Method for synthesizing 5, 5-disubstituted 2-isoxazoline

Abstract

The invention relates to a synthesis method of 5, 5-disubstituted 2-isoxazoline, according to the method, oxime of a formula (II) and a carbonyl compound of a formula (I) react in the presence of a boron trifluoride complex and in the presence of an optional organic solvent or no solvent, the reaction conditions are mild, and the product yield is high.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing 5,5-disubstituted 2-isoxazoline. Background Art

[0002] 5,5-disubstituted 2-isoxazolines are important intermediates for the preparation of active agrochemical and pharmaceutical compounds, and can be used to synthesize sulfonepyraclostrobin, benzylpyraclostrobin, etc.

[0003] Prior art discloses the direct reaction of α,β-unsaturated aldehydes with acetone oxime or hydroxylamine compounds to produce 2-isoxazoline. Patent CN102666503A discloses using crotonaldehyde and acetone oxime as raw materials, reacting in the presence of an acid catalyst or an acid-base catalyst. However, this method suffers from long reaction times and low yields. Furthermore, the reaction system uses aromatic hydrocarbon organic solvents, which are highly toxic and produce a high amount of waste products. Furthermore, the product purity needs to be further improved.

[0004] Therefore, it is necessary to develop a method that has short reaction time, high efficiency, mild conditions and avoids the use of toxic solvents to effectively synthesize 5,5-disubstituted 2-isoxazoline compounds. Summary of the Invention

[0005] The present invention aims to provide a method for synthesizing 5,5-disubstituted 2-isoxazoline with short reaction time, high efficiency, mild conditions and avoidance of toxic solvents, which is conducive to industrial production.

[0006] The present invention provides a method for synthesizing a 5,5-disubstituted 2-isoxazoline of formula (III):

[0007]

[0008] in

[0009] R3 and R4 are each independently C1-C6 alkyl or C1-C4 haloalkyl, or R3 and R4 together form a C2-C5 alkylene chain which may be mono- to tetra-substituted by C1-C4 alkyl and / or interrupted by oxygen or nitrogen optionally substituted by C1-C4 alkyl,

[0010] The method comprises reacting an oxime of formula (II):

[0011]

[0012] in

[0013] R1 and R2 are each independently hydrogen, C1-C6 alkyl, C1-C4 alkylcarbonyl, hydroxyimino-C1-C4 alkyl, phenyl, phenyl-C1-C4 alkyl or phenyl-C2-C4 alkenyl, wherein the phenyl ring may be mono- or polysubstituted by C1-C4 alkyl, C1-C4 alkoxy, di-C1-C4 alkylamino, halogen, hydroxy or nitro, or R1 and R2 together form a C2-C5 alkylene chain;

[0014] With a carbonyl compound of formula (I) in the presence of a boron trifluoride complex and optionally in the presence of an organic solvent or without a solvent:

[0015]

[0016] wherein R3 and R4 are each as defined above.

[0017] In the process according to the invention, preferably, compounds of the following formulae (I) and (II) are used, wherein the variables are each defined as follows, individually or in combination:

[0018] R1 is hydrogen, C1-C6 alkyl, C1-C4 alkylcarbonyl, hydroxyimino-C1-C4 alkyl;

[0019] R2 is a C1-C6 alkyl group or R1 and R2 form a C2-C5 alkylene chain;

[0020] R3 is C1-C6 alkyl or C1-C4 haloalkyl;

[0021] R4 is a C1-C6 alkyl group or a C1-C4 haloalkyl group.

[0022] Particularly preferably, compounds of the formulae (I) and (II) are used, in which the variables, in each case alone or in combination, are each as defined below:

[0023] R1 is hydrogen, C1-C4 alkyl, especially methyl, ethyl, isopropyl or isobutyl, more preferably methyl and ethyl;

[0024] R2 is C1-C4 alkyl, especially methyl or ethyl; or R1 and R2 form a C2-C5 alkylene chain;

[0025] R3 is C1-C4 alkyl, especially methyl or ethyl, more preferably methyl;

[0026] R4 is C1-C4 alkyl, especially methyl or ethyl, more preferably methyl.

[0027] Particularly preferably, compounds of the formulae (I) and (II) are used, in which the variables, in each case alone or in combination, are each as defined below:

[0028] R1 is methyl or ethyl;

[0029] R2 is methyl or ethyl;

[0030] R3 is a methyl group;

[0031] R4 is methyl.

[0032] Particularly preferably, the compound of formula (III) synthesized by the method of the present invention is 5,5-dimethyl-2-isoxazoline (IIIa) wherein both R3 and R4 are methyl.

