CN109678804B - Method for preparing fluacrypyrim - Google Patents
Method for preparing fluacrypyrim Download PDFInfo
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- CN109678804B CN109678804B CN201910034357.4A CN201910034357A CN109678804B CN 109678804 B CN109678804 B CN 109678804B CN 201910034357 A CN201910034357 A CN 201910034357A CN 109678804 B CN109678804 B CN 109678804B
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- fluacrypyrim
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Abstract
The invention discloses aThe method for preparing the fluacrypyrim comprises the following steps: (1) and (3) etherification reaction: taking (E) -2- (2' -chloromethyl) phenyl-3-methoxy methyl acrylate and 2-isopropoxy-4-hydroxy-6-trifluoromethyl pyrimidine as raw materials, adding the raw materials into a solvent DMF, and simultaneously adding K2CO3Taking the reaction product as an acid binding agent, reacting at 120-150 ℃, finishing the reaction after the (E) -2- (2' -chloromethyl) phenyl-3-methoxy methyl acrylate disappears to obtain a feed liquid, and cooling to room temperature; (2) and (3) extracting a crude product: adding the cooled feed liquid into an alkaline aqueous solution, stirring to obtain a viscous substance, extracting, washing with water, drying, and concentrating to dryness to obtain a crude product of fluacrypyrim; (3) refining: recrystallizing the crude fluacrypyrim to obtain the fluacrypyrim product with the purity not lower than 96 percent. The method has the advantages of high industrial feasibility, higher yield, more stable quality, lower cost, safety and environmental protection.
Description
Technical Field
The invention belongs to the field of synthesis of acaricide fluacrypyrim, and particularly relates to a method for preparing fluacrypyrim.
Background
The fluacrypyrim is the first strobilurin acaricide developed by basf company and Japanese Caoda company, has the insecticidal principle of mainly inhibiting death of worms caused by mitochondrial respiration of the worms, and is mainly used for preventing and controlling mites of various fruits such as oranges, apples and the like. At present, the types of effective acaricides in China are few, the synthesis process of the fluacrypyrim stays at the laboratory small-scale research and development stage at home at present, the process requirement is high, column separation chromatography is needed for purification (the comparison document: Liu Ruo Lin, Zhang jin Bo. the synthesis and acaricidal activity of the fluacrypyrim, pesticide, volume 48, No. 3, 2009, 3) and the possibility of industrial production is unavailable.
The synthetic route adopted by the reference is as follows:
the reaction is an SN2The reaction mechanism is that 2-isopropoxy-4-hydroxy-6-trifluoromethyl pyrimidine II (hereinafter referred to as pyrimidine) forms oxygen anions under alkaline conditions to attack the chloro group of (E) -2- (2' -chloromethyl) phenyl-3-methoxy methyl acrylate I (hereinafter referred to as methyl ester) to form ether bond, and the reaction is the main reaction.
This reaction has the following side reaction due to acid-base neutralization of potassium carbonate with pyrimidineReacting to produce an equivalent of H2The presence of water, in turn, competes with the main reaction, causing hydrolysis of the chloro group of the methyl ester to a hydroxyl group and thereby losing the ability to form an ether or hydrolysis of the ester group of the methyl ester, which can typically occur above 60 ℃. This side reaction means that for every equivalent of fluacrypyrim formed, one equivalent of methyl ester is hydrolysed, resulting in a loss of methyl ester starting material, and the hydrolysed product is difficult to remove by work-up operations and requires column separation to obtain the product. The technical level that the reference can reach can only stay within 100g, need obtain the target product through column separation, the column separation method is very big to the use amount of organic solvent, and the product that obtains is also very little, and the chromatographic column capacity is limited, makes the cost of separation and purification very high, purify 0.5g crude pyriminostrobin needs 200g silica gel, 2kg organic solvent at least, add to pack the column separation process and need more than 3 days, organic solvent is difficult to retrieve and recycle these problems, easily cause the pollution to the environment, the cost is expensive, it is difficult to adapt to the industrial production.
