CN116063200A - A kind of isoxazoline pet insecticide Freilaner intermediate and preparation method thereof - Google Patents

Abstract

The invention provides an isoxazoline pesticide fluorine Lei Lana intermediate for pets and a preparation method thereof. The method takes cheap and easily available 2, 4-dimethylbenzoate as a raw material, two brominated products are generated through bromination, the brominated products are subjected to selective amidation reaction with N, O-di-tert-butoxycarbonyl-hydroxylamine with large steric hindrance, another brominated byproduct is removed, the para-amidation product of 2, 4-dimethylbenzoate is obtained with high yield, and then the intermediate of fluorine Lei Lana is obtained through salification and ionization reactions. The method has the advantages of cheap and easily obtained raw material reagent, mild reaction condition and good operability, and is very suitable for the industrialized preparation of the efficient animal insecticide Flirana.

Description

An isoxazoline pet insecticide flurellana intermediate and its preparation method

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to an isoxazoline pet insecticide flurellan intermediate and a preparation method thereof.

Background Art

Fluralaner, a new veterinary drug, is an isoxazoline compound and a highly effective insecticide for parasites inside and outside the body of animals such as cats and dogs. Its chemical name is 4,5-[(3,5-dichlorophenyl)-4,5-dihydro-5-trifluoromethyl-3-isoxazolyl]-2-methyl-nitrogen-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-benzamide. Nissan Chemical Industries, Ltd. of Japan successfully synthesized Fluralaner. Fluralaner was applied for listing by Intervet. In 2014, the U.S. Food and Drug Administration approved Fluralaner for sale in the European and American markets (trade name Bravecto), with quarterly sales of $100 million. Fluralaner antagonizes the chloride ion channels gated by γ-aminobutyric acid receptors and glutamate receptors, preventing chloride ions from penetrating into the postsynaptic membrane, interfering with the transmembrane signal transmission of the nervous system, causing disorders in the insect nervous system and death. Compared with traditional animal insecticides such as phenylpyrazoles, cyclopentadienes and macrolides, flurellana has significant differences in molecular structure, site of action, selectivity and cross-resistance. It has few side effects on mammals and has good insecticidal activity against most agricultural pests except animal parasites. It is expected to become a new type of pesticide with huge market prospects.

There are two main methods for the synthesis of flurellanine at present. One method, as reported in patent WO2005085216/WO2009080250, uses 2-methyl-4-formaldehyde oxime benzoic acid methyl ester 1 as a raw material and uses NCS to oxidize to obtain chlorooxime compound 2; 2 then reacts with 1,3-dichloro-5-(1-trifluoromethyl-vinyl)benzene 3 to undergo 1,3 dipolar cycloaddition reaction to obtain product 4, which is then hydrolyzed and condensed with 2-amino-N-trifluoroethylacetamide 6 to obtain flurellanine 7. The reaction formula is shown in route 1:

In route 1, the raw material 2-methyl-4-formaldehyde oxime benzoic acid methyl ester 1 is not easy to prepare, resulting in extremely high production costs.

Another synthesis method is reported in patent CN113512007A, where 1-(3,5-dichlorophenyl)-trifluoroacetyl ketone 8 and 4-acetyl-2-methylbenzonitrile 9 react with a base to produce 10; 10 undergoes an elimination reaction to produce (Z)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enone)-2-methyl-benzonitrile 11, and 11 undergoes a cycloaddition reaction with hydroxylamine hydrochloride to produce product 12. After hydrolysis, it undergoes a condensation reaction with 2-amino-N-trifluoroethylacetamide 6 to produce flurellane 7. The reaction formula is shown in Scheme 2:

Route 2:

In route 2, raw materials 8 and 9 are also not easy to prepare, and this route also has the disadvantage of high cost.

Therefore, it is imperative to develop a process route for synthesizing flurana with readily available raw materials, mild reaction conditions, environmental protection and low cost.

Summary of the invention

The technical problem to be solved by the present invention is to provide a preparation method of a flurellane intermediate with mild reaction conditions, environmental protection and low cost in view of the current status of the prior art, so as to make it possible to prepare flurellane on a large scale.

The technical solution adopted by the present invention to solve the above technical problems is as follows:

The present invention provides an isoxazoline pet insecticide flurellan intermediate, the structure of which is any one of the following structural formulas:

Wherein HY is a mixture of at least one or more of hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, acetic acid, trifluoroacetic acid, formic acid, sulfuric acid, and phosphoric acid;

或者

其中Z为H、F、Cl、Br、C1～C17的饱和脂肪烃基。Wherein R is H, a C1-C17 saturated aliphatic hydrocarbon group or alicyclic hydrocarbon group,

or

Wherein Z is H, F, Cl, Br, or a C1-C17 saturated aliphatic hydrocarbon group.

The present invention provides a method for preparing the above-mentioned isoxazoline pet insecticide flurellan intermediate, and the synthetic route is as follows:

Wherein X is Cl, Br, I;

或者

其中Z为H、F、Cl、Br、C1～C17的饱和脂肪烃基；Wherein R is H, a C1-C17 saturated aliphatic hydrocarbon group or alicyclic hydrocarbon group,

or

Wherein Z is H, F, Cl, Br, or a C1-C17 saturated aliphatic hydrocarbon group;

In the formula, HY is a mixture of at least one or more of hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, acetic acid, trifluoroacetic acid, formic acid, sulfuric acid, and phosphoric acid.

The specific preparation steps of the isoxazoline pet insecticide flurellana intermediate are as follows:

Step 1, selective halogenation reaction: reacting raw material I (2,4-dimethylbenzoate), a halogenation agent and an initiator in an organic solvent to obtain intermediates I and II;

Step 2, selective amidation reaction: Intermediate I and Intermediate II are mixed, the resulting mixture is dissolved in an organic solvent, and a base is added to react with raw material II to obtain intermediate III;

Step 3, N-deprotection and salt formation reaction: reacting intermediate III with an organic solvent mixture containing HY to obtain intermediate IV;

Step 4, ionization reaction: reacting intermediate IV with a base in an organic solvent, and then filtering to obtain intermediate V.