[0033]

[0034] In the process of the present invention, a carbonyl compound of formula (I) is reacted with an oxime of formula (II) in the presence of a boron trifluoride complex and optionally in the presence of an organic solvent or in the absence of a solvent:

[0035]

[0036] Among them, the oxime of formula (II) is commercially available or can be prepared according to Yamane, M.; Narasaka, K., Science of Synthesis, 27 (2004), page 605. The carbonyl compound of formula (I) is also commercially available or can be prepared according to Escher, I.; Glorius, F., Science of Synthesis, 25 (2006), page 733.

[0037] In the method of the present invention, the following reaction conditions can be adopted:

[0038] Wherein, the molar ratio of the oxime of formula (II) to the carbonyl compound of formula (I) is 2.0:1.0-1.0:2.0. Preferably, the molar ratio of the two is 1.0:0.9-1.0:1.1, more preferably, the molar ratio of the two is 1.0:0.9-1.0:1.0. In some embodiments, the excess of the carbonyl compound of formula (I) is at most 10 mol%.

[0039] Wherein, the present invention reacts in the presence of a boron trifluoride complex, and the boron trifluoride complex can be selected from:

[0040] 1) Boron trifluoride.

[0041] 2) Boron trifluoride-alcohol complex {BF3·OR / BF3·(OR)2}, for example, R is C1-C 17 Alcohol complexes such as alkyl, aryl, and aralkyl can be selected from boron trifluoride methanol complex and boron trifluoride ethanol complex.

[0042] 3) Boron trifluoride-ether compounds {BF3·OR2 / BF3·(OR2)2}, for example, R is C1-C 10 Alkyl, aralkyl; various ether complexes such as boron trifluoride tetrahydrofuran, boron trifluoride dioxane, etc. Specifically, it can be selected from boron trifluoride diethyl ether complex, boron trifluoride dimethyl ether complex, and boron trifluoride butyl ether complex.

[0043] 4) Boron trifluoride-acid complex {RCO2·BF3}, for example, R is C1-C 16 Various acid complexes such as alkyl, aryl, and aralkyl can be selected from boron trifluoride acetic acid complex, boron trifluoride propionic acid complex, and boron trifluoride-methanesulfonic acid.

[0044] 5) Boron trifluoride-anhydride complex {BF3·O(COR)2}, for example, R is C1-C 16 Various acid anhydride complexes such as alkyl, aryl, and aralkyl.

[0045] 6) Boron trifluoride-amine complex {R·BF3}, for example, R is C1-C 16 Various amine complexes such as alkylamine, arylamine, nitrile, alcoholamine and pyridine / pyrrole, etc. Specifically, the complex can be selected from boron trifluoride ethylamine complex and boron trifluoride benzylamine complex.

[0046] 7) Boron trifluoride-phosphoric acid complexes and various boron trifluoride-ketone / aldehyde complexes.

[0047] 8) Boron trifluoride-zinc chloride, boron trifluoride-aluminum trichloride, boron trifluoride-ferric chloride, etc.

[0048] Preferably, the boron trifluoride complex is one or more of boron trifluoride methanol complex, boron trifluoride ether complex, and boron trifluoride acetic acid complex.

[0049] Furthermore, the boron trifluoride complex is added to the reaction system in a catalytic amount as a catalyst. The molar ratio of the compound of formula (II) to the boron trifluoride complex is 1.0:0.001-1.0:0.1. Preferably, the molar ratio of the two is 1.0:0.001-1.0:0.05, and particularly preferably, the molar ratio of the two is 1.0:0.001-1.0:0.02. In the present invention, the reaction can be carried out without adding a solvent or with adding a suitable solvent.

[0050] When a solvent is added to carry out the reaction, suitable solvents include, for example, acetone, halogenated aliphatic hydrocarbon solvents such as tetrachloroethane, chloroform, dichloromethane and dichloroethylene; aliphatic hydrocarbon solvents such as pentane, hexane, heptane, octane, cyclopentane, methylcyclopentane and cyclohexane; ether solvents such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and dioxane; alcohol solvents such as methanol and ethanol; ester solvents such as ethyl acetate; nitrile solvents such as acetonitrile; or mixtures of the above solvents.

[0051] Preferably, the reaction solvent is acetone, halogenated aliphatic hydrocarbons, aliphatic hydrocarbons, ethers and alcohols.

[0052] Particularly preferably, the reaction solvent is acetone and alcohols, in particular acetone, methanol, ethanol, tert-butanol and mixtures thereof.