Disclosure of Invention
The invention aims to solve the technical problems and provide a method for preparing fluacrypyrim, which has the advantages of high industrial feasibility, higher yield, more stable quality, lower cost, safety and environmental protection.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a process for the preparation of fluacrypyrim, which comprises the steps of:
(1) etherification reaction: taking (E) -2- (2' -chloromethyl) phenyl-3-methoxy methyl acrylate and 2-isopropoxy-4-hydroxy-6-trifluoromethyl pyrimidine as raw materials, adding the raw materials into a solvent DMF, and simultaneously adding K2CO3As an acid-binding agent, reacting at 120-150 ℃, and obtaining a feed liquid after the reaction is finished after (E) -2- (2' -chloromethyl) phenyl-3-methoxy methyl acrylate disappears, and cooling to room temperature;
(2) and (3) extracting a crude product: adding the cooled feed liquid into an alkaline aqueous solution, stirring to obtain a viscous substance, extracting, washing with water, drying, and concentrating to dryness to obtain a crude product of fluacrypyrim;
(3) refining: recrystallizing the crude fluacrypyrim to obtain the fluacrypyrim product with the purity not lower than 96 percent.
As a further technical scheme, the mass ratio of the (E) -2- (2' -chloromethyl) phenyl-3-methoxy methyl acrylate to the 2-isopropoxy-4-hydroxy-6-trifluoromethyl pyrimidine is 1: 1-1.5.
As a further technical scheme, the mass ratio of the (E) -2- (2' -chloromethyl) phenyl-3-methoxy methyl acrylate to DMF is 1: 9-20.
As a further technical scheme, the (E) -2- (2' -chloromethyl) phenyl-3-methoxy acrylic acid methyl ester and K2CO3The mass ratio of (1) to (0.3-1.6).
As a further technical scheme, the alkaline aqueous solution is a sodium hydroxide aqueous solution with the mass content of 0.5%, and the amount of the sodium hydroxide is 10 times of the mass of the (E) -2- (2' -chloromethyl) phenyl-3-methoxy methyl acrylate.
According to a further technical scheme, ethyl acetate is used as an extracting agent in the extraction, the addition amount of the ethyl acetate is 4 times of the mass of the (E) -2- (2' -chloromethyl) phenyl-3-methoxy methyl acrylate, and the extraction frequency is more than 3 times.
As a further technical scheme, the recrystallization comprises the steps of adding an organic solvent into the crude fluacrypyrim, heating, dissolving, refluxing, filtering to remove insoluble substances while the solution is hot, cooling the filtrate to separate out crystals, and then carrying out suction filtration and drying on the crystals.
According to a further technical scheme, the mass ratio of the (E) -2- (2' -chloromethyl) phenyl-3-methoxy methyl acrylate to the organic solvent is 1: 7-15, and the organic solvent is ethanol.
As a further technical scheme, the heating and dissolving temperature is 35 ℃ to the reflux temperature, the cooling temperature is below 25 ℃, and the cooling time is 0.5 h-1 h.
As a further technical scheme, the drying temperature is 80-100 ℃, and the material drying time is 2h to constant weight.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention has higher yield and more stable quality.
According to the invention, by increasing the reaction temperature of the etherification reaction, the reaction rate is increased along with the increase of the reaction temperature, the reaction time is shortened, the reaction which originally needs 12 hours can be completed only by 4 hours, and the labor cost is greatly saved; meanwhile, as the reaction temperature of the etherification reaction is increased to 120-150 ℃, water generated by the acid-base neutralization reaction of potassium carbonate and 2-isopropoxy-4-hydroxy-6-trifluoromethylpyrimidine can be evaporated, and the temperature range obtained by experiments can reduce the reaction of water and (E) -2- (2' -chloromethyl) phenyl-3-methoxy methyl acrylate to the maximum extent, so that the competitive reaction is reduced, the main reaction can be carried out more smoothly, the waste of raw materials is reduced, and the yield of the crude product of the fluacrypyrim ester is improved; meanwhile, the recrystallization operation also improves the yield of the product to over 80 percent.
2. The invention has the advantages of high industrial feasibility, lower cost, safety and environmental protection.
In the column separation process in the prior art, because a large amount of mixed organic solvent is used in the column separation process, the capacity of the column is limited, large-scale product refining is difficult to carry out, a large amount of organic reagents cannot be recovered and wasted, and environmental pollution is caused.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited to the scope of the examples.
The molar mass of each component in the invention is as follows: (E) 240.68g/mol of methyl (2- (2' -chloromethyl) phenyl-3-methoxyacrylate), 222.17g/mol of 2-isopropoxy-4-hydroxy-6-trifluoromethylpyrimidine, 426.39g/mol of fluacrypyrim, 138.21g/mol of potassium carbonate, 73.09g/mol of DMF, and 46.07g/mol of ethanol.
