cyclization reaction requires reduced pressure conditions , the process is complex and unfavorable for industrialized production.

The synthesis method of 3-(2,4,6-trimethylphenyl)-2-oxo-1-oxaspiro[4.4]-non-3-en-4-ol has not been reported yet.

Contents of the invention

The technical problem to be solved by the present invention is to provide a method for preparing spiromethin suitable for industrial batch production.

In order to solve the above-mentioned technical problems, the present invention provides a kind of preparation method of spiromethin, with 1-carboxycyclopentanol, 2,4,6-trimethylphenylacetyl chloride and 3,3-dimethylbutyryl chloride as The main raw material comprises the following steps:

1), generate compound II:

React 1-carboxycyclopentanol with 2,4,6-trimethylphenylacetyl chloride in a catalyst and an organic solvent, the reaction temperature is 0-30°C, the reaction time is 10-15h, 1-carboxycyclopentanol, 2 , The mol ratio of 4,6-trimethylphenylacetyl chloride and catalyst is 1: 1～2: 2.5～3; The compound II structural formula of gained is:

2), generate compound III:

Heat compound II and strong base in alcohol solution or aprotic strong polar solvent to carry out reflux reaction, the reaction time is 10-15h, the molar ratio of compound II and strong base is 1:1-20, the obtained compound III structural formula is :

3), generate spiromethine:

React compound III and 3,3-dimethylbutyryl chloride in a catalyst and an organic solvent, the reaction temperature is 0-30°C, the reaction time is 0.5-5h, the compound III, 3,3-dimethylbutyryl chloride and catalyst The molar ratio is: 1:1～2:2～6; the structural formula of the obtained spiromethin is:

As a further improvement of the preparation method of spiromethin of the present invention: the product obtained in step 3) is recrystallized with any primary alcohol in C ₁ -C ₄ to obtain high-purity spiromethin.

As a further improvement of the preparation method of spiromethin of the present invention: the catalysts in step 1) and step 3) are all tertiary amine acid-binding agents, such as triethylamine or pyridine. The organic solvents in step 1) and step 3) are all aprotic organic solvents, such as alkanes, ethers, aromatic hydrocarbons or substituted alkanes, preferably n-hexane, cyclohexane, ether, benzene, toluene, di Chloromethane and 1,2-dichloroethane.

As a further improvement of the preparation method of spiromethin of the present invention: the strong base in step 2) is alkali metal alkoxide, alkali metal hydroxide or metal hydride, preferably magnesium ethoxide, sodium methoxide and the like. The alcoholic solution in step 2) is any one-level alcohol in C ₁ -C ₄ , and the aprotic strong polar solvent is DMF (dimethylformamide), DMAC (dimethylacetamide) or DMSO (dimethylacetamide) base sulfoxide).

The preparation method of spiromethin of the present invention, the reaction formula of step 1) is as follows:

The 1-carboxycyclopentanol in the reaction formula can be obtained according to the synthetic method disclosed in Journal of Organic Chemistry, 53(9), 2011-15; 1988.

The reaction formula of step 2) is as follows:

Step 3) reaction formula is as follows:

In the preparation method of the present invention, both step 1) and step 2) can be used in the next reaction only after simple post-treatment without purification.

The post-treatment process of step 1) is specifically as follows: after the reaction of step 1), the obtained product is concentrated, and a HCl aqueous solution with a mass fraction of 3% is added, extracted three times with ethyl acetate, and then washed with water, anhydrous Na ₂ SO ₄ dry.

The post-treatment process of step 2) is specifically: after the reaction of step 2) is completed, after decompressing to remove most of the solvent, add hydrochloric acid with a mass fraction of 3%, extract three times with ethyl acetate, then wash with water, anhydrous Na Dry over ₂ SO ₄ and concentrate to give a solid product.

The preparation method of spiromethin of the present invention has the following beneficial effects with respect to the prior art:

First of all, the product obtained from the reaction can be recrystallized without column purification, the process is simple and effective, saves time and effort, and can improve efficiency.

Secondly, the reaction yield is higher than before (the three-step reaction yield of the present invention is more than 60%), so the production cost can be reduced.

Finally, the present invention improves step 2), cancels the decompression condition, and makes the production steps simpler and more effective; this is the advantage of the present invention.

To sum up, the preparation method of spiromethonate of the present invention adopts a brand-new three-step method, has sufficient sources of raw materials, mild reaction conditions, high yield, meets the requirements of green chemistry, and is suitable for industrialized mass production.

Detailed ways

Embodiment 1, the preparation of compound II, i.e. 1-[2-(2,4,6-trimethylphenyl)-acetoxy]-cyclopentylcarboxylic acid:

Add 8.0g (61.5mmol) 1-carboxycyclopentanol, 13.5g (171mmol) pyridine, 60mL dichloromethane into the reaction flask, drop 15.6g (79.3mmol) 2,4 , The dosing of 6-trimethylphenylacetyl chloride and 40mL of dichloromethane. After the dropwise addition was completed within 1 h, the stirring reaction was continued at room temperature for 12 h.

After the reaction was completed, it was concentrated, 100 mL of 3% HCl was added, extracted three times with ethyl acetate, and washed with water. Dry over anhydrous Na ₂ SO ₄ and concentrate to give 15.9 g of brown solid product, Y=89.2%.