Furthermore, in step 1, the halogenating agent includes but is not limited to at least one of elemental bromine, chlorine, N-iodosuccinimide (NIS), N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), a mixture of sodium bromide/sodium bromate/acid, and sodium iodide/sodium iodate/acid.

Furthermore, in step 1, the initiator includes but is not limited to azobisisobutyronitrile, benzoyl peroxide, tert-butyl peroxide, or a mixture of one or more of tert-butyl peroxide.

Furthermore, in step 1, the organic solvent includes but is not limited to one or more mixtures of benzene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,3-dichloroethane, acetonitrile, ethyl acetate, propyl acetate, butyl acetate, tetrahydrofuran, ether, diisopropyl ether, petroleum ether, methyl tert-butyl ether, 1,4-dioxane, and ethylene glycol dimethyl ether.

Furthermore, in step 1, the ratio of the amount of raw material I to the initiator is 100:1 to 1:0.8; the ratio of the amount of raw material I to the halogenation reagent is 10:1 to 1:10; the reaction temperature is 0 to 120° C., and the reaction time is 10 to 20 hours.

Furthermore, in step 2, in the mixture of intermediate I and intermediate II, only intermediate I and the bulky steric hindrance raw material II undergo selective amidation reaction.

Further, in step 2, the base includes but is not limited to sodium hydroxide, potassium hydroxide, cesium hydroxide, potassium acetate, sodium acetate, cesium acetate, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, potassium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium bicarbonate, sodium bicarbonate, sodium phosphate, potassium fluoride, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, triethylamine, pyridine, diisopropylethylamine and one or more mixtures of N-methylmorpholine.

Furthermore, in step 2, the organic solvent includes but is not limited to at least one of benzene, toluene, o-xylene, p-xylene, 2,4,6-trimethylbenzene, chlorobenzene, fluorobenzene, dichloromethane, dichloroethane, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, methyl acetate, propyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, tetrahydrofuran, ether, 1,4-dioxane, hexafluoroisopropanol, and 1-methyl 2-pyrrolidone.

Furthermore, in step 2, the mass ratio of the mixture of intermediate I and intermediate II to the base is 100:1 to 1:100; the reaction temperature is -20 to 120° C., and the reaction time is 8 to 12 hours.

Furthermore, in step three, the organic solvent includes but is not limited to at least one of benzene, toluene, o-xylene, p-xylene, 2,4,6-trimethylbenzene, chlorobenzene, fluorobenzene, dichloromethane, dichloroethane, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, methyl acetate, propyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, tetrahydrofuran, ether, 1,4-dioxane, hexafluoroisopropanol, and 1-methyl 2-pyrrolidone.

Furthermore, in step 3, the molar ratio of the intermediate III to HY is 100:1 to 1:100. The reaction temperature is -20 to 120°C, and the reaction time is 2 to 6 hours.

Furthermore, in step 4, the base includes but is not limited to one or more mixtures of sodium hydroxide, potassium hydroxide, cesium hydroxide, potassium acetate, sodium acetate, cesium acetate, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, potassium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium bicarbonate, sodium bicarbonate, sodium phosphate, potassium fluoride, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, triethylamine, pyridine, diisopropylethylamine and N-methylmorpholine.

Furthermore, in step 4, the organic solvent includes but is not limited to at least one of benzene, toluene, o-xylene, p-xylene, 2,4,6-trimethylbenzene, chlorobenzene, fluorobenzene, dichloromethane, dichloroethane, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, methyl acetate, propyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, tetrahydrofuran, ether, 1,4-dioxane, hexafluoroisopropanol, and 1-methyl 2-pyrrolidone.

Furthermore, in step 4, the molar ratio of the intermediate IV to the base is 100:1 to 1:100. The reaction temperature is -20 to 120°C, and the reaction time is 4 to 8 hours.

(原料II)发生选择性酰胺化反应，因邻位溴代产物即中间体Ⅱ分子中靠近反应中心的酯基占据一定的空间位置，从而影响分子反应活性的效应，使得N,O-二叔丁氧羰基-羟胺与中间体Ⅰ反应的选择性增大，在反应完成后用石油醚和乙酸乙酯(4:1)作展开剂进行简单的柱层析处理，较高收率得到2,4-二甲基苯甲酸酯对位酰胺化产物。The present invention uses cheap and readily available 2,4-dimethylbenzoate as a raw material, undergoes bromination, and the bromination product is then reacted with a large sterically hindered N,O-di-tert-butyloxycarbonyl-hydroxylamine.

(Raw material II) undergoes a selective amidation reaction, because the ortho-brominated product, i.e., the ester group close to the reaction center in the intermediate II molecule occupies a certain spatial position, thereby affecting the molecular reactivity, thereby increasing the selectivity of the reaction between N,O-di-tert-butyloxycarbonyl-hydroxylamine and intermediate I. After the reaction is completed, a simple column chromatography treatment is performed using petroleum ether and ethyl acetate (4:1) as a developing solvent, and a para-amidation product of 2,4-dimethylbenzoate is obtained in a high yield.

