CN110028462B - Method for preparing isoxazoline intermediate and isoxazoline - Google Patents
Method for preparing isoxazoline intermediate and isoxazoline Download PDFInfo
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- CN110028462B CN110028462B CN201910292049.1A CN201910292049A CN110028462B CN 110028462 B CN110028462 B CN 110028462B CN 201910292049 A CN201910292049 A CN 201910292049A CN 110028462 B CN110028462 B CN 110028462B
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- C07—ORGANIC CHEMISTRY
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- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses a method for preparing isoxazoline intermediate and isoxazoline, and intermediateThe preparation comprises using
Description
Technical Field
The invention relates to the field of chemical industry, in particular to a compound intermediate and preparation of a compound, and specifically relates to a method for preparing an isoxazoline intermediate and isoxazoline.
Background
Isoxazolines are a new class of highly potent insecticides that die by interfering with the parasite's gamma-aminobutyric acid (GABA) gated chloride channel leading to its nervous system being over-excited. Compared with the traditional pesticide, the isoxazoline compound has obvious differences in the aspects of target, molecular structure, selectivity and the like. The isoxazoline compound is mainly used for treating parasites of pet cats or dogs, such as fleas, ticks and the like.
The compounds shown in the following formulas 1-1, 1-2 and 1-3 are important intermediates for synthesizing 3 isoxazoline insecticides, and are simply the compounds shown in the general formula 1.
The routes reported in the literature for synthesizing the compounds of formula 1-1 and formula 1-2 are shown in scheme 1(WO2008122375A2, CN102149695A, R ═ Me; WO2009080250A2, R ═ t-Bu) and scheme 2(CN101765592A, R ═ Me), respectively.
The synthetic routes shown in scheme 1 and scheme 2 are simplified to the general formula scheme 3.
In the general formula route 3, corresponding p-aldehyde aromatic carboxylic acid is used as a raw material, and 4 steps of esterification, hydroxylamine oximation, substitution and elimination (obtaining nitrile oxide), cyclization and hydrolysis are performed to obtain an isoxazoline intermediate.
In the above route, the intermediate is an oil, except for the starting material and the product. The oily intermediate not only brings inconvenience to the material feeding in the reaction process, but also increases the difficulty of impurity purification, reduces the purity of the intermediate and the product, and finally causes adverse effects on the quality and yield of the product.
Therefore, how to prepare high-quality isoxazoline intermediates with low cost and high efficiency is a problem to be solved.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a production process of an isoxazoline intermediate with mild reaction conditions and low impurity content.
The technical scheme adopted by the invention is as follows:
a method for preparing an isoxazoline intermediate, the structural general formula of the isoxazoline intermediate is shown as a compound formula 1,
the synthetic route is as follows:
the method comprises the following operations:
hydroxylamine oximation reaction: reacting the intermediate-0 with hydroxylamine hydrochloride in a solvent; after the reaction is finished, an intermediate-1 is obtained by extraction, separation and concentration;
and (3) substitution reaction: reacting the intermediate-1, N-halogenated succinimide in a solvent; after the reaction is finished, adding water to precipitate out a solid, and then filtering and drying to obtain an intermediate 2-1;
elimination&And (3) cyclization reaction: intermediate 2-1, trifluoromethyl ethylene intermediate
Reacting in a solvent; after the reaction is finished, an intermediate 1-1 or 1-2 or 1-3 is obtained through post-treatment.
In some examples, the temperature of the hydroxylamine oximation reaction is from 15 ℃ to the solvent reflux temperature.
In some examples, the solvent of the hydroxylamine oximation reaction is a basic solvent.
In some examples, the base in the basic solvent of the hydroxylamine oximation reaction is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, dipropylamine, trimethylamine, triethylamine, tripropylamine, N-diisopropylethylamine, sodium acetate, potassium acetate, sodium bicarbonate, or mixtures thereof.
In some examples, the solvent of the hydroxylamine oximation reaction is selected from: a mixed solution of water and at least one of methanol, ethanol, N-propanol, isopropanol, tetrahydrofuran, benzene, toluene, N-dimethylformamide, 1, 4-dioxane, dimethyl sulfoxide and acetonitrile.
In some examples, the solvent of extraction is selected from ethyl acetate, toluene, dichloromethane, ethyl acetate, chloroform, butyl acetate, carbon tetrachloride, diethyl ether.
