CN109134563B - Catalytic synthesis process of methylamino abamectin key intermediate - Google Patents
Catalytic synthesis process of methylamino abamectin key intermediate Download PDFInfo
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Abstract
The invention relates to the technical field of pesticide intermediate synthesis, and particularly discloses a catalytic synthesis process of a key intermediate of emamectin benzoate, wherein a specific esterification catalyst, namely triethylene diamine or tetramethyl ethylene diamine, is selected in the process, a method for carrying out esterification reaction of 5-hydroxyl under mild conditions is determined, the method has high selectivity on the 5-hydroxyl, the reaction effect is good, the yield is high, the next oxidation reaction of 4' -hydroxyl can be carried out without treatment after the esterification reaction is finished, and an acid-binding agent can be recovered after the reaction is finished, so that the environmental pollution is reduced, and the production cost is reduced.
Description
Technical Field
The invention relates to the technical field of pesticide intermediate synthesis, in particular to a catalytic synthesis process of a key intermediate of emamectin benzoate.
Background
The emamectin benzoate is used as a mature pesticide, and has large annual yield and wide application. Patents US5362863 and US005288710 report synthetic methods of emamectin benzoate, which takes the avermectin as raw material, and esterifies and oxidizes hydroxyl groups at 5-position and 4-position respectively to prepare intermediates, and then further prepare emamectin benzoate from the intermediates. And the 5-position hydroxyl and the 4' -position hydroxyl of the abamectin have higher activity, so the selectivity of the reaction needs to be improved. According to the traditional production method, tetramethylethylenediamine is used as an acid-binding agent at low temperature (-30 to-20 ℃), esterification reaction is selectively carried out on tetramethylethylenediamine and 5-hydroxyl, then 4' -hydroxyl is oxidized into carbonyl, water is added after the reaction is finished to terminate the reaction, the acid-binding agent tetramethylethylenediamine is extremely high in water solubility and is discharged with water, the content of ammonia nitrogen in wastewater is extremely high, and excessive COD and ammonia nitrogen bring great pressure to a wastewater treatment system. Therefore, the traditional production process using tetramethylethylenediamine as an acid-binding agent faces a serious challenge.
In the prior art, triethylamine, tributylamine and the like are also used as acid-binding agents, and the invention finds that when triethylamine, tributylamine and the like are used as acid-binding agents, the reaction can not be completely carried out no matter the reaction temperature or the feeding ratio is adjusted, and the selectivity of hydroxyl groups at the 5-position and the 4-position is poor.
Disclosure of Invention
Aiming at the problems of high pollution, low yield, poor selectivity and the like in the prior art, the invention provides a catalytic synthesis process of a key intermediate of emamectin benzoate, which can selectively carry out esterification reaction on 5-hydroxyl under mild conditions, and has high yield and good selectivity.
In order to achieve the purpose, the invention adopts the following technical scheme:
a catalytic synthesis process of a key intermediate of emamectin benzoate is characterized in that under the action of an acid binding agent and a catalyst, raw material abamectin (II) and a hydroxyl protective reagent react in an inert solvent to generate the key intermediate (I) of emamectin benzoate;
R1is methyl or ethyl; A-B is CH ═ CH or CH2-CH(OH)；
R2-X is a hydroxyl protecting reagent, wherein X is halogen;
wherein the catalyst is any one or a mixture of more than two of triethylene diamine and tetramethyl ethylene diamine in any proportion.
Preferably, the dosage of the catalyst is 0.1-20% of the mole number of the raw material abamectin (II).
Preferably, the acid-binding agent is any one or a mixture of more than two of triethylamine, tripropylamine, tributylamine, ethyldiisopropylamine and propyldiisopropylamine in any proportion.
Further preferably, the dosage of the acid-binding agent is 0.8-3.0 times of the mole number of the raw material abamectin (II).
The hydroxyl protecting reagent can be allyl chloroformate, trimethylchlorosilane or tert-butyldimethylsilyl and the like, but is not limited to the above, and the dosage of the hydroxyl protecting reagent is 1.0-2.0 times of the mole number of the raw material abamectin (II).
Preferably, the inert solvent is dichloromethane, 1, 2-dichloroethane, sec-butyl acetate, isopropyl acetate or 1, 4-dioxane.
Preferably, the reaction temperature is-30 ℃, and the reaction time is 10-60 min.
The invention also provides a 4-site oxidation method of the key intermediate (I) of the emamectin benzoate, namely, after the reaction for catalytically synthesizing the key intermediate (I) is finished, the 4-site oxidation reaction is directly carried out in the reaction system without treatment, and the specific steps of the oxidation reaction can refer to related reports in the prior art.
Preferably, after the oxidation reaction is finished, adding water into the reaction system, adjusting the pH value to be acidic, more preferably 2-3, extracting, separating a water phase from an organic phase after extraction, evaporating the solvent from the organic phase to obtain a 4' -position oxidized intermediate of carbonyl, adjusting the pH value of the water phase to be alkaline, more preferably equal to or more than 11, layering the organic base and the water phase, separating the acid-binding agent, drying, recycling, and recycling the separated water phase for extraction of the reaction system.
