Preparation method of ketoxime compound

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of ketoxime compounds. Substituted benzaldehyde as shown in a formula (II) and ketoxime as shown in a formula (III) react in the presence of an organic base catalyst and a solvent to generate the ketoxime compound containing substituted phenyl as shown in a formula (I), the preparation method disclosed by the invention can be completed by a one-pot method, the reaction efficiency and the yield are improved under mild conditions, the complexity of reaction steps is reduced, and the production cost is reduced.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a method for preparing ketoxime compounds. Background Art

[0002] In recent years, 4-(2,6-Dichlorophenyl)-3-buten-2-one oxime (CAS RN: 343337-48-4) has attracted much attention due to its significant application value in many fields. This compound shows potential biological activity in drug development and can be used as a precursor or intermediate of drug molecules. Its unique structure makes it play an important role in the development of antibacterial, anti-inflammatory, anti-tumor and other drugs.

[0003] In the field of materials science, 4-(2,6-dichlorophenyl)-3-butene-2-one oxime has important applications as a key intermediate for the synthesis of high-performance materials. Its specific chemical properties enable it to exhibit excellent performance in the synthesis of polymers and composite materials. As an important intermediate in organic synthesis, this compound can participate in a variety of key reactions. Its stable structure and reactivity make it occupy an important position in organic chemical synthesis.

[0004] In the study of catalysis and reaction mechanism, 4-(2,6-dichlorophenyl)-3-butene-2-one oxime can be used as a model compound to study reaction pathways and catalytic mechanisms, providing theoretical support for the optimization of chemical reactions. In addition, this compound also has application potential in the fields of environment and agriculture. It can be used to synthesize new pesticides and environmentally friendly chemicals, and has broad application prospects. However, since the activities of the Z configuration and the E configuration of 4-(2,6-dichlorophenyl)-3-butene-2-one oxime are completely different, the Z configuration is basically inactive and has low industrial application value, while the E configuration has very excellent fungicidal activity. Therefore, the preparation of the E configuration of 4-(2,6-dichlorophenyl)-3-butene-2-one oxime has more industrial application value.

[0005] At present, only two documents disclose 4-(2,6-dichlorophenyl)-3-butene-2-one oxime derivatives of specific structure: US Pat. No. 6,303,818 uses 2,6-dichlorobenzaldehyde as raw material to prepare trans-1-(2,6-dichlorophenyl)-3-butene-2-one-2-oxime (E / Z mixture of oxime) by two-step synthesis method, and the yield is only 58.2%; Dichlorphenyl-alkenone und ihre Oxime (Arch. Pharm. (Weinheim) 311, 262-267 (1978)) discloses the reaction of 2,6-dichlorophenyl-3-butene-2-one with hydroxylamine, and the reaction yield is low, and the generated oxime product inevitably contains E / Z configuration products. The main reason for the coexistence of E / Z isomers is that the energy barriers of E / Z configurations are similar, so that the two configurations can be generated simultaneously during the reaction process, and it is difficult to achieve selective control through reaction conditions. In addition, there is a conjugated effect on the π bond in the product, and this electronic effect further stabilizes the E / Z isomer structure of the ketoxime. Due to the presence of the conjugated system, the E / Z isomers are relatively close in energy, lacking significant energy differences to favor the generation of a single configuration. These factors together lead to the uncontrollable generation of E / Z isomers, thereby increasing the difficulty of separation and purification, and becoming a technical challenge for the process in industrial applications. Therefore, the development of a preparation method that is conducive to the generation of E-configuration derivatives of ketoxime has become an urgent problem to be solved. Summary of the invention

[0006] In order to solve the above problems, the present invention provides a new process for synthesizing ketoxime compounds, and the specific technical scheme is as follows:

[0007] The substituted benzaldehyde represented by formula (II) reacts with the ketoxime represented by formula (III) in the presence of an organic base catalyst and a solvent to generate a ketoxime compound containing a substituted phenyl group represented by formula (I);

[0008]

[0009] In the formula, X is a halogen; n is 1 or 2;

[0010] R is a C1-C4 alkyl group.

[0011] Further, under a nitrogen atmosphere, the substituted benzaldehyde represented by formula (II) and the ketoxime represented by formula (III) are heated in the presence of an organic base catalyst and a solvent to react to generate a ketoxime compound containing a substituted phenyl group represented by formula (I);

[0012] In the formula, X is chlorine; n is 1 or 2;

[0013] R is methyl, ethyl, n-propyl or isopropyl.