A method for preparing isoxazoline compounds, which is characterized by comprising the following steps:
1) preparing an isoxazoline intermediate shown in a compound formula 1 according to the method;
2) isoxazoline intermediates
And
amidation reaction to obtain isoOxazoline compounds.
The invention has the beneficial effects that:
the method has mild reaction conditions, is easy to realize industrially, and can obtain the isoxazoline intermediate with low impurity.
The invention has safe raw materials and low cost, and effectively reduces the production cost.
Compared with the prior route 3, the method adjusts the original 4-step reaction (esterification, hydroxylamine oximation, substitution & elimination (obtaining nitrile oxide), cyclization and hydrolysis) into 2-step reaction (hydroxylamine oximation, substitution & elimination (obtaining nitrile oxide) & cyclization). The adjusted process reduces the esterification and hydrolysis steps, and simultaneously, the prepared intermediate can be separated into solid, thereby facilitating the delivery of materials in the reaction process. Furthermore, the method of the invention reduces the difficulty of intermediate purification, improves the product quality and yield, and finally improves the product competitiveness.
Detailed Description
A method for preparing an isoxazoline intermediate, the structural general formula of the isoxazoline intermediate is shown as a compound formula 1,
the synthetic route is as follows:
the method comprises the following operations:
hydroxylamine oximation reaction: reacting the intermediate-0 with hydroxylamine hydrochloride in a solvent; after the reaction is finished, an intermediate-1 is obtained by extraction, separation and concentration;
and (3) substitution reaction: reacting the intermediate-1, N-halogenated succinimide in a solvent; after the reaction is finished, adding water to precipitate out a solid, and then filtering and drying to obtain an intermediate 2-1;
elimination&And (3) cyclization reaction: intermediate 2-1, trifluoromethylEthylene intermediates
Reacting in a solvent; after the reaction is finished, an intermediate 1-1 or 1-2 or 1-3 is obtained through post-treatment.
In some examples, the temperature of the hydroxylamine oximation reaction is from 15 ℃ to the solvent reflux temperature.
In some examples, the solvent of the hydroxylamine oximation reaction is a basic solvent.
In some examples, the base in the basic solvent of the hydroxylamine oximation reaction is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, dipropylamine, trimethylamine, triethylamine, tripropylamine, N-diisopropylethylamine, sodium acetate, potassium acetate, sodium bicarbonate, or mixtures thereof.
In some examples, the solvent of the hydroxylamine oximation reaction is selected from: a mixed solution of water and at least one of methanol, ethanol, N-propanol, isopropanol, tetrahydrofuran, benzene, toluene, N-dimethylformamide, 1, 4-dioxane, dimethyl sulfoxide and acetonitrile.
Hydroxylamine oximation is a classical chemical reaction, as defined by the company chen, xu rui qiu et al, basic organic chemistry, under 2 nd edition, beijing: higher education publishers, 1983.09, etc. are described in more detail. In some embodiments, the reaction temperature for the hydroxylamine oximation reaction is from 15 ℃ to the solvent reflux temperature, preferably room temperature. The reaction temperature is increased, which is beneficial to accelerating the reaction speed and simultaneously obtaining a product with higher purity. Generally speaking, the reaction can be carried out at room temperature without deliberately raising the temperature, so that satisfactory reaction results can be obtained, energy conservation is facilitated, and control of reaction conditions is reduced.
The hydroxylamine oximation reaction has no special requirements, and can be a base commonly used in the hydroxylamine oximation reaction. The available base can be selected by those skilled in the art according to actual needs, and the type of the base has no significant influence on the reaction. In some embodiments, the base in the basic solvent of the hydroxylamine oximation reaction is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, dipropylamine, trimethylamine, triethylamine, tripropylamine, N-diisopropylethylamine, sodium acetate, potassium acetate, sodium bicarbonate, or mixtures thereof.
The solvent has better solubility to the reactants, and the type of the solvent has no special requirement. In some embodiments, the solvent of the hydroxylamine oximation reaction is selected from: a mixed solution of water and at least one of methanol, ethanol, N-propanol, isopropanol, tetrahydrofuran, benzene, toluene, N-dimethylformamide, 1, 4-dioxane, dimethyl sulfoxide and acetonitrile.