Compared with the prior art, the method has the following positive effects:
1. the catalyst is selected, so that the method for carrying out esterification reaction on 5-position hydroxyl under mild conditions is determined, and the method has high selectivity on the 5-position hydroxyl, high reaction speed and high yield.
2. After the esterification reaction is finished, the next oxidation reaction of the 4' -hydroxyl can be carried out without treatment, so that the production process is simplified, and the production efficiency is improved.
3. The process is environment-friendly, overcomes the defect that the COD and the ammonia nitrogen value of the wastewater are extremely high and are difficult to treat because the acid-binding agent completely enters the wastewater in the traditional production method, and accords with the development direction of the industry.
4. The acid-binding agent can be recovered after the oxidation reaction is finished, and can be recycled for reuse, so that the production cost is greatly reduced, and the condition that the acid-binding agent cannot be recycled for reuse once in the traditional production method is improved.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
Dissolving 10g of abamectin B1 (the content of B1a is more than 90%) in 40g of dichloromethane at room temperature, adding 1.8g of allyl chloroformate, stirring for 15min, slowly dropwise adding a mixed solution of 2.8g of triethylamine, 0.5g of triethylene diamine and 2.0g of dichloromethane, finishing the addition for about 10min, stirring for 10min at room temperature after the dropwise addition is finished, continuing to perform the next oxidation reaction, adding 2.4g of DMSO, 2.3g of triethylamine, slowly dropwise adding 2.3g of phenyl phosphate diacid chloride, finishing the dropwise addition for 5min, and stirring for reaction for 30min at room temperature. After the reaction, 20g of water was added, 1mol/L hydrochloric acid was added to adjust pH to 2.5, the mixture was stirred, the phases were separated, and the organic phase was concentrated to give 10.36g of a pale yellow solid with a yield of 95%.
Adding 30% NaOH solution into water layer to adjust pH to 11, standing, and separating phases. The upper layer is colorless transparent triethylamine 3.58g, 0.5g flake alkali is added to obtain 3.4g after drying, the recovery rate is 92%, and the lower layer of water phase can be used for extraction of an oxidation reaction system again.
Example 2
Dissolving 10g of abamectin B2 (the content of B2a is more than 90%) in 40g of dichloromethane, adding 2.4g of allyl chloroformate after complete dissolution, stirring at room temperature for 15min, slowly dropwise adding a mixed solution of 3.8g of tributylamine and 0.002g of triethylene diamine, stirring at-25 ℃ for 60min after 5min of dropwise addition is completed, completely reacting, continuing to perform the next oxidation reaction, adding 2.5g of DMSO and 4.0g of tributylamine, slowly dropwise adding 2.4g of phenyl phosphate diacid chloride, dropwise adding for 5min, and stirring at room temperature for 30 min. After the reaction was completed, 20g of water was added, 1mol/L hydrochloric acid was added to adjust the pH to 3.0, the mixture was stirred, the phases were separated, and the organic phase was concentrated to obtain 10.54g of a pale yellow solid with a yield of 97%.
Adding 30% NaOH solution into water layer to adjust pH to 11, standing, and separating phases. The upper layer was 7.0g of light yellow tributylamine, which was dried by adding 0.8g of caustic soda flakes to give 6.5g with a recovery of 90.2%.
Example 3
Dissolving 10g of abamectin B1 (the content of B1a is more than 90 percent) in 40g of sec-butyl acetate, adding 1.9g of allyl chloroformate after complete dissolution, stirring for 15min at room temperature, slowly dropwise adding a mixed solution of 1.5g of ethyl diisopropylamine, 1.2g of triethylamine and 0.4g of tetramethyl ethylene diamine, after 5min of dropwise addition, stirring for 40min at 0 ℃ after complete addition, completely reacting, continuing the next oxidation reaction, adding 2.4g of DMSO, 3.0g of ethyl diisopropylamine, slowly dropwise adding 3ml of a dichloromethane solution of 1.8g of solid phosgene, after 5min of dropwise addition, stirring for 30min at room temperature. After the reaction, 20g of water was added, 1mol/L hydrochloric acid was added to adjust the pH to 3.0, and the mixture was stirred and phase-separated. The organic phase is concentrated to give 10.15g of a pale yellow solid in 93% yield.
Adding 30% NaOH solution into water layer to adjust pH to 11, standing, and separating phases. The upper layer is 5.6g of light yellow ethyl diisopropylamine, 5.4g is obtained by adding caustic soda flakes and drying, and the recovery rate is 94%.