Example 1:
(1) a500 mL three-necked flask equipped with a mechanical stirrer and a thermometer was charged with 20g (0.083moL) of methyl (E) -2- (2 '-chloromethyl) phenyl-3-methoxyacrylate, 22.15g (0.100moL) of 2-isopropoxy-4-hydroxy-6-trifluoromethylpyrimidine, 6.32g (0.046moL) of potassium carbonate, and 189.6g of DMF189.6g, dissolved with stirring, heated to 120 ℃ and TLC-traced to completion of the reaction of methyl (E) -2- (2' -chloromethyl) phenyl-3-methoxyacrylate.
(2) Cooling the feed liquid, pouring into 200g of 0.5% sodium hydroxide aqueous solution, stirring to separate out a viscous substance, extracting with industrial ethyl acetate for 80g multiplied by 3 times, washing with water, drying, and concentrating under reduced pressure to dryness to obtain 37g of orange red oily substance (namely crude fluacrypyrim) which is all used for refining.
(3) Adding 140g of ethanol into the crude fluacrypyrim, heating for dissolving, transferring into a 500mL three-necked flask with a mechanical stirrer and a thermometer, stirring, heating for refluxing, filtering while hot, transferring the filtrate into the 500mL three-necked flask with the mechanical stirrer and the thermometer, continuously heating for refluxing for dissolving, continuously stirring, cooling to 15 ℃, continuing stirring for 0.5 hour after reaching the temperature to precipitate a large amount of white-like solids, filtering, and drying to constant weight to obtain 31g of the refined fluacrypyrim. The peak position of the refined product has no significant difference with a standard sample of fluacrypyrim (the commercial content is sold at 99.9 percent) through HPLC comparison. (HPLC content ≧ 96%, yield ≧ 87.5%)
Example 2:
(1) to a 3000mL three-necked flask equipped with a mechanical stirrer and a thermometer were added 90g (0.37moL) of methyl (E) -2- (2 '-chloromethyl) phenyl-3-methoxyacrylate, 99g (0.45moL) of 2-isopropoxy-4-hydroxy-6-trifluoromethylpyrimidine, 54g (0.39moL) of potassium carbonate and DMF900g, and the mixture was dissolved with stirring, heated to 120 ℃ and followed by TLC until the reaction was completed by methyl (E) -2- (2' -chloromethyl) phenyl-3-methoxyacrylate.
(2) Cooling the feed liquid, pouring into 900g of 0.5% sodium hydroxide aqueous solution, stirring to separate out a viscous substance, extracting with industrial ethyl acetate for 360g multiplied by 3 times, washing with water, drying, and concentrating under reduced pressure to dryness to obtain 170g of orange red oily substance (i.e. crude fluacrypyrim), which is used for refining.
(3) Adding 810g of ethanol into the crude fluacrypyrim, heating for dissolving, transferring into a 3000mL three-necked flask with a mechanical stirrer and a thermometer, stirring, heating for refluxing, filtering while hot, transferring the filtrate into the 3000mL three-necked flask with the mechanical stirrer and the thermometer, continuously heating for refluxing for dissolving, continuously stirring and cooling to 15 ℃, continuously stirring for 0.5h after reaching the temperature to separate out a large amount of white-like solids, filtering, and drying to constant weight to obtain 133.9g of the refined fluacrypyrim. The peak position of the refined product has no significant difference with a fluacrypyrim standard sample (the commercial content is 99.9 percent) through HPLC comparison. (HPLC content ≧ 96%, yield ═ 85%)
Example 3:
(1) 720g (2.99moL) of methyl (E) -2- (2 '-chloromethyl) phenyl-3-methoxyacrylate, 792g (3.56moL) of 2-isopropoxy-4-hydroxy-6-trifluoromethylpyrimidine, 216g (1.56moL) of potassium carbonate and 7.2kg of DMF7 were added to a 10L three-necked flask with mechanical stirring and thermometer, dissolved with stirring, heated to 135 ℃ and the reaction was followed by TLC until completion of the reaction of methyl (E) -2- (2' -chloromethyl) phenyl-3-methoxyacrylate.