Compared with the prior art, the present invention has the following advantages and beneficial effects:

The invention provides a method for preparing an isoxazoline pet insecticide flurella intermediate, which is different from the prior art flurella synthesis route that requires the addition of expensive reactants. The preparation method of the invention has the advantages of mild and safe reaction process, green and environmental protection, cheap and easy-to-obtain raw materials, and a high yield of the product, and provides a simple and convenient preparation route for obtaining a highly effective animal insecticide flurella, and has certain industrial application prospects and good economic benefits.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a hydrogen nuclear magnetic resonance spectrum of the raw material 2,4-dimethylbenzoate of Example 1;

FIG2 is a hydrogen nuclear magnetic resonance spectrum of the intermediate I obtained in step (1) of Example 1;

FIG3 is a hydrogen nuclear magnetic resonance spectrum of the intermediate II obtained in step (1) of Example 1;

FIG4 is a hydrogen nuclear magnetic resonance spectrum of the intermediate III obtained in step (2) of Example 1;

FIG5 is a hydrogen nuclear magnetic resonance spectrum of the intermediate IV obtained in step (3) of Example 1;

FIG6 is a hydrogen nuclear magnetic resonance spectrum of intermediate V obtained in step (4) of Example 1.

Specific embodiment

The present invention is further described in detail below in conjunction with the examples, but the embodiments of the present invention are not limited thereto. It should be noted that if there are processes that are not particularly described in detail below, they can be implemented or understood by those skilled in the art with reference to the prior art. If the manufacturer of the reagents or instruments used is not indicated, they are deemed to be conventional products that can be purchased commercially.

Example 1

The preparation method of the fluororana intermediate in this embodiment comprises the following steps:

Step (1): Add methyl 2,4-dimethylbenzoate (16.4 g, 0.1 mol) to a 500 mL three-necked flask, then add N-bromosuccinimide (NBS, 35.2 g, 0.2 mol), azobisisobutyronitrile (1.64 g, 0.01 mol) and chloroform (200 mL), and heat to 65° C. and reflux for 12 hours under a nitrogen atmosphere. After the reactant is cooled to room temperature, the solid is filtered out, and the filtrate is distilled under reduced pressure to remove the solvent to obtain a crude product that is directly used in the next step.

(17.6g，10mmol)，K₂CO₃(13.8g，0.1mol)和THF(200mL)，反应混合物在室温下反应11小时。反应完后过滤除去固体，滤液减压蒸馏脱除溶剂后得油状物直接用于下一步。Step (2): Add the oil prepared in step (1) and

(17.6 g, 10 mmol), K ₂ CO ₃ (13.8 g, 0.1 mol) and THF (200 mL), the reaction mixture was reacted at room temperature for 11 hours. After the reaction, the solid was removed by filtration, and the filtrate was distilled under reduced pressure to remove the solvent to obtain an oily product which was directly used in the next step.

Step (3): The oily substance obtained in step (2) was mixed with an ethyl acetate solution (200 mL) containing saturated HCl gas and stirred at 30° C. for 2 hours to obtain a solid. The solid was then filtered and dried under reduced pressure at room temperature to obtain a solid intermediate IV (14.35 g).

Step (4): Add the solid obtained in step (3), potassium carbonate (13.8 g, 0.1 mol) and dichloromethane (200 mL) into a 500 mL three-necked flask and stir at room temperature for 6 hours. After the reaction is completed, filter to remove the solid, and distill the filtrate under reduced pressure to remove the solvent to obtain an oily intermediate V (12.09 g). The total yield of the four steps is 61.9%.

Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the raw material methyl 2,4-dimethylbenzoate in step (1) of this embodiment, ¹ H NMR (400 MHz, Chloroform-d) δ7.85 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 7.7 Hz, 2H), 3.89 (s, 3H), 2.60 (s, 3H), 2.37 (s, 3H).

Figure 2 is a hydrogen nuclear magnetic resonance spectrum of the intermediate I obtained in step (1) of this example, ¹ H NMR (400 MHz, Chloroform-d) δ7.96–7.86 (m, 1H), 7.28 (dd, J＝5.9, 2.3 Hz, 2H), 4.47 (s, 2H), 3.91 (s, 3H), 2.62 (s, 3H).

Figure 3 is a hydrogen nuclear magnetic resonance spectrum of the intermediate II obtained in step (1) of this example, ¹ H NMR (400 MHz, Chloroform-d) δ7.90 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 1.5 Hz, 1H), 7.19 (dd, J = 8.0, 1.8 Hz, 1H), 4.96 (s, 2H), 3.94 (s, 3H), 2.40 (s, 3H).

FIG4 is a hydrogen nuclear magnetic resonance spectrum of the intermediate III obtained in step (2) of this example, ¹ H NMR (400 MHz, DMSO-d6) δ7.86–7.78 (m, 1H), 7.22 (d, J = 6.8 Hz, 2H), 4.74 (s, 2H), 3.82 (s, 3H), 2.50 (s, 4H), 1.42 (d, J = 1.5 Hz, 18H)

Figure 5 is a hydrogen nuclear magnetic resonance spectrum of the intermediate IV obtained in step (3) of this example, ¹ H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 11.02 (s, 0H), 10.42 (s, 1H), 7.82 (d, J = 8.0 Hz, 0H), 7.57–7.47 (m, 1H), 4.32 (s, 1H), 3.83 (s, 1H), 2.51 (s, 2H).

Figure 6 is a hydrogen nuclear magnetic resonance spectrum of the intermediate V obtained in step (4) of this example, ¹ H NMR (400 MHz, Chloroform-d) δ7.91 (d, J = 8.4 Hz, 1H), 7.26-7.19 (m, 2H), 4.03 (s, 2H), 3.90 (s, 3H).

Example 2

The preparation method of the fluororana intermediate in this embodiment comprises the following steps:

Step (1): Add ethyl 2,4-dimethylbenzoate (17.8 g, 0.1 mol) to a 500 mL three-necked flask, then add N-bromosuccinimide (NBS, 35.2 g, 0.2 mol), azobisisobutyronitrile (1.64 g, 0.01 mol) and chloroform (200 mL), and heat to 65°C under nitrogen atmosphere and reflux for 12 hours. After the reactant is cooled to room temperature, the solid is filtered out, and the filtrate is distilled under reduced pressure to remove the solvent to obtain a crude product that is directly used in the next step.