[0014] Furthermore, formula (II) is 2,6-dichlorobenzaldehyde or p-chlorobenzaldehyde.

[0015] The organic base is one or more of piperidine, diethylamine, triethylamine and piperazine; the molar ratio of the organic base to the compound of formula II is (0.05-0.1):1.

[0016] The solvent is one or more of methanol, ethanol and isobutanol, and the mass of the solvent is 2 to 3 times that of the compound of formula II.

[0017] The molar ratio of the compound of formula II to the compound of formula III is 1:1-1.2, preferably 1:1.15.

[0018] The reaction time is 8-10 hours, and the heating temperature is 65-85°C, preferably 65-82°C.

[0019] After the reaction is completed, the reaction solution is distilled to remove the solvent, extracted with dichloroethane, dried, cooled to precipitate crystals, and filtered to obtain the ketoxime compound containing a substituted phenyl group represented by formula (I).

[0020] The molar ratio of the compound of general formula II to the amount of ethylene dichloride is 1:3-4.

[0021] The cooling to precipitate crystals is to cool the reaction solution to -5°C for crystallization.

[0022] The purity of the obtained ketoxime compound containing substituted phenyl represented by formula (I) is ≥90%.

[0023] Furthermore, the purity of the ketoxime compound containing substituted phenyl groups represented by formula (I) is 90% to 95%.

[0024] Beneficial effects:

[0025] The present invention provides an efficient synthesis method of ketoxime compounds, which achieves high-yield synthesis under mild conditions by optimizing reaction conditions. Specifically, the substituted benzaldehyde shown in formula (II) and the ketoxime shown in formula (III) react in the presence of an organic base catalyst (such as piperidine, diethylamine, triethylamine, etc.) and a solvent such as ethanol or methanol under a nitrogen atmosphere to generate a ketoxime compound containing a substituted phenyl group shown in formula (I). The reaction temperature of the method is mild, controlled between 79-82°C, the reaction time is 8 hours, and no expensive catalysts and high-pressure equipment are required, thereby reducing production costs, and achieving a very good yield of up to 74%, and the E configuration in the product is as high as 93.2%. The product has very good bactericidal activity in the agricultural field, as follows:

[0026] (1) High yield: The present invention significantly improves the yield of the target product from 58.2% to 74% by optimizing the reaction conditions and steps, and the purity of the E-configuration of 4-(2,6-dichlorophenyl)-3-butene-2-one oxime in the product is as high as 93.2%.

[0027] (2) Simplified operation: The present invention adopts a one-pot method, which reduces the complexity of the reaction steps, makes the operation simpler, and is suitable for large-scale industrial production.

[0028] (3) Reduce costs: The present invention does not require expensive catalysts and high-energy consumption equipment, thus reducing production costs.

[0029] The preparation method of the present invention provides more effective technical support for large-scale production and application of 4-(2,6-dichlorophenyl)-3-butene-2-one oxime, which not only improves the yield and purity, but also has good economic benefits and industrialization prospects. The present invention provides new ideas and directions for the development of related fields and has significant commercial value and application potential. DETAILED DESCRIPTION

[0030] The specific implementation modes of the present invention are further described below in conjunction with examples. It should be noted that the specific implementation modes described here are only for illustrating and explaining the present invention, and are not limited to the present invention.

[0031] The chemical reagents used in the present invention are all provided by Sinopharm Group.

[0032] Example 1

[0033] Under a nitrogen atmosphere, 2,6-dichlorobenzaldehyde (17.5 g, 0.1 mol), acetone oxime (8.4 g, 0.115 mol), piperidine (0.4257 g, 0.005 mol) and ethanol (40 g) were added to a four-necked bottle reaction device. The reaction solution was stirred and heated to 79-82 ° C and kept at reflux for 8 hours. After the reaction was completed, ethanol was directly removed by distillation. Then 30 g of dichloroethane was used for extraction, the organic layer was collected, and dried with anhydrous sodium sulfate, cooled to 5 ° C to precipitate crystals, filtered, and dried to obtain the target product of 4-(2,6-dichlorophenyl)-3-butene-2-one oxime (E configuration) 17.65 g, with a yield of 70% and a purity of 91.2%.