Example 4
Dissolving 10g of abamectin B1 (the content of B1a is more than 90%) in 40g of dichloromethane at room temperature, adding 1.8g of allyl chloroformate, stirring for 15min, slowly dropwise adding a mixed solution of 0.95g of triethylamine, 0.3g of triethylene diamine, 0.2g of tetramethyl ethylene diamine and 2.0g of dichloromethane which are recovered in example 1, completing the addition for about 10min, stirring for 10min at room temperature after the dropwise addition is completed, continuing the next oxidation reaction after the reaction is completed, adding 2.4g of DMSO, 2.3g of triethylamine (2.0 g of which is the triethylamine recovered in example 1, newly supplementing triethylamine, slowly dropwise adding 2.3g of phenyl phosphate diacid chloride, completing the dropwise addition for 6min, and stirring for reacting for 30min at room temperature. After the reaction was completed, 20g of water was added, 1mol/L hydrochloric acid was added to adjust pH to 2.1, and the mixture was stirred, phase-separated, and the organic phase was concentrated to obtain 10.25g of a pale yellow solid with a yield of 94%.
Adding 30% NaOH solution into water layer to adjust pH to 11, standing, and separating phases. The upper layer was 3.6g of colorless transparent triethylamine, and after adding 0.5g of caustic soda flakes and drying, 3.38g was obtained, with a recovery rate of 91.5%.
In the above embodiment, the oxidation reaction of the 4 "-position hydroxyl group is directly performed by using a one-pot method, so that the yield of the key intermediate (i) is not detected, but the yield of the oxidation reaction product is directly detected, the yield of the oxidation reaction product can reflect the yield of the key intermediate (i), and the oxidation reaction product has a correspondingly high yield only on the premise that the key intermediate (i) has a high yield.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (9)
1. A catalytic synthesis process of a key intermediate of emamectin benzoate is characterized by comprising the following steps: under the action of an acid binding agent and a catalyst, raw material abamectin (II) and a hydroxyl protective reagent react in an inert solvent to generate a key intermediate (I) of the emamectin benzoate; wherein the reaction temperature is 0-30 ℃;
R1is methyl or ethyl; A-B is CH ═ CH or CH2-CH(OH)；
R2-X is a hydroxyl protecting reagent, allyl chloroformate, trimethylchlorosilane;
wherein the catalyst is one of triethylene diamine and tetramethyl ethylene diamine or a mixture of the triethylene diamine and the tetramethyl ethylene diamine in any proportion;
the acid binding agent is any one or a mixture of more than two of triethylamine, tripropylamine, tributylamine, ethyldiisopropylamine and propyldiisopropylamine in any proportion.
2. The catalytic synthesis process of the methylamino abamectin key intermediate as claimed in claim 1, which is characterized in that: the dosage of the catalyst is 0.1-20% of the mole number of the raw material abamectin (II).
3. The catalytic synthesis process of the methylamino abamectin key intermediate as claimed in claim 1, which is characterized in that: the dosage of the acid-binding agent is 0.8-3.0 times of the mole number of the raw material abamectin (II).
4. The catalytic synthesis process of the methylamino abamectin key intermediate as claimed in claim 1, which is characterized in that: the adding amount of the hydroxyl protecting reagent is 1.2-2.0 times of the mole number of the raw material abamectin (II).
5. The catalytic synthesis process of the methylamino abamectin key intermediate as claimed in claim 1, which is characterized in that: the inert solvent is dichloromethane, 1, 2-dichloroethane, sec-butyl acetate, isopropyl acetate or 1, 4-dioxane.
6. The catalytic synthesis process of the methylamino abamectin key intermediate as claimed in claim 1, which is characterized in that: the reaction time is 10 min-60 min.
7. A4' oxidation method of a key intermediate of emamectin benzoate is characterized in that: the reaction according to claim 1 is carried out, and after the reaction is completed, the oxidation reaction is carried out directly in the reaction system.
8. The method for oxidizing the 4' position of the emamectin benzoate key intermediate as claimed in claim 7, wherein the method comprises the following steps: after the oxidation reaction is finished, adding water into the reaction system, adjusting the pH value to be acidic, extracting, separating a water phase from an organic phase, evaporating the organic phase to remove a solvent to obtain a 4' position oxidized intermediate of carbonyl, adjusting the pH value of the water phase to be alkaline, separating the acid-binding agent from water, and separating the acid-binding agent for recycling.
9. The method for oxidizing the 4' position of the emamectin benzoate key intermediate as claimed in claim 8, wherein the method comprises the following steps: and after the oxidation reaction is finished, adding water into the reaction system, adjusting the pH value to be 2-3 for extraction, separating a water phase from an organic phase, evaporating the solvent from the organic phase to obtain a 4' -position oxidized intermediate of carbonyl, adjusting the pH value of the water phase to be more than or equal to 11, layering the acid-binding agent and water, and separating the acid-binding agent for recycling.
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| CN113354695A (en) * | 2021-05-26 | 2021-09-07 | 河北威远生物化工有限公司 | Continuous production process of emamectin benzoate B1/B2 |
| CN115109103B (en) * | 2022-07-27 | 2023-05-12 | 内蒙古新威远生物化工有限公司 | Synthesis method of emamectin benzoate |
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