(17.6g，10mmol)，三乙胺(10.12g，0.1mol)和THF(200mL)，反应混合物在室温下反应11小时。反应完后过滤除去固体，滤液减压蒸馏脱除溶剂后得油状物直接用于下一步。Step (2): Add the oil prepared in step (1) and

(17.6 g, 10 mmol), triethylamine (10.12 g, 0.1 mol) and THF (200 mL), the reaction mixture was reacted at room temperature for 11 hours. After the reaction was completed, the solid was removed by filtration, and the filtrate was distilled under reduced pressure to remove the solvent to obtain an oily product which was directly used in the next step.

Step (3): The oily substance obtained in step (2) was mixed with an ethyl acetate solution (200 mL) containing saturated HCl gas and stirred at 30° C. for 2 hours to obtain a solid. The solid was then filtered and dried under reduced pressure at room temperature to obtain a solid intermediate IV (13.82 g).

Step (4): Add the solid obtained in step (3), potassium carbonate (13.8 g, 0.1 mol) and dichloromethane (200 mL) into a 500 mL three-necked flask and stir at 40° C. for 6 hours. After the reaction is completed, filter to remove the solid, and distill the filtrate under reduced pressure to remove the solvent to obtain an oily intermediate V (12.14 g). The total yield of the four steps is 62.2%.

Example 3

The preparation method of the fluororana intermediate in this embodiment comprises the following steps:

Step (1): Add 2,4-dimethylbenzoic acid n-propyl ester (19.2 g, 0.1 mol) to a 500 mL three-necked flask, then add N-bromosuccinimide (NBS, 35.2 g, 0.2 mol), azobisisobutyronitrile (1.64 g, 0.01 mol) and chloroform (200 mL), and heat to 65° C. and reflux for 12 hours under a nitrogen atmosphere. After the reactant is cooled to room temperature, the solid is filtered out, and the filtrate is distilled under reduced pressure to remove the solvent to obtain a crude product that is directly used in the next step.

(17.6g，10mmol)，CH₃COONa(8.20g，0.1mol)和二氯乙烷(200mL)，反应混合物在室温下反应11小时。反应完后过滤除去固体，滤液减压蒸馏脱除溶剂后得油状物直接用于下一步。Step (2): Add the oil prepared in step (1) and

(17.6 g, 10 mmol), CH ₃ COONa (8.20 g, 0.1 mol) and dichloroethane (200 mL), the reaction mixture was reacted at room temperature for 11 hours. After the reaction, the solid was removed by filtration, and the filtrate was distilled under reduced pressure to remove the solvent to obtain an oily product which was directly used in the next step.

Step (3): The oily substance obtained in step (2) was mixed with an ethyl acetate solution (200 mL) containing saturated HCl gas and stirred at 30° C. for 2 hours to obtain a solid. The solid was then filtered and dried under reduced pressure at room temperature to obtain a solid intermediate IV (14.90 g).

Step (4): Add the solid obtained in step (3), potassium carbonate (13.8 g, 0.1 mol) and dichloromethane (200 mL) into a 500 mL three-necked flask and stir at 60° C. for 6 hours. After the reaction is completed, the solid is filtered out, and the filtrate is distilled under reduced pressure to remove the solvent to obtain an oily intermediate V (13.00 g). The total yield of the four steps is 66.7%.

Example 4

The preparation method of the fluororana intermediate in this embodiment comprises the following steps:

Step (1): Add isobutyl 2,4-dimethylbenzoate (20.6 g, 0.1 mol) to a 500 mL three-necked flask, then add N-bromosuccinimide (NBS, 35.2 g, 0.2 mol), azobisisobutyronitrile (1.64 g, 0.01 mol) and chloroform (200 mL), and heat to 65° C. and reflux for 12 hours under a nitrogen atmosphere. After the reactant is cooled to room temperature, the solid is filtered out, and the filtrate is distilled under reduced pressure to remove the solvent to obtain a crude product that is directly used in the next step.

(17.6g，10mmol)，K₂CO₃(13.8g，0.1mol)和二氯甲烷(200mL)，反应混合物在室温下反应10小时。反应完后过滤除去固体，滤液减压蒸馏脱除溶剂后得油状物直接用于下一步。Step (2): Add the oil prepared in step (1) and

(17.6 g, 10 mmol), K ₂ CO ₃ (13.8 g, 0.1 mol) and dichloromethane (200 mL), the reaction mixture was reacted at room temperature for 10 hours. After the reaction, the solid was removed by filtration, and the filtrate was distilled under reduced pressure to remove the solvent to obtain an oily product which was directly used in the next step.

Step (3): The oily substance obtained in step (2) was mixed with an ethyl acetate solution (200 mL) containing saturated HCl gas and stirred at 30° C. for 2 hours to obtain a solid. The solid was then filtered and dried under reduced pressure at room temperature to obtain a solid intermediate IV (15.98 g).

Step (4): Add the solid obtained in step (3), potassium carbonate (13.8 g, 0.1 mol) and 1,2-dichloroethane (200 mL) into a 500 mL three-necked flask and stir at 80°C for 6 hours. After the reaction is completed, filter to remove the solid, and distill the filtrate under reduced pressure to remove the solvent to obtain an oily intermediate V (14.21 g). The total yield of the four steps is 72.3%.

Example 5

The preparation method of the fluororana intermediate in this embodiment comprises the following steps:

Step (1): Add methyl 2,4-dimethylbenzoate (16.4 g, 0.1 mol) to a 500 mL three-necked flask, then add N-chlorosuccinimide (NCS, 26.4 g, 0.2 mol), azobisisobutyronitrile (1.64 g, 0.01 mol) and chloroform (200 mL), and heat to 65°C under nitrogen atmosphere and reflux for 10 hours. After the reactant is cooled to room temperature, the solid is filtered out, and the filtrate is distilled under reduced pressure to remove the solvent to obtain a crude product that is directly used in the next step.