[0034] Example 2

[0035] Under a nitrogen atmosphere, 2,6-dichlorobenzaldehyde (17.5 g, 0.1 mol), acetone oxime (8.4 g, 0.115 mol), piperidine (0.5960 g, 0.007 mol) and ethanol (40 g) were added to a four-necked bottle reaction device. The reaction solution was stirred and heated to 79-82 ° C and kept at reflux for 8 hours. After the reaction was completed, ethanol was directly removed by distillation. Then 30 g of dichloroethane was used for extraction, the organic layer was collected, and dried with anhydrous sodium sulfate, cooled to 5 ° C to precipitate crystals, filtered, and dried to obtain the target product of 4-(2,6-dichlorophenyl)-3-butene-2-one oxime (E configuration) 18.8 g, with a yield of 74% and a purity of 90.5%.

[0036] Example 3

[0037] Under a nitrogen atmosphere, 2,6-dichlorobenzaldehyde (17.5 g, 0.1 mol), acetone oxime (8.4 g, 0.115 mol), piperidine (0.7663 g, 0.009 mol) and ethanol (40 g) were added to a four-necked bottle reaction device. The reaction solution was stirred and heated to 79-82 ° C and kept at reflux for 8 hours. After the reaction was completed, ethanol was directly removed by distillation. Then 30 g of dichloroethane was used for extraction, the organic layer was collected, and dried with anhydrous sodium sulfate, cooled to 5 ° C to precipitate crystals, filtered, and dried to obtain the target product of 4-(2,6-dichlorophenyl)-3-butene-2-one oxime (E configuration) 18.09 g, with a yield of 72.2% and a purity of 91.8%.

[0038] Example 4

[0039] Under a nitrogen atmosphere, 2,6-dichlorobenzaldehyde (17.5 g, 0.1 mol), acetone oxime (8.4 g, 0.115 mol), diethylamine (0.3657 g, 0.005 mol) and ethanol (40 g) were added to a four-necked bottle reaction device. The reaction solution was stirred and heated to 79-82 ° C and kept at reflux for 8 hours. After the reaction was completed, ethanol was directly removed by distillation. Then 30 g of dichloroethane was used for extraction, the organic layer was collected, and dried with anhydrous sodium sulfate, cooled to 5 ° C to precipitate crystals, filtered, and dried to obtain the target product of 4-(2,6-dichlorophenyl)-3-butene-2-one oxime (E configuration) 17.38 g, with a yield of 68.8% and a purity of 91%.

[0040] Example 5

[0041] Under a nitrogen atmosphere, 2,6-dichlorobenzaldehyde (17.5 g, 0.1 mol), acetone oxime (8.4 g, 0.115 mol), diethylamine (0.5120 g, 0.007 mol) and ethanol (40 g) were added to a four-necked bottle reaction device. The reaction solution was stirred and heated to 79-82 ° C and kept at reflux for 8 hours. After the reaction was completed, ethanol was directly removed by distillation. Then 30 g of dichloroethane was used for extraction, the organic layer was collected, and dried with anhydrous sodium sulfate, cooled to 5 ° C to precipitate crystals, filtered, and dried to obtain the target product of 4-(2,6-dichlorophenyl)-3-butene-2-one oxime (E configuration) 17.53 g, with a yield of 69.2% and a purity of 90.8%.

[0042] Example 6

[0043] Under a nitrogen atmosphere, 2,6-dichlorobenzaldehyde (17.5 g, 0.1 mol), acetone oxime (8.4 g, 0.115 mol), diethylamine (0.6582 g, 0.009 mol) and ethanol (40 g) were added to a four-necked bottle reaction device. The reaction solution was stirred and heated to 79-82 ° C and kept at reflux for 8 hours. After the reaction was completed, ethanol was directly removed by distillation. Then 30 g of dichloroethane was used for extraction, the organic layer was collected, and dried with anhydrous sodium sulfate, cooled to 5 ° C to precipitate crystals, filtered, and dried to obtain the target product of 4-(2,6-dichlorophenyl)-3-butene-2-one oxime (E configuration) 17.42 g, with a yield of 69.1% and a purity of 91.2%.

[0044] Example 7

[0045] Under a nitrogen atmosphere, 2,6-dichlorobenzaldehyde (17.5 g, 0.1 mol), acetone oxime (8.4 g, 0.115 mol), piperidine (0.4257 g, 0.005 mol) and methanol (40 g) were added to a four-necked bottle reaction device. The reaction solution was stirred and heated to 65-70 ° C and kept at reflux for 8 hours. After the reaction was completed, methanol was directly removed by distillation. Then 30 g of dichloroethane was used for extraction, the organic layer was collected, and dried with anhydrous sodium sulfate, cooled to 5 ° C to precipitate crystals, filtered, and dried to obtain the target product of 4-(2,6-dichlorophenyl)-3-butene-2-one oxime (E configuration) 16.40 g, with a yield of 64.2% and a purity of 90.0%.