The extraction solvent may be determined according to the characteristics of the reaction product, and the same or different extraction solvents may be selected for different reaction products. In some examples, the solvent of extraction is selected from ethyl acetate, toluene, dichloromethane, ethyl acetate, chloroform, butyl acetate, carbon tetrachloride, diethyl ether.
A method for preparing isoxazoline compounds, which is characterized by comprising the following steps:
1) preparing an isoxazoline intermediate shown in a compound formula 1 according to the method;
2) isoxazoline intermediates
And
carrying out amidation reaction to obtain the isoxazoline compound.
The amide condensation reaction is an extremely mature chemical reaction whose reaction conditions can be determined according to the prior art. For example, amide condensation conditions include: the condensation was carried out in DCC and DMAP with DCM as solvent. The condensation is carried out in DPPA and triethylamine by taking DMF as solvent. Toluene or dichloromethane or tetrahydrofuran is used as a solvent, and acyl chloride is formed in thionyl chloride and DMF for condensation.
To ensure the reaction is fully performed and avoid wasting materials, in some embodiments, the molar ratio of the intermediate to the reaction raw materials is 1: (1-1.5), 1: (1-1.2), 1: (1-1.1). If the molar ratio of the intermediate 0 to the hydroxylamine hydrochloride is 1: (1-1.5).
In order to further clarify the technical problems solved by the present invention and the effects of the technical solutions, the present invention will be further described with reference to the following examples.
In the following examples, unless otherwise indicated, the experimental method specific conditions are generally in accordance with conventional conditions or manufacturer's recommended practice conditions; the raw materials and the reagents are purchased from commercial products; the proportions, ratios, percentages or parts are by weight.
Example 1 (preparation of compound formula 1-1):
hydroxylamine oximation reaction
1) In a 500ml round bottom flask, 150ml of THF, 80ml of water and 023.5 g (0.14mol) of intermediate were sequentially added, and 11.2g (0.16mol) of hydroxylamine hydrochloride was added after the solution was dissolved by stirring, followed by 17.2g (0.21mol) of sodium acetate. Stirring the reaction solution at room temperature for 4 hours;
2) the reaction was stopped, and 200ml of water and 100ml of ethyl acetate (X3 times) were added to the reaction mixture to extract the aqueous phase. After combining the ethyl acetate phases, the organic phase was dried over anhydrous sodium sulfate;
3) and distilling off ethyl acetate under reduced pressure at the temperature of 45-50 ℃ to obtain 122.6 g of an intermediate with the yield of 90.2%.
The intermediate-1 can be directly put into the subsequent reaction without further treatment.
MS(m/z)：[M+H]+＝180.1。
Substitution reaction
4) 100ml of DMF, intermediate-122.6 g (0.13mol) and NCS18.7g (0.14mol) were added in this order to a 500ml round bottom flask, and after the mixture was stirred and dissolved, the mixture was heated at 40 ℃ for 2 hours;
5) the reaction was stopped and the solution was cooled to room temperature. 200ml of water was slowly added and a solid precipitated. Stirring was continued and cooling was carried out to 5 ℃. And filtering and separating the solid, and drying the solid in vacuum at the temperature of 55-60 ℃ to obtain an intermediate 2-125.5 g with the yield of 92.0%.
The intermediate-2-1 can be directly put into the subsequent reaction without further treatment.
MS(m/z)：[M+H]+＝214.0。
Elimination & cyclization reaction
6) In a 500ml round bottom flask, 150ml of DMF, 2 to 125.5 g (0.12mol) of intermediate-and 35.0g (0.14mol) of trifluoroethylene intermediate were added successively with stirring. After the mixture solution is dissolved, 13.2g (0.13mol) of triethylamine is added, and the reaction is continued for 10 hours at room temperature;
7) the reaction was stopped, 200ml of water was added to the reaction solution, and 100ml of ethyl acetate was added to the reaction solution in this order, and the aqueous phase was extracted 3 times. After combining the ethyl acetate phases, the organic phase was dried over anhydrous sodium sulfate;
8) and distilling off ethyl acetate under reduced pressure at the temperature of 45-50 ℃ to obtain an intermediate-2 crude product. The crude product was recrystallized from ethyl acetate/petroleum ether to yield-242.9 g of intermediate, 99.5% HPLC purity, 85.4% yield.