[0053] Furthermore, in the reaction system, before the reaction begins, the proportion of the solvent is less than 60% by weight, preferably less than 40% by weight, and particularly preferably less than 10% by weight.

[0054] In addition, the present invention can also be carried out without adding a solvent.

[0055] The reaction temperature of the present invention is 25°C to 100°C, preferably 50°C to 100°C, and particularly preferably 70-80°C.

[0056] In the present invention, the oxime of formula (II), the carbonyl compound of formula (I), the catalyst and the optional solvent are added to a reaction vessel in any order. Preferably, the oxime of formula (II) and the optional solvent are added first, then the catalyst is added and the desired temperature is generated, and finally the carbonyl compound of formula (I) is slowly added dropwise, preferably, the carbonyl compound of formula (I) is slowly added dropwise over 3-10 hours.

[0057] The product mixture obtained in the present invention can be directly used in the next reaction without further post-treatment, or the target product can be obtained from the reaction mixture by direct distillation, extraction or chromatography.

[0058] In the prior art, the manufacture of the compound of formula (III) is usually carried out under trifluoroacetic acid catalyst, and trifluoroacetic acid has hygroscopicity and serious corrosiveness, and reaction needs strict water control, and operation risk coefficient is large, and the acid as catalyst is easily diluted and inactivation causes productive rate to reduce significantly, and therefore infers that reaction is difficult to carry out. And the applicant has studied and found that lewis acid boron trifluoride (BF ) catalyst is easy to improve its reactive behavior and start to participate in catalyzed reaction by forming covalent bond by adsorption carbonyl oxygen atom, the present invention uses boron trifluoride complex as catalyst, by controlling the amount of addition and the time for adding of formula (I) compound, can significantly improve reaction yield and product purity, and three wastes discharge amount is lower; Further, under the catalysis of boron trifluoride complex, the polymerization reaction of aldehyde easily occurs and produces high molecular polymer, excessive boron trifluoride catalyst easily and formula (III) compound complexing ammonium salt are synthesized, the application is by controlling the addition of catalyst, formula (I) compound, and coordinates the time for adding of reactant, effectively reduces the generation of by product, improves the yield of product.

[0059] Compared with the prior art, the advantages of the present invention are:

[0060] By using a specific boron trifluoride complex as a catalyst and controlling the amount and time of addition of the compound of formula (I), the reaction yield and product purity are higher, the post-treatment is simple, the discharge of three wastes is lower, and it is more conducive to industrial production. DETAILED DESCRIPTION

[0061] Example 1 (Boron Trifluoride Methanol Catalysis): Synthesis of 5,5-Dimethyl-2-isoxazoline

[0062] In the reaction apparatus, 36.92 kg of acetone oxime (0.5 kmol, content 99%) and 44.25 kg of isopentenal (0.501 kmol, content 97%) were added, and 2.0 kg of boron trifluoride methanol complex (10 mol, content 50%) was added under stirring. The mixture was thoroughly stirred at 80 ° C for 6-10 hours.

[0063] After the reaction, the temperature was maintained at 40°C, and the reaction by-product acetone was distilled off under reduced pressure. The temperature was maintained at 40-45°C, and vacuum distillation was performed. A fraction boiling in the range of approximately 26-30°C was quickly collected, yielding 40.64 kg of compound III (pale yellow oil, 98.0% content, 80.1% yield). This product was used directly in the next production step without further processing.

[0064] Example 2 (Boron Trifluoride Methanol Catalysis): Synthesis of 5,5-Dimethyl-2-isoxazoline

[0065] In a reaction apparatus, 2.0 kg of boron trifluoride methanol complex (10 mol, content 50%) was dissolved in 50 L of methanol solution, followed by the addition of 36.92 kg of acetone oxime (0.5 kmol, content 99%) and 44.25 kg of isopentenal (0.501 kmol, content 97%), and the mixture was stirred at 70 ° C for 6-10 hours.

[0066] After the reaction, the temperature was maintained at 40°C, and the reaction by-product acetone was distilled off under reduced pressure. The temperature was maintained at 40-45°C, and vacuum distillation was performed. A fraction with a boiling range of approximately 26-30°C was quickly collected, yielding 41 kg of compound III (a pale yellow oil, 98.0% content, 81.1% yield). This product was used directly in the next production step without further processing.