(17.6g，10mmol)，叔丁醇钠(9.61g，0.1mol)和THF(200mL)，反应混合物在室温下反应10小时。反应完后过滤除去固体，滤液减压蒸馏脱除溶剂后得油状物直接用于下一步。Step (2): Add the oil prepared in step (1) and

(17.6 g, 10 mmol), sodium tert-butoxide (9.61 g, 0.1 mol) and THF (200 mL), the reaction mixture was reacted at room temperature for 10 hours. After the reaction was completed, the solid was removed by filtration, and the filtrate was distilled under reduced pressure to remove the solvent to obtain an oily product which was directly used in the next step.

Step (3): The oily substance obtained in step (2) was mixed with a dichloromethane solution (200 mL) containing saturated HCl gas and stirred at 30° C. for 2 hours to obtain a solid. The solid was then filtered and dried under reduced pressure at room temperature to obtain a solid intermediate IV (14.08 g).

Step (4): Add the solid obtained in step (3), potassium carbonate (13.8 g, 0.1 mol) and dichloromethane (200 mL) into a 500 mL three-necked flask and stir at room temperature for 6 hours. After the reaction is completed, filter to remove the solid, and distill the filtrate under reduced pressure to remove the solvent to obtain an oily intermediate V (11.88 g). The total yield of the four steps is 60.9%.

Example 6

The preparation method of the fluororana intermediate in this embodiment comprises the following steps:

Step (1): Add methyl 2,4-dimethylbenzoate (16.4 g, 0.1 mol) to a 500 mL three-necked flask, then add N-chlorosuccinimide (NCS, 26.4 g, 0.2 mol), benzoyl peroxide (2.42 g, 0.01 mol) and chloroform (200 mL), and heat to 65° C. and reflux for 13 hours under a nitrogen atmosphere. After the reactant is cooled to room temperature, the solid is filtered out, and the filtrate is distilled under reduced pressure to remove the solvent to obtain a crude product that is directly used in the next step.

(17.6g，10mmol)，K₂CO₃(13.8g，0.1mol)和THF(200mL)，反应混合物在室温下反应10小时。反应完后过滤除去固体，滤液减压蒸馏脱除溶剂后得油状物直接用于下一步。Step (2): Add the oil prepared in step (1) and

(17.6 g, 10 mmol), K ₂ CO ₃ (13.8 g, 0.1 mol) and THF (200 mL), the reaction mixture was reacted at room temperature for 10 hours. After the reaction, the solid was removed by filtration, and the filtrate was distilled under reduced pressure to remove the solvent to obtain an oily product which was directly used in the next step.

Step (3): The oily substance obtained in step (2) was mixed with an ethyl acetate solution (200 mL) containing saturated HCl gas and stirred at 10° C. for 3 hours to obtain a solid. The solid was then filtered and dried under reduced pressure at room temperature to obtain a solid intermediate IV (13.90 g).

Step (4): Add the solid obtained in step (3), sodium carbonate (10.6 g, 0.1 mol) and dichloromethane (200 mL) into a 500 mL three-necked flask and stir at room temperature for 6 hours. After the reaction is completed, filter to remove the solid, and distill the filtrate under reduced pressure to remove the solvent to obtain an oily intermediate V (11.95 g). The total yield of the four steps is 61.3%.

Example 7

The preparation method of the fluororana intermediate in this embodiment comprises the following steps:

Step (1): Add methyl 2,4-dimethylbenzoate (16.4 g, 0.1 mol) to a 500 mL three-necked flask, then add N-bromosuccinimide (NBS, 35.2 g, 0.2 mol), azobisisobutyronitrile (1.64 g, 0.01 mol) and 1,2-dichloroethane (200 mL), and stir at 0°C for 20 hours under a nitrogen atmosphere. After the reactant is cooled to room temperature, the solid is filtered out, and the filtrate is distilled under reduced pressure to remove the solvent to obtain a crude product that is directly used in the next step.

(17.6g，10mmol)，K₂CO₃(13.8g，0.1mol)和THF(200mL)，反应混合物在室温下反应10小时。反应完后过滤除去固体，滤液减压蒸馏脱除溶剂后得油状物直接用于下一步。Step (2): Add the oil prepared in step (1) and

(17.6 g, 10 mmol), K ₂ CO ₃ (13.8 g, 0.1 mol) and THF (200 mL), the reaction mixture was reacted at room temperature for 10 hours. After the reaction, the solid was removed by filtration, and the filtrate was distilled under reduced pressure to remove the solvent to obtain an oily product which was directly used in the next step.

Step (3): The oily substance obtained in step (2) was mixed with an ethyl acetate solution (200 mL) containing saturated HCl gas and stirred at 60° C. for 2 hours to obtain a solid. The solid was then filtered and dried under reduced pressure at room temperature to obtain a solid intermediate IV (13.85 g).

Step (4): Add the solid obtained in step (3), NaOH (4.0 g, 0.1 mol) and dichloromethane (200 mL) into a 500 mL three-necked flask and stir at room temperature for 6 hours. After the reaction is completed, filter to remove the solid, and distill the filtrate under reduced pressure to remove the solvent to obtain an oily intermediate V (9.92 g). The total yield of the four steps is 50.9%.

Example 8

The preparation method of the fluororana intermediate in this embodiment comprises the following steps:

Step (1): Add methyl 2,4-dimethylbenzoate (16.4 g, 0.1 mol) to a 500 mL three-necked flask, then add N-bromosuccinimide (NBS, 35.2 g, 0.2 mol), azobisisobutyronitrile (1.64 g, 0.01 mol) and 1,2-dichloroethane (200 mL), and heat to 110° C. and reflux for 12 hours under a nitrogen atmosphere. After the reactant is cooled to room temperature, the solid is filtered out, and the filtrate is distilled under reduced pressure to remove the solvent to obtain a crude product that is directly used in the next step.