MS(m/z)：[M+H]+＝418.1。
1H NMR(400MHz，CDCl3)(ppm)：8.10(d，1H)，7.42-7.63(m，5H)，4.12(d，1H)，3.72(d，1H)，2.72(s，3H)。
Example 2 (preparation of compound formula 1-2):
hydroxylamine oximation reaction
1) In a 500ml round bottom flask, 150ml of toluene, 50ml of water and 020.0 g (0.10mol) of intermediate were sequentially added, and 7.7g (0.11mol) of hydroxylamine hydrochloride was added after the solution was dissolved by stirring. Stirring the reaction solution under the condition of heating reflux for 2 hours;
2) the reaction was stopped, the layers were separated and the toluene phase was washed with 100ml × 3 times of water. Drying the toluene organic phase with anhydrous sodium sulfate;
3) and (3) evaporating toluene at 75-80 ℃ under reduced pressure to obtain-120.6 g of an intermediate with the yield of 96.0%.
The intermediate-1 can be directly put into the subsequent reaction without further treatment.
MS(m/z)：[M+H]+＝216.1。
Substitution reaction
4) In a 500ml round bottom flask, acetonitrile 200ml, intermediate-120.6 g (0.09mol) and NBS 17.6g (0.10mol) were added in this order, and after the mixture was stirred to be clear, the reaction was refluxed for 2 hours;
5) the reaction was stopped and the solution was cooled to room temperature. 400ml of water was slowly added and a solid precipitated. Stirring was continued and cooling was carried out to 5 ℃. And filtering and separating the solid, and drying the solid in vacuum at the temperature of 55-60 ℃ to obtain an intermediate 2-125.3 g with the yield of 95.3%.
The intermediate-2-1 can be directly put into the subsequent reaction without further treatment.
MS(m/z)：[M+H]+＝294.0。
Elimination & cyclization reaction
6) In a 500ml round bottom flask, 150ml of acetonitrile, 2 to 125.3 g (0.08mol) of intermediate-and 26.4g (0.96mol) of trifluoroethylene intermediate were sequentially added under stirring. After the mixture solution is dissolved, adding 9.1g (0.09mol) of triethylamine, heating and refluxing for continuous reaction for 3 hours;
7) the reaction was stopped, 300ml of water was added to the reaction solution, and 100ml of ethyl acetate was added to the reaction solution in this order, and the aqueous phase was extracted 3 times. After combining the ethyl acetate phases, the organic phase was dried over anhydrous sodium sulfate;
8) and distilling off ethyl acetate under reduced pressure at the temperature of 45-50 ℃ to obtain a crude intermediate 2. The crude product was recrystallized from ethyl acetate/petroleum ether and intermediate-235.7 g, HPLC purity 99.6%, yield 91.6%.
MS(m/z)：[M+H]+＝488.1。
1H NMR(400MHz，CDCl3)(ppm)：7.38-8.81(m，9H)，4.15(d，1H)，3.75(d，1H)。
Example 3 (preparation of compounds of formulae 1-3):
hydroxylamine oximation reaction
1) To a 500ml round bottom flask, DMF250ml, water 100ml and intermediate 034.0 g (0.20mol) were added in this order, and after the solution was stirred and dissolved, 15.3g (0.22mol) of hydroxylamine hydrochloride was added, followed by 29.4g (0.3mol) of potassium acetate. Stirring the reaction solution at 50 ℃ to react for 2 hours;
2) the reaction was stopped, and 300ml of water and 100ml of ethyl acetate, X3 times of extraction of the aqueous phase were added to the reaction mixture in this order. After combining the ethyl acetate phases, the organic phase was dried over anhydrous sodium sulfate;
3) and distilling off ethyl acetate under reduced pressure at the temperature of 45-50 ℃ to obtain an intermediate product of-134.1 g with the yield of 92.1%.
The intermediate-1 can be directly put into the subsequent reaction without further treatment.