Example 2, the preparation of compound III, namely 3-(2,4,6-trimethylphenyl)-2-oxo-1-oxaspiro[4.4]-non-3-en 4-ol:

Add 10.6g (36.5mmol) 1-[2-(2,4,6-trimethylphenyl)-acetoxy]-cyclopentyl formic acid, 5.0g ( 44mmol) magnesium ethylate and 120mL of ethanol, heated to reflux for 12h.

After the reaction was completed, evaporate most of the solvent under reduced pressure, add 50 mL of 3% hydrochloric acid, extract three times with ethyl acetate, wash with water, dry over anhydrous Na ₂ SO ₄ , and concentrate to obtain 7.2 g of solid product, Y=72.5% .

Example 3, Spiromethazol, namely 3-(2,4,6-trimethylphenyl)-2-oxo-1-oxaspiro[4.4]-non-3-en 4-yl-3 , the preparation of 3-dimethylbutyl ester:

Add 2.0 g (7.4 mmol) of 3-(2,4,6-trimethylphenyl)-2-oxo-1-oxaspiro[4.4]-nonan-3 obtained in Example 2 above to the reaction flask -en 4-alcohol and 3.0g (30.0mmol) triethylamine and 50mL dichloromethane, then add dropwise 1.3g (9.7mmol) 3,3-dimethylbutyryl chloride, and stir the reaction at room temperature (ie 0～30°C) 2h.

After the reaction, the resulting reaction liquid was washed three times with 1% hydrochloric acid, then washed twice with saturated NaHCO ₃ solution, and finally washed twice with water, dried over anhydrous Na ₂ SO ₄ , and concentrated to obtain 2.9 g of a solid product. After recrystallization from 95% ethanol, 2.5 g of product was obtained, Y=93.1%, content 90%-95%. Finally, the product with a content of more than 99% was obtained through silica gel column purification.

)，0.84(9H，s，(CH₃)₃-C-)。ESI-MS: 371 (M+1) ⁺ ; ¹ H-NMR (400MHz, CDCl3, δppm): 6.84 (2H, s, ph-H ₂ ), 2.24 (3H, s, Me-Ph), 2.21 (2H , s, O=C-CH ₂ -), 2.16 (6H, s, Me-Ph), 2.09-1.82 (8H, m,

), 0.84 (9H, s, (CH ₃ ) ₃ -C-).

Finally, it should be noted that the above examples are only some specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments, and many variations are possible. All deformations that can be directly derived or associated by those skilled in the art from the content disclosed in the present invention should be considered as the protection scope of the present invention.

Claims (10)

1. a preparation method of spiromethimen, is characterized in that, with 1-carboxycyclopentanol, 2,4,6-trimethylphenylacetyl chloride and 3,3-dimethylbutyryl chloride as main raw material, Include the following steps: 1), generate compound II: React 1-carboxycyclopentanol with 2,4,6-trimethylphenylacetyl chloride in a catalyst and an organic solvent, the reaction temperature is 0-30°C, the reaction time is 10-15h, 1-carboxycyclopentanol, 2 , The mol ratio of 4,6-trimethylphenylacetyl chloride and catalyst is 1: 1～2: 2.5～3; The compound II structural formula of gained is:

2), generate compound III: Heat compound II and strong base in an alcohol solution or an aprotic strong polar solvent for reflux reaction, the reaction time is 10-15 hours, the molar ratio of compound II to strong base is 1:1-20, and the obtained compound III has the following structural formula :

3), generate spiromethine: React compound III and 3,3-dimethylbutyryl chloride in a catalyst and an organic solvent, the reaction temperature is 0-30°C, the reaction time is 0.5-5h, the compound III, 3,3-dimethylbutyryl chloride and catalyst The molar ratio is: 1:1～2:2～6; the structural formula of the obtained spiromethin is as follows:

2. The preparation method of spiromethicone according to claim 1, characterized in that: the step 3) resultant is recrystallized through any primary alcohol in C ₁ -C ₄ to obtain high-purity spiromethicone Micarid. 3. The preparation method of spiromethin according to claim 1 or 2, characterized in that: the catalysts in step 1) and step 3) are all tertiary amine acid-binding agents. 4. The preparation method of spiromethin according to claim 3, characterized in that: the tertiary amine acid-binding agent is triethylamine or pyridine. 5. The preparation method of spiromethin according to claim 4, characterized in that: the organic solvents in the step 1) and step 3) are all aprotic organic solvents. 6. The preparation method of spiromethin according to claim 5, characterized in that: the aprotic organic solvent is alkanes, ethers, aromatic hydrocarbons or substituted alkanes. 7. the preparation method of spiromethin according to claim 6 is characterized in that: described alkane is normal hexane or hexanaphthene, and described ether is ether, described aromatic hydrocarbon is benzene or toluene, The substituted alkanes are dichloromethane or 1,2-dichloroethane. 8. The preparation method of spiromethin according to claim 7, characterized in that: the strong base in the step 2) is an alkali metal alkoxide, an alkali metal hydroxide or a metal hydride. 9. The preparation method of spiromethin according to claim 8, characterized in that: the alkali metal alkoxide is magnesium ethylate or sodium methylate. 10. the preparation method of spiromethin according to claim 9, is characterized in that: the alcoholic solution in described step 2) is any primary alcohol in C ₁ -C ₄ , aprotic strong polar solvent It is dimethylformamide, dimethylacetamide or dimethyl sulfoxide.