[0067] Example 3 (catalyzed by boron trifluoride ether): Synthesis of 5,5-dimethyl-2-isoxazoline

[0068] In the reaction apparatus, 36.92 kg of acetone oxime (0.5 kmol, content 99%) and 44.25 kg of isopentenal (0.501 kmol, content 97%) were added, and 2.9 kg of boron trifluoride ether complex (10 mol, content 98%) was added under stirring. The mixture was thoroughly stirred at 80 ° C for 6-10 hours.

[0069] After the reaction, the temperature was maintained at 40°C, and the reaction by-product acetone was distilled off under reduced pressure. The temperature was maintained at 40-45°C, and vacuum distillation was performed. A fraction boiling in the range of approximately 26-30°C was quickly collected, yielding 40.45 kg of compound III (pale yellow oil, 98.1% content, 80% yield). This product was used directly in the next production step without further processing.

[0070] Example 4 (catalyzed by boron trifluoride ether): Synthesis of 5,5-dimethyl-2-isoxazoline

[0071] In a reaction apparatus, 2.9 kg of boron trifluoride ether complex (10 mol, content 98%) was dissolved in 50 L of ethanol solution, followed by the addition of 36.92 kg of acetone oxime (0.5 kmol, content 99%) and 44.25 kg of isopentenal (0.501 kmol, content 97%), and the mixture was stirred at 80 ° C for 6-10 hours.

[0072] After the reaction, the temperature was maintained at 40°C, and the reaction by-product acetone was distilled off under reduced pressure. The temperature was maintained at 40-45°C, and vacuum distillation was performed. A fraction with a boiling range of approximately 26-30°C was quickly collected, yielding 40.85 kg of compound III (pale yellow oil, 98.0% content, 80.1% yield). This product was used directly in the next production step without further processing.

[0073] Example 5 (Boron Trifluoride Methanol Catalysis): Synthesis of 5,5-Dimethyl-2-isoxazoline

[0074] In a reaction apparatus, 36.92 kg of acetone oxime (0.5 kmol, content 99%) was dissolved in 20 L of acetone, the temperature was raised to 80 ° C, 2.0 kg of boron trifluoride methanol complex (10 mol, content 50%) was added and stirred for 20 minutes, and then 41.20 kg of isopentenal (0.475 kmol, content 97%) was added dropwise within 6-8 hours. After the addition was completed, the mixture was fully stirred at 80 ° C for 6-10 hours.

[0075] After the reaction, the temperature was maintained at 40°C, and the reaction by-product acetone was distilled off under reduced pressure. The temperature was maintained at 40-45°C, and vacuum distillation was performed. A fraction boiling in the range of approximately 26-30°C was quickly collected, yielding 41.77 kg of compound III (pale yellow oil, 98.0% content, 87.1% yield). This product was used directly in the next production step without further processing.

[0076] Example 6 (Boron Trifluoride Methanol Catalysis): Synthesis of 5,5-Dimethyl-2-isoxazoline

[0077] In a reaction apparatus, 36.92 kg of acetone oxime (0.5 kmol, content 99%) was dissolved in 20 L of methanol, the temperature was raised to 80 ° C, 2.0 kg of boron trifluoride methanol complex (10 mol, content 50%) was added and stirred for 20 minutes, and then 41.20 kg of isopentenal (0.475 kmol, content 97%) was added dropwise within 6-8 hours. After the addition was completed, the mixture was fully stirred at 80 ° C for 6-10 hours.

[0078] After the reaction, the temperature was maintained at 40°C, and the reaction by-product acetone was distilled off under reduced pressure. The temperature was maintained at 40-45°C, and vacuum distillation was performed. A fraction with a boiling point of approximately 26-30°C was quickly collected, yielding 41.09 kg of compound III (pale yellow oil, 98.1% content, 85.5% yield). This product was used directly in the next production step without further processing.

[0079] Example 7 (boron trifluoride acetic acid catalysis)

[0080] In a reaction apparatus, 36.92 kg of acetone oxime (0.5 kmol, content 99%) was dissolved in 20 L of acetone, the temperature was raised to 80 ° C, 1.9 kg of boron trifluoride acetic acid complex (10 mol, content 98%) was added and stirred for 20 minutes, and then 41.20 kg of isopentenal (0.475 kmol, content 97%) was added dropwise within 6-8 hours. After the addition was completed, the mixture was stirred at 80 ° C for 6-10 hours.

[0081] After the reaction, the temperature was maintained at 40°C, and the reaction by-product acetone was distilled off under reduced pressure. The temperature was maintained at 40-45°C, and vacuum distillation was performed. A fraction boiling in the range of approximately 26-30°C was quickly collected, yielding 41.96 kg of compound III (pale yellow oil, 98.0% content, 87.5% yield). This product was used directly in the next production step without further processing.