MS(m/z)：[M+H]+＝186.1。
Substitution reaction
4) 250ml of acetonitrile, 134.1g (0.18mol) of intermediate and 27.0g (0.20mol) of NCS are sequentially added into a 500ml round-bottom flask, and after the mixture is stirred and dissolved, the mixture is heated and refluxed for 2 hours;
5) the reaction was stopped and the solution was cooled to room temperature. 500ml of water was slowly added and a solid precipitated. Stirring was continued and cooling was carried out to 5 ℃. And filtering and separating the solid, and drying the solid in vacuum at the temperature of 55-60 ℃ to obtain an intermediate 2-136.9 g with the yield of 93.5%.
The intermediate-2-1 can be directly put into the subsequent reaction without further treatment.
MS(m/z)：[M+H]+＝220.1。
Elimination & cyclization reaction
6) Into a 500ml round-bottom flask were charged, while stirring, 300ml of acetonitrile, 2 to 136.9 g (0.17mol) of intermediate-2 and 56.2g (0.20mol) of intermediate trifluoromethylethylene, in that order. After the mixture solution is dissolved, 18.9g (0.19mol) of triethylamine is added, and then the mixture is heated at 60 ℃ to continue the reaction for 5 hours;
7) the reaction was stopped, 600ml of water was added to the reaction solution, and 200ml of ethyl acetate was added to the reaction solution in this order, and the aqueous phase was extracted 3 times. After combining the ethyl acetate phases, the organic phase was dried over anhydrous sodium sulfate;
8) and distilling off ethyl acetate under reduced pressure at the temperature of 45-50 ℃ to obtain an intermediate-2 crude product. Intermediate 268.8 g after recrystallization of the crude product from ethyl acetate/petroleum ether, HPLC purity 99.6%, yield 88.2%.
MS(m/z)：[M+H]+＝458.1。
1H NMR(400MHz，CDCl3)(ppm)：7.24(s，2H)，6.83(s，1H)，2.63(d，1H)，2.42(d，1H)，2.35(s，3H)。
Comparative example 1: r ═ Me. The compound of formula 1-1 (see scheme 1) was prepared by the method disclosed in WO2008122375A2 (examples 5-1&5-2), CN 102149695A.
Comparative example 2: and R is t-Bu. The compounds of formula 1-1 (see scheme 1) were prepared by the method disclosed in WO2009080250A2 (example 118-120).
Comparative example 3: r ═ Me. CN101765592A (example 1, steps a, B, C) discloses a process for the preparation of compounds of formula 1-2 (see scheme 2).
The different methods for preparing isoxazoline intermediates are compared as follows:
TABLE 1 comparative tables of the preparation of isoxazoline intermediates in different comparative examples
Note 1: to simplify the evaluation, the yield data missing in the literature are calculated as 100%; note 2: NCS refers to N-chlorosuccinimide; the literature reports no purity data due to being an intermediate.
TABLE 2 comparative tables of the preparation of isoxazoline intermediates in the different examples
Note 1: NCS refers to N-chlorosuccinimide, NBS refers to N-bromosuccinimide.
As can be seen from the data in tables 1 and 2:
compared with comparative examples 1-3:
1) examples 1 to 3 are different in that the reaction steps of esterification and hydrolysis are reduced;
2) the total yield of the step 2-1 → 2-3 of the examples 1 to 3 is 78.6 to 87.3 percent, which is also obviously higher than the yield range of 32.1 to 65.3 percent of the same reaction step 3-1 → 3-3 of the comparative examples 1 to 3;
3) the purity of the intermediate in each of examples 1 to 3 was 99.5% or more.
In summary, the following steps: the embodiment 1-3 ensures that the product purity is greatly improved, and simultaneously, the product cost is greatly reduced by improving the total reaction yield, and the product competitiveness is obviously improved.
The comparative cases for the preparation of isoxazoline intermediates with different process parameters are as follows:
TABLE 3 comparative table of the preparation of isoxazoline intermediates with different process parameters
From the data in the table, it can be seen from the comparison of examples 1 to 3 that:
1) in reaction step 1 hydroxylamine oximation, more polar solvents, higher reaction temperature and stronger basicity (DMF &50℃ & potassium acetate VS example 1 THF & rt & sodium acetate) favoured higher yields (92.1% VS example 3 90.2% of example 1); meanwhile, the toluene solvent is used, so that the solvent recovery is more convenient while the higher yield (96.5%) is ensured;
2) in the reaction step 2-1 substitution reaction, more active solvents, reagents and higher reaction temperatures (acetonitrile & NBS & reflux VS example 1 DMF & NCS &40 ℃) favoured higher yields (95.3% VS example 1 of example 2 92.0%) in the reaction step 2-1 substitution reaction;
3) in the elimination & cyclization reactions of reaction steps 2-3, the more active solvent and higher reaction temperature (acetonitrile & reflux VS example 1 DMF & room temperature of example 2) favor higher yields (91.6% VS example 1 of example 2 85.4%).