(17.6g，10mmol)，NaOH(4g，0.1mol)和THF(200mL)，反应混合物在室温下反应10小时。反应完后过滤除去固体，滤液减压蒸馏脱除溶剂后得油状物直接用于下一步。Step (2): Add the oil prepared in step (1) and

(17.6 g, 10 mmol), NaOH (4 g, 0.1 mol) and THF (200 mL), the reaction mixture was reacted at room temperature for 10 hours. After the reaction was completed, the solid was removed by filtration, and the filtrate was distilled under reduced pressure to remove the solvent to obtain an oily product which was directly used in the next step.

Step (3): The oily substance obtained in step (2) was mixed with an ethyl acetate solution (200 mL) containing saturated HCl gas and stirred at 70° C. for 4 hours to obtain a solid. The solid was then filtered and dried under reduced pressure at room temperature to obtain a solid intermediate IV (13.67 g).

Step (4): Add the solid obtained in step (3), potassium tert-butoxide (9.61 g, 0.1 mol) and dichloromethane (200 mL) into a 500 mL three-necked flask and stir at room temperature for 6 hours. After the reaction is completed, filter to remove the solid, and distill the filtrate under reduced pressure to remove the solvent to obtain an oily intermediate V (11.72 g). The total yield of the four steps is 60.1%.

Example 9

The preparation method of the fluororana intermediate in this embodiment comprises the following steps:

Step (1): Add methyl 2,4-dimethylbenzoate (16.4 g, 0.1 mol) to a 500 mL three-necked flask, then add N-bromosuccinimide (NBS, 35.2 g, 0.2 mol), azobisisobutyronitrile (1.64 g, 0.01 mol) and chloroform (200 mL), and heat to 65° C. and reflux for 12 hours under a nitrogen atmosphere. After the reactant is cooled to room temperature, the solid is filtered out, and the filtrate is distilled under reduced pressure to remove the solvent to obtain a crude product that is directly used in the next step.

(17.6g，10mmol)，K₂CO₃(13.8g，0.1mol)和THF(200mL)，反应混合物在室温下反应10小时。反应完后过滤除去固体，滤液减压蒸馏脱除溶剂后得油状物直接用于下一步。Step (2): Add the oil prepared in step (1) and

(17.6 g, 10 mmol), K ₂ CO ₃ (13.8 g, 0.1 mol) and THF (200 mL), the reaction mixture was reacted at room temperature for 10 hours. After the reaction, the solid was removed by filtration, and the filtrate was distilled under reduced pressure to remove the solvent to obtain an oily product which was directly used in the next step.

Step (3): The oily substance of step (2) was mixed with an ethyl acetate solution (200 mL) containing trifluoroacetic acid (22.8 g, 0.2 mol) and stirred at 100° C. for 4 hours to obtain a solid. The solid was then filtered and dried under reduced pressure at room temperature to obtain a solid intermediate IV (15.46 g).

Step (4): Add the solid obtained in step (3), sodium phosphate (16.4 g, 0.1 mol) and dichloromethane (200 mL) into a 500 mL three-necked flask and stir at room temperature for 6 hours. After the reaction is completed, filter to remove the solid, and distill the filtrate under reduced pressure to remove the solvent to obtain an oily intermediate V (11.85 g). The total yield of the four steps is 60.7%.

Example 10

The preparation method of the fluororana intermediate in this embodiment comprises the following steps:

Step (1): Add methyl 2,4-dimethylbenzoate (16.4 g, 0.1 mol) to a 500 mL three-necked flask, then add N-bromosuccinimide (NBS, 35.2 g, 0.2 mol), azobisisobutyronitrile (1.64 g, 0.01 mol) and 1,2-dichloroethane (200 mL), and heat to 65° C. and reflux for 12 hours under a nitrogen atmosphere. After the reactant is cooled to room temperature, the solid is filtered out, and the filtrate is distilled under reduced pressure to remove the solvent to obtain a crude product that is directly used in the next step.

(17.6g，10mmol)，K₂CO₃(13.8g，0.1mol)和THF(200mL)，反应混合物在室温下反应10小时。反应完后过滤除去固体，滤液减压蒸馏脱除溶剂后得油状物直接用于下一步。Step (2): Add the oil prepared in step (1) and

(17.6 g, 10 mmol), K ₂ CO ₃ (13.8 g, 0.1 mol) and THF (200 mL), the reaction mixture was reacted at room temperature for 10 hours. After the reaction, the solid was removed by filtration, and the filtrate was distilled under reduced pressure to remove the solvent to obtain an oily product which was directly used in the next step.

Step (3): The oily substance of step (2) was mixed with an ether solution (200 mL) containing trifluoroacetic acid (22.8 g, 0.2 mol) and stirred at 40° C. for 6 hours to obtain a solid. The solid was then filtered and dried under reduced pressure at room temperature to obtain a solid intermediate IV (15.25 g).

Step (4): Add the solid obtained in step (3), potassium carbonate (13.8 g, 0.1 mol) and 1,4-dioxane (200 mL) into a 500 mL three-necked flask and stir at 10 degrees Celsius for 8 hours. After the reaction is completed, filter to remove the solid, and distill the filtrate under reduced pressure to remove the solvent to obtain an oily intermediate V (12.01 g). The total yield of the four steps is 61.6%.

Embodiment 11

The preparation method of the fluororana intermediate in this embodiment comprises the following steps:

Step (1): Add methyl 2,4-dimethylbenzoate (16.4 g, 0.1 mol) to a 500 mL three-necked flask, then add N-bromosuccinimide (NBS, 35.2 g, 0.2 mol), azobisisobutyronitrile (1.64 g, 0.01 mol) and ethyl acetate (200 mL), and heat to 30° C. and reflux for 14 hours under a nitrogen atmosphere. After the reactant is cooled to room temperature, the solid is filtered out, and the filtrate is distilled under reduced pressure to remove the solvent to obtain a crude product that is directly used in the next step.