(2) The feed liquid is cooled and poured into 7.2kg of 0.5 percent sodium hydroxide aqueous solution, viscous substances are separated out by stirring, industrial ethyl acetate is used for extracting for 2.8kg multiplied by 3 times, water washing, drying and decompression concentrating are carried out until the substances are dried to obtain 1.4kg of orange red oily substances (namely the crude products of the fluacrypyrim), and all the substances are used for refining.
(3) Adding 6.5kg of ethanol into the crude oil of the fluacrypyrim, heating to dissolve, transferring into a 10L three-necked flask with a mechanical stirrer and a thermometer, stirring, heating to reflux, filtering while hot, transferring the filtrate into the 10L three-necked flask with the mechanical stirrer and the thermometer, continuously heating, refluxing, dissolving, cooling to 15 ℃, continuously stirring for 0.5h after reaching the temperature to precipitate a large amount of white-like solids, filtering, and drying to constant weight to obtain a refined fluacrypyrim product 1052 g. The peak position of the refined product has no significant difference with a standard sample of fluacrypyrim (the commercial content is sold at 99.9 percent) through HPLC comparison. (HPLC content ≧ 96%, yield ≧ 82.5%)
Example 4:
(1) A50L reactor equipped with a mechanical stirrer and a thermometer was charged with 3.0kg (12.5moL) of methyl (E) -2- (2 '-chloromethyl) phenyl-3-methoxyacrylate, 3.0kg (13.5moL) of 2-isopropoxy-4-hydroxy-6-trifluoromethylpyrimidine, 900g (6.5moL) of potassium carbonate and 27.0kg of DMF27, and the mixture was dissolved with stirring, heated to 120 ℃ and subjected to TLC tracing until the reaction was completed until methyl (E) -2- (2' -chloromethyl) phenyl-3-methoxyacrylate was obtained. Raw material mass ratio is 1:1, methyl ester: DMF ═ 1:9, methyl ester: 1:0.3 of potassium carbonate
(2) Cooling the feed liquid, adding into 30kg of 0.5% sodium hydroxide aqueous solution, stirring to separate out viscous substance, extracting with industrial ethyl acetate for 12.0kg × 3 times, washing with water, drying, concentrating under reduced pressure to dry to obtain orange red oily substance (crude fluacrypyrim) 5.5kg, and refining.
(3) Adding 30kg of ethanol into the crude fluacrypyrim, heating for dissolving, transferring into a 50L reaction kettle with a mechanical stirrer and a thermometer, stirring, heating for refluxing, filtering while hot, transferring the filtrate into a 50L reaction kettle with a mechanical stirrer and a thermometer again, continuously heating for refluxing, dissolving, continuously stirring, cooling to 15 ℃, continuously stirring for 0.5h after reaching the temperature, precipitating a large amount of white-like solids, filtering, and drying to constant weight to obtain 4.4kg of the refined fluacrypyrim product. The peak position of the refined product has no significant difference with a standard sample of fluacrypyrim (the commercial content is sold at 99.9 percent) through HPLC comparison. (HPLC content ≧ 96%, yield ≧ 83.5%)
Example 5:
(1) A100L reactor equipped with mechanical stirring and thermometer was charged with 3.0kg (12.5moL) of methyl (E) -2- (2 '-chloromethyl) phenyl-3-methoxyacrylate, 4.5kg (20.3moL) of 2-isopropoxy-4-hydroxy-6-trifluoromethylpyrimidine, 4.8kg (34.7moL) of potassium carbonate and DMF60kg, dissolved with stirring, heated to 150 ℃ and TLC-tracked until the end of the (E) -2- (2' -chloromethyl) phenyl-3-methoxyacrylate. Raw material mass ratio is 1:1.5, methyl ester: DMF 1:20, methyl ester: 1:1.6 of potassium carbonate
(2) Cooling the feed liquid, adding into 30kg of 0.5% sodium hydroxide aqueous solution, stirring to separate out viscous substance, extracting with industrial ethyl acetate for 12kg × 3 times, washing with water, drying, concentrating under reduced pressure to dry to obtain orange red oily substance (crude fluacrypyrim) 5.4kg, and refining.