In summary, the following steps: by optimizing the process conditions, the overall yield of example 2 was also significantly improved compared to examples 1 and 3 while maintaining high product purity (84.2% VS of example 2 70.9% of example 1 and 76.0% of example 3).
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (3)
1. A method for producing an isoxazoline intermediate, characterized in that: the method comprises the following steps:
hydroxylamine oximation reaction:
1) 150ml of THF, 80ml of water and 023.5 g of intermediate are sequentially added into a 500ml round-bottom flask, 11.2g of hydroxylamine hydrochloride is added after the solution is stirred and dissolved, and 17.2g of sodium acetate is added; stirring the reaction solution at room temperature for 4 hours;
2) stopping the reaction, and sequentially adding 200ml of water and 100ml of ethyl acetate into the reaction solution for extracting the water phase for 3 times; after combining the ethyl acetate phases, the organic phase was dried over anhydrous sodium sulfate;
3) distilling off ethyl acetate under reduced pressure at 45-50 ℃ to obtain an intermediate-1, wherein the intermediate-1 can be directly put into subsequent reaction without further treatment;
and (3) substitution reaction:
4) sequentially adding 100ml of DMF, 122.6 g of intermediate and 18.7g of NCS into a 500ml round-bottom flask, and heating and reacting at 40 ℃ for 2 hours after the mixture is stirred and dissolved;
5) stopping the reaction, and cooling the solution to room temperature; slowly adding 200ml of water, and separating out solids; continuously stirring and cooling to 5 ℃; filtering and separating the solid, and drying the solid in vacuum at the temperature of 55-60 ℃ to obtain an intermediate-2-1; the intermediate-2-1 can be directly put into subsequent reaction without further treatment;
elimination & cyclization reaction:
6) in a 500ml round-bottom flask, adding 150ml of DMF, 2-125.5 g of intermediate and 35.0g of trifluoromethyl ethylene intermediate in turn under the condition of stirring; after the mixture solution is dissolved, 13.2g of triethylamine is added, and the reaction is continued for 10 hours at room temperature;
7) stopping the reaction, adding 200ml of water into the reaction solution, and sequentially adding 100ml of ethyl acetate and 3 times of extraction water phase into the reaction solution; after combining the ethyl acetate phases, the organic phase was dried over anhydrous sodium sulfate;
8) distilling the ethyl acetate under reduced pressure at 45-50 ℃ to obtain an intermediate-2 crude product; intermediate-2 after recrystallization of the crude product from ethyl acetate/petroleum ether.
2. A method for producing an isoxazoline intermediate, characterized in that: the method comprises the following steps:
hydroxylamine oximation reaction
1) 150ml of toluene, 50ml of water and 020.0 g of intermediate are sequentially added into a 500ml round-bottom flask, and 7.7g of hydroxylamine hydrochloride is added after the solution is stirred and dissolved; stirring the reaction solution under the condition of heating reflux for 2 hours;
2) the reaction was stopped, the phases were separated and the toluene phase was washed with 100ml × 3 times of water; drying the toluene organic phase with anhydrous sodium sulfate;
3) evaporating toluene at 75-80 ℃ under reduced pressure to obtain an intermediate-1; the intermediate-1 can be directly put into subsequent reaction without further treatment;
substitution reaction
4) Adding 200ml of acetonitrile, 120.6 g of intermediate and 17.6g of NBS into a 500ml round-bottom flask in sequence, and heating and refluxing for 2 hours after the mixture is stirred and dissolved;
5) stopping the reaction, and cooling the solution to room temperature; slowly adding 400ml of water, and separating out solids; continuously stirring and cooling to 5 ℃; filtering and separating the solid, and drying the solid in vacuum at the temperature of 55-60 ℃ to obtain an intermediate-2-1; the intermediate-2-1 can be directly put into subsequent reaction without further treatment;
elimination & cyclization reaction
6) In a 500ml round bottom flask, 150ml of acetonitrile, 2 to 125.3 g (0.08mol) of intermediate-and 26.4g (0.96mol) of trifluoromethyl ethylene intermediate were added in this order with stirring; after the mixture solution is dissolved, adding 9.1g (0.09mol) of triethylamine, heating and refluxing for continuous reaction for 3 hours;
7) stopping the reaction, adding 300ml of water into the reaction solution, and sequentially adding 100ml of ethyl acetate and 3 times of extraction water phase into the reaction solution; after combining the ethyl acetate phases, the organic phase was dried over anhydrous sodium sulfate;
8) distilling the ethyl acetate under reduced pressure at 45-50 ℃ to obtain a crude intermediate 2; the crude product was recrystallized from ethyl acetate/petroleum ether and intermediate-235.7 g, HPLC purity 99.6%, yield 91.6%.