(17.6g，10mmol)，K₂CO₃(13.8g，0.1mol)和1,4-二氧六环(200mL)，反应混合物在室温下反应8小时。反应完后过滤除去固体，滤液减压蒸馏脱除溶剂后得油状物直接用于下一步。Step (2): Add the oil prepared in step (1) and

(17.6 g, 10 mmol), K ₂ CO ₃ (13.8 g, 0.1 mol) and 1,4-dioxane (200 mL), the reaction mixture was reacted at room temperature for 8 hours. After the reaction, the solid was removed by filtration, and the filtrate was distilled under reduced pressure to remove the solvent to obtain an oily product which was directly used in the next step.

Step (3): The oily substance obtained in step (2) was mixed with an ethyl acetate solution (200 mL) containing saturated HCl gas and stirred at 10° C. for 2 hours to obtain a solid. The solid was then filtered and dried under reduced pressure at room temperature to obtain a solid intermediate IV (13.68 g).

Step (4): Add the solid obtained in step (3), sodium carbonate (10.6 g, 0.1 mol) and dichloromethane (200 mL) into a 500 mL three-necked flask and stir at room temperature for 4 hours. After the reaction is completed, filter to remove the solid, and distill the filtrate under reduced pressure to remove the solvent to obtain an oily intermediate V (10.85 g). The total yield of the four steps is 55.6%.

Example 12

The preparation method of the fluororana intermediate in this embodiment comprises the following steps:

Step (1): Add methyl 2,4-dimethylbenzoate (16.4 g, 0.1 mol) to a 500 mL three-necked flask, then add N-bromosuccinimide (NBS, 35.2 g, 0.2 mol), azobisisobutyronitrile (1.64 g, 0.01 mol) and dichloromethane (200 mL), and react at 10° C. for 20 h under a nitrogen atmosphere. After the reactant is cooled to room temperature, the solid is filtered out, and the filtrate is distilled under reduced pressure to remove the solvent to obtain a crude product, which is directly used in the next step.

(17.6g，10mmol)，K₂CO₃(13.8g，0.1mol)和THF(200mL)，反应混合物在室温下反应10小时。反应完后过滤除去固体，滤液减压蒸馏脱除溶剂后得油状物直接用于下一步。Step (2): Add the oil prepared in step (1) and

(17.6 g, 10 mmol), K ₂ CO ₃ (13.8 g, 0.1 mol) and THF (200 mL), the reaction mixture was reacted at room temperature for 10 hours. After the reaction, the solid was removed by filtration, and the filtrate was distilled under reduced pressure to remove the solvent to obtain an oily product which was directly used in the next step.

Step (3): The oily substance obtained in step (2) was mixed with an ethyl acetate solution (200 mL) containing saturated HCl gas and stirred at 100° C. for 4 hours to obtain a solid. The solid was then filtered and dried under reduced pressure at room temperature to obtain a solid intermediate IV (13.68 g).

Step (4): Add the solid obtained in step (3), sodium carbonate (10.6 g, 0.1 mol) and tetrahydrofuran (200 mL) into a 500 mL three-necked flask and stir at room temperature for 6 hours. After the reaction is completed, filter to remove the solid, and distill the filtrate under reduced pressure to remove the solvent to obtain an oily intermediate V (11.67 g). The total yield of the four steps is 59.8%.

Example 13

The preparation method of the fluororana intermediate in this embodiment comprises the following steps:

Step (1): Add 2,4-dimethylbenzoate (29.04 g, 0.1 mol) to a 500 mL three-necked flask, then add N-bromosuccinimide (NBS, 35.6 g, 0.2 mol), azobisisobutyronitrile (1.64 g, 0.01 mol) and chloroform (200 mL), and heat to 65° C. and reflux for 14 hours under a nitrogen atmosphere. After the reactant is cooled to room temperature, the solid is filtered out, and the filtrate is distilled under reduced pressure to remove the solvent to obtain a crude product that is directly used in the next step.

(17.6g，10mmol)，K₂CO₃(13.8g，0.1mol)和THF(200mL)，反应混合物在室温下反应10小时。反应完后过滤除去固体，滤液减压蒸馏脱除溶剂后得油状物直接用于下一步。Step (2): Add the oil prepared in step (1) and

(17.6 g, 10 mmol), K ₂ CO ₃ (13.8 g, 0.1 mol) and THF (200 mL), the reaction mixture was reacted at room temperature for 10 hours. After the reaction, the solid was removed by filtration, and the filtrate was distilled under reduced pressure to remove the solvent to obtain an oily product which was directly used in the next step.

Step (3): The oily substance obtained in step (2) was mixed with an ethyl acetate solution (200 mL) containing saturated HCl gas and stirred at -10°C for 2 hours to obtain a solid. The solid was then filtered and dried under reduced pressure at room temperature to obtain a solid intermediate IV (24.51 g).

Step (4): Add the solid obtained in step (3), sodium carbonate (10.6 g, 0.1 mol) and tetrahydrofuran (200 mL) into a 500 mL three-necked flask and stir at 50° C. for 6 hours. After the reaction is completed, filter to remove the solid, and distill the filtrate under reduced pressure to remove the solvent to obtain an oily intermediate V (22.67 g). The total yield of the four steps is 70.5%.

The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims (10)

1. The isoxazoline pesticide fluorine Lei Lana intermediate for pets is characterized in that the intermediate has any one of the following structural formulas:

wherein HY is at least one or a mixture of more of hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, acetic acid, trifluoroacetic acid, formic acid, sulfuric acid and phosphoric acid;

wherein R is H, saturated aliphatic hydrocarbon radicals of C1-C17, alicyclic hydrocarbon radicals,

or->

Wherein Z is a saturated aliphatic hydrocarbon group of H, F, cl, br, C to C17.