[0082] Example 8 (boron trifluoride-ferric chloride catalysis)

[0083] In a reaction apparatus, 36.92 kg of acetone oxime (0.5 kmol, content 99%) was dissolved in 20 L of acetone, the temperature was raised to 80 ° C, 0.68 kg of boron trifluoride (10 mol) and 1.62 kg of ferric chloride were added and stirred for 40 minutes, followed by the dropwise addition of 41.20 kg of isopentanal (0.475 kmol, content 97%) within 6-8 hours. After the addition was complete, the mixture was stirred at 80 ° C for 6-10 hours.

[0084] After the reaction, the temperature was maintained at 40°C, and the reaction by-product acetone was distilled off under reduced pressure. The temperature was maintained at 40-45°C, and vacuum distillation was performed. A fraction boiling in the range of approximately 26-30°C was quickly collected, yielding 41.66 kg of compound III (pale yellow oil, 98.0% content, 86.9% yield). This product was used directly in the next production step without further processing.

[0085] Compared with the prior art, the present application uses a boron trifluoride methanol complex instead of a trifluoroacetic acid catalyst, enriching the catalytic system for preparing the compound of formula (III); by reducing the input amount of the compound of formula (I) and extending the dropwise addition time, the generation of by-products is effectively suppressed, the yield of the compound of formula (III) is increased, and the discharge of three wastes is reduced; the increase in temperature is conducive to shortening the reaction time and improving the efficiency of industrial production.

[0086] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for synthesizing a 5,5-disubstituted 2-isoxazoline of formula (III), characterized in that: The steps include: in R3 and R4 are each independently C1-C6 alkyl or C1-C4 haloalkyl, or R3 and R4 together form a C2-C5 alkylene chain which may be mono- to tetra-substituted by C1-C4 alkyl and / or interrupted by oxygen or nitrogen optionally substituted by C1-C4 alkyl; The method comprises reacting an oxime of formula (II): in R1 and R2 are each independently hydrogen, C1-C6 alkyl, C1-C4 alkylcarbonyl, hydroxyimino-C1-C4 alkyl, phenyl, phenyl-C1-C4 alkyl or phenyl-C2-C4 alkenyl, wherein the phenyl ring may be mono- or polysubstituted by C1-C4 alkyl, C1-C4 alkoxy, di-C1-C4 alkylamino, halogen, hydroxy or nitro, or R1 and R2 together form a C2-C5 alkylene chain; With a carbonyl compound of formula (I) in the presence of a boron trifluoride complex and optionally in the presence of an organic solvent or without a solvent: wherein R3 and R4 are each as defined above.

2. The method according to claim 1, characterized in that in R1 is hydrogen, C1-C6 alkyl, C1-C4 alkylcarbonylhydroxyimino-C1-C4 alkyl; R2 is a C1-C6 alkyl group or R1 and R2 form a C2-C5 alkylene chain. R3 is C1-C6 alkyl or C1-C4 haloalkyl; R4 is C1-C6 alkyl or C1-C4 haloalkyl; 3. The method according to claim 1, characterized in that R3 and R4 are each methyl.

4. The method according to claim 2, characterized in that R3 and R4 are each methyl.

5. The method according to any one of claims 1 to 4, characterized in that The R1 and R2 are each independently a methyl group or an ethyl group.

6. The method according to claim 5, characterized in that The organic solvent is one or more of acetone, halogenated aliphatic hydrocarbons, aliphatic hydrocarbons, ethers or alcohols.

7. The method according to claim 5, characterized in that The boron trifluoride complex is selected from one or more of boron trifluoride, boron trifluoride-alcohol complexes, boron trifluoride-ether compounds, boron trifluoride-acid complexes, boron trifluoride-anhydride complexes, boron trifluoride-amine complexes, boron trifluoride-phosphoric acid complexes, and boron trifluoride-ketone / aldehyde complexes.

8. The method according to claim 5, characterized in that The reaction temperature is 25° C. to 100° C.; the molar ratio of the oxime of formula (II) to the carbonyl compound of formula (I) is 2.0:1.0-1.0:2.0; and the molar ratio of the compound of formula (II) to the boron trifluoride complex is 1.0:0.001-1.0:0.

1.

9. The method according to claim 5, characterized in that The reaction temperature is 50° C. to 100° C., the molar ratio of the oxime of formula (II) to the carbonyl compound of formula (I) is 1.0:0.9-1.0:1.1; and the molar ratio of the compound of formula (II) to the boron trifluoride complex is 1.0:0.001-1.0:0.05.

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