3. A method for producing an isoxazoline intermediate, characterized in that: the method comprises the following steps:
hydroxylamine oximation reaction
1) Sequentially adding 250ml of DMF, 100ml of water and 034.0 g of intermediate into a 500ml round-bottom flask, adding 15.3g of hydroxylamine hydrochloride after the solution is stirred and dissolved, and then adding 29.4g of potassium acetate; stirring the reaction solution at 50 ℃ to react for 2 hours;
2) stopping the reaction, and sequentially adding 300ml of water and 100ml of ethyl acetate into the reaction solution, and extracting the water phase for 3 times; after combining the ethyl acetate phases, the organic phase was dried over anhydrous sodium sulfate;
3) distilling off ethyl acetate under reduced pressure at 45-50 ℃ to obtain an intermediate-1; the intermediate-1 can be directly put into subsequent reaction without further treatment;
MS(m/z)：[M+H]+＝186.1；
substitution reaction
4) Adding 250ml of acetonitrile, 134.1g of intermediate and 27.0g of NCS into a 500ml round-bottom flask in sequence, and heating and refluxing for 2 hours after the mixture is stirred and dissolved;
5) stopping the reaction, and cooling the solution to room temperature; slowly adding 500ml of water, and separating out solids; continuously stirring and cooling to 5 ℃; filtering and separating the solid, and drying the solid in vacuum at the temperature of 55-60 ℃ to obtain an intermediate-2-1; the intermediate-2-1 can be directly put into subsequent reaction without further treatment;
elimination & cyclization reaction
6) Adding 300ml of acetonitrile, 2-136.9 g of intermediate and 56.2g of trifluoromethyl ethylene intermediate into a 500ml round-bottom flask in turn under the condition of stirring; after the mixture solution is dissolved, 18.9g of triethylamine is added, and the mixture is heated at 60 ℃ to continue to react for 5 hours;
7) stopping the reaction, adding 600ml of water into the reaction solution, and sequentially adding 200ml of ethyl acetate and 3 times of extraction water phase into the reaction solution; after combining the ethyl acetate phases, the organic phase was dried over anhydrous sodium sulfate;
8) distilling the ethyl acetate under reduced pressure at 45-50 ℃ to obtain an intermediate-2 crude product; intermediate-2 after recrystallization of the crude product from ethyl acetate/petroleum ether.
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| WO2022016490A1 (en) * | 2020-07-24 | 2022-01-27 | Elanco Us Inc. | Process for lotilaner intermediate |
| CN112457267B (en) * | 2020-11-27 | 2023-09-05 | 麦蒂辛生物医药科技成都有限公司 | Preparation method of isoxazoline insecticide |
| CN113735681B (en) * | 2021-10-11 | 2023-12-12 | 丽珠集团新北江制药股份有限公司 | Florarana intermediate and method for preparing same |
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| CN102149695A (en) * | 2008-07-09 | 2011-08-10 | 日产化学工业株式会社 | Process for production of isoxazoline-substituted benzoic acid amide compound |
| CN105906655A (en) * | 2011-11-21 | 2016-08-31 | 安纳考尔医药公司 | Isoxazoline derivatives used in the control of ectoparasites |
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| CN105906655A (en) * | 2011-11-21 | 2016-08-31 | 安纳考尔医药公司 | Isoxazoline derivatives used in the control of ectoparasites |
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