(3) Adding 45kg of ethanol into the crude fluacrypyrim product, heating for dissolving, transferring into a 50L reaction kettle with a mechanical stirrer and a thermometer, stirring, heating for refluxing, filtering while hot, transferring the filtrate into the 50L reaction kettle with the mechanical stirrer and the thermometer, continuously heating, refluxing, dissolving, cooling to 15 ℃, continuing to stir for 0.5h after reaching the temperature to precipitate a large amount of white-like solids, filtering, and drying to constant weight to obtain 4.3kg of the refined fluacrypyrim product. The peak position of the refined product has no significant difference with a standard sample of fluacrypyrim (the commercial content is sold at 99.9 percent) through HPLC comparison. (HPLC content ≧ 96%, yield ═ 81%)
The data not shown in the other steps can be understood by those skilled in the art according to the routine operation in the field.
The above-described embodiments are only specific examples for further explaining the object, technical solution and advantageous effects of the present invention in detail, and the present invention is not limited thereto. Any modification, equivalent replacement, improvement and the like made within the scope of the present disclosure are included in the protection scope of the present invention.
Claims (7)
1. A process for the preparation of fluacrypyrim, characterised in that it is carried out by the steps of:
(1) and (3) etherification reaction: taking (E) -2- (2' -chloromethyl) phenyl-3-methoxy methyl acrylate and 2-isopropoxy-4-hydroxy-6-trifluoromethyl pyrimidine as raw materials, adding the raw materials into a solvent DMF, and simultaneously adding K2CO3As an acid binding agent, reacting at 120-150 ℃, and obtaining a feed liquid after the reaction is finished after (E) -2- (2' -chloromethyl) phenyl-3-methoxy methyl acrylate disappears, and cooling to room temperature; the mass ratio of the (E) -2- (2' -chloromethyl) phenyl-3-methoxy methyl acrylate to the 2-isopropoxy-4-hydroxy-6-trifluoromethyl pyrimidine is 1: 1-1.5; the mass ratio of the (E) -2- (2' -chloromethyl) phenyl-3-methoxy methyl acrylate to the DMF is 1: 9-20; the (E) -2- (2' -chloromethyl) phenyl-3-methoxyacrylate methyl ester and K2CO3The mass ratio of (1) to (0.3-1.6);
(2) and (3) extracting a crude product: adding the cooled feed liquid into an alkaline aqueous solution, stirring to obtain a viscous substance, extracting, washing with water, drying, and concentrating to dryness to obtain a crude product of fluacrypyrim;
(3) refining: recrystallizing the crude fluacrypyrim to obtain a fluacrypyrim product with the purity of not less than 96%.
2. A process for the preparation of fluacrypyrim according to claim 1, wherein: the alkaline aqueous solution is a sodium hydroxide aqueous solution with the mass content of 0.5%, and the using amount of the sodium hydroxide is 10 times of the mass of the (E) -2- (2' -chloromethyl) phenyl-3-methoxy methyl acrylate.
3. A process for the preparation of fluacrypyrim according to claim 1, wherein: the extraction adopts ethyl acetate as an extractant, the addition amount of the ethyl acetate is 4 times of the mass of the (E) -2- (2' -chloromethyl) phenyl-3-methoxy methyl acrylate, and the extraction times are more than 3.
4. A process for the preparation of fluacrypyrim according to any one of claims 1 to 3, which comprises: and the recrystallization comprises the steps of adding an organic solvent into the crude fluacrypyrim, heating, dissolving, refluxing, filtering to remove insoluble substances while the solution is hot, cooling the filtrate to separate out crystals, and then carrying out suction filtration and drying on the crystals.
5. A process for the preparation of fluacrypyrim according to claim 4, wherein: the mass ratio of the (E) -2- (2' -chloromethyl) phenyl-3-methoxy methyl acrylate to the organic solvent is 1: 7-15, and the organic solvent is ethanol.
6. A process for the preparation of fluacrypyrim according to claim 4, wherein: the heating and dissolving temperature is 35 ℃ to the reflux temperature, the cooling temperature is below 25 ℃, and the cooling time is 0.5-1 h.
7. A process for the preparation of fluacrypyrim according to claim 4, wherein: the drying temperature is 80-100 ℃, and the material drying time is 2h to constant weight.
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| 嘧螨酯的合成技术与防治效果;陆阳等;《化工中间体》;20101231(第03期);第47-51页 * |
| 新型甲氧基丙烯酸酯类杀螨剂嘧螨酯;刘长令等;《世界农药》;20021231;第24卷(第4期);第30、44-45页 * |
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