2. The method for preparing the isoxazoline insecticide fluorine Lei Lana intermediate for pets according to claim 1, which is characterized in that the synthetic route is as follows:

wherein X is Cl, br or I;

wherein R is H, saturated aliphatic hydrocarbon radicals of C1-C17, alicyclic hydrocarbon radicals,

or->

Wherein Z is a saturated aliphatic hydrocarbon group of H, F, cl, br, C to C17;

wherein HY is at least one or a mixture of more of hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, acetic acid, trifluoroacetic acid, formic acid, sulfuric acid and phosphoric acid;

the preparation method comprises the following specific steps:

step one, selective halogenation reaction: reacting the raw material I, a halogenated reagent and an initiator in an organic solvent to obtain an intermediate I and an intermediate II;

step two, selective amidation reaction: mixing the intermediate I and the intermediate II, dissolving the obtained mixture in an organic solvent, and then adding alkali and a raw material II for full reaction to obtain an intermediate III;

step three, N-deprotection and salification reaction: reacting the intermediate III with an organic solvent mixture containing HY to obtain an intermediate IV;

step four, ionization reaction: intermediate IV is reacted with a base in an organic solvent and then filtered to give intermediate V.

3. The method for preparing the isoxazoline pet insecticide fluoride Lei Lana intermediate according to claim 2, wherein in the first step, the halogenated reagent comprises at least one of elemental bromine, chlorine, N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide, sodium bromide/sodium bromate/acid, and a mixture of sodium iodide/sodium iodate/acid; the initiator comprises one or a mixture of more of azodiisobutyronitrile, benzoyl peroxide, tert-butyl peroxide and tert-butyl peroxide; the organic solvent comprises one or more of benzene, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, 1, 3-dichloroethane, acetonitrile, ethyl acetate, propyl acetate, butyl acetate, tetrahydrofuran, diethyl ether, diisopropyl ether, petroleum ether, methyl tertiary butyl ether, 1, 4-dioxane and ethylene glycol dimethyl ether.

4. The method for preparing the isoxazoline insecticide fluorine Lei Lana intermediate for pets according to claim 2, wherein in the first step, the ratio of the amount of the raw material I to the amount of the initiator is 100:1-1:0.8; the ratio of the raw material I to the halogenated agent is 10:1-1:10; the reaction temperature is 0-120 ℃, and the reaction time is 10-20 h.

5. The method for preparing the isoxazoline pet insecticide fluoride Lei Lana intermediate according to claim 2, wherein in the second step, the base comprises one or more of sodium hydroxide, potassium hydroxide, cesium hydroxide, potassium acetate, sodium acetate, cesium acetate, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, potassium t-butoxide, sodium t-butoxide, potassium hydrogen carbonate, sodium phosphate, potassium fluoride, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, triethylamine, pyridine, diisopropylethylamine, and N-methylmorpholine; the organic solvent comprises at least one of benzene, toluene, o-xylene, p-xylene, 2,4, 6-trimethylbenzene, chlorobenzene, fluorobenzene, dichloromethane, dichloroethane, acetonitrile, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, methyl acetate, propyl acetate, N-butyl acetate, isobutyl acetate, tert-butyl acetate, tetrahydrofuran, diethyl ether, 1, 4-dioxane, hexafluoroisopropanol and 1-methyl-2-pyrrolidone.

6. The method for preparing the isoxazoline insecticide fluorine Lei Lana intermediate for pets according to claim 2, wherein in the second step, the mass ratio of the mixture of the intermediate I and the intermediate II to the alkali is 100:1-1:100; the reaction temperature is between 20 ℃ below zero and 120 ℃ and the reaction time is between 8 and 12 hours.

7. The method for preparing the intermediate of the isoxazoline pet insecticide fluorine Lei Lana according to claim 2, wherein in the third step, the organic solvent comprises at least one of benzene, toluene, o-xylene, p-xylene, 2,4, 6-trimethylbenzene, chlorobenzene, fluorobenzene, methylene chloride, dichloroethane, acetonitrile, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, methyl acetate, propyl acetate, N-butyl acetate, isobutyl acetate, t-butyl acetate, tetrahydrofuran, diethyl ether, 1, 4-dioxane, hexafluoroisopropanol, and 1-methyl-2-pyrrolidone.

8. The method for preparing the isoxazoline insecticide fluorine Lei Lana intermediate for pets according to claim 2, wherein in the third step, the ratio of the amount of the intermediate III to the amount of the HY is 100:1-1:100; the reaction temperature is between-20 and 120 ℃ and the reaction time is between 2 and 6 hours.

9. The method for preparing the isoxazoline pet insecticide fluoride Lei Lana intermediate according to claim 2, wherein in the fourth step, the base comprises one or more of sodium hydroxide, potassium hydroxide, cesium hydroxide, potassium acetate, sodium acetate, cesium acetate, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, potassium t-butoxide, sodium t-butoxide, potassium hydrogen carbonate, sodium phosphate, potassium fluoride, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, triethylamine, pyridine, diisopropylethylamine, and N-methylmorpholine; the organic solvent comprises at least one of benzene, toluene, o-xylene, p-xylene, 2,4, 6-trimethylbenzene, chlorobenzene, fluorobenzene, dichloromethane, dichloroethane, acetonitrile, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, methyl acetate, propyl acetate, N-butyl acetate, isobutyl acetate, tert-butyl acetate, tetrahydrofuran, diethyl ether, 1, 4-dioxane, hexafluoroisopropanol and 1-methyl-2-pyrrolidone.

10. The method for preparing an isoxazoline insecticide fluorine Lei Lana intermediate for pets according to any of claims 2 to 9, wherein in the fourth step, the ratio of the amount of the intermediate IV to the amount of the base substance is 100:1 to 1:100; the reaction temperature is between-20 and 120 ℃ and the reaction time is between 4 and 8 hours.

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