[0046] Example 8

[0047] Under a nitrogen atmosphere, 2,6-dichlorobenzaldehyde (17.5 g, 0.1 mol), acetone oxime (8.4 g, 0.115 mol), piperidine (0.5960 g, 0.007 mol) and methanol (40 g) were added to a four-necked bottle reaction device. The reaction solution was stirred and heated to 79-82 ° C and kept at reflux for 10 hours. After the reaction was completed, methanol was directly removed by distillation. Then 30 g of dichloroethane was used for extraction, the organic layer was collected, and dried with anhydrous sodium sulfate, cooled to 5 ° C to precipitate crystals, filtered, and dried to obtain the target product of 4-(2,6-dichlorophenyl)-3-butene-2-one oxime (E configuration) 16.79 g, with a yield of 66.8% and a purity of 91.5%.

[0048] Example 9

[0049] Under a nitrogen atmosphere, 2,6-dichlorobenzaldehyde (17.5 g, 0.1 mol), acetone oxime (8.4 g, 0.115 mol), piperidine (0.7663 g, 0.009 mol) and methanol (40 g) were added to a four-necked bottle reaction device. The reaction solution was stirred and heated to 79-82 ° C, and kept at reflux for 12 hours. After the reaction was completed, methanol was directly removed by distillation. Then 30 g of dichloroethane was used for extraction, the organic layer was collected, and dried with anhydrous sodium sulfate, cooled to 5 ° C to precipitate crystals, filtered, and dried to obtain the target product of 4-(2,6-dichlorophenyl)-3-butene-2-one oxime (E configuration) 17.19 g, with a yield of 69% and a purity of 92.3%.

[0050] Example 10

[0051] Under a nitrogen atmosphere, 2,6-dichlorobenzaldehyde (17.5 g, 0.1 mol), acetone oxime (8.4 g, 0.115 mol), triethylamine (0.5060 g, 0.005 mol) and ethanol (40 g) were added to a four-necked bottle reaction device. The reaction solution was stirred and heated to 79-82 ° C and kept at reflux for 8 hours. After the reaction was completed, ethanol was directly removed by distillation. Then 30 g of dichloroethane was used for extraction, the organic layer was collected, and dried with anhydrous sodium sulfate, cooled to 5 ° C to precipitate crystals, filtered, and dried to obtain the target product of 4-(2,6-dichlorophenyl)-3-butene-2-one oxime (E configuration) 16.28 g, with a yield of 65% and a purity of 91.8%.

[0052] Embodiment 11

[0053] Under nitrogen atmosphere, p-chlorobenzaldehyde (14.0g, 0.1mol), acetone oxime (8.4g, 0.115mol), triethylamine (0.7083g, 0.007mol) and ethanol (40g) were added to a four-necked bottle reaction device. The reaction solution was stirred and heated to 79-82°C, and kept refluxed for 8 hours. After the reaction was completed, ethanol was directly removed by distillation. Then 30g of dichloroethane was extracted, the organic layer was collected, and anhydrous sodium sulfate drying was used, the temperature was cooled to 5°C to precipitate crystals, filter, and dry to obtain the target product of 4-(p-chlorophenyl)-3-butene-2-ketoxime (E configuration) 14.68g, with a yield of 70% and a purity of 93.2%.

[0054] Comparative Example 1:

[0055] Under a nitrogen atmosphere, 2,6-dichlorobenzaldehyde (17.5 g, 0.1 mol), acetone oxime (8.4 g, 0.115 mol), piperidine (0.5960 g, 0.007 mol) and ethanol (40 g) were added to a four-necked bottle reaction device. The reaction solution was stirred and heated to 60 ° C and kept at reflux for 8 hours. After the reaction was completed, ethanol was directly removed by distillation. Then 30 g of dichloroethane was used for extraction, the organic layer was collected, and the target product obtained by cooling to 5 ° C with anhydrous sodium sulfate drying, filtering and drying was 4-(2,6-dichlorophenyl)-3-butene-2-one oxime (E configuration) 15.179 g, with a yield of 52% and a purity of 78.8%.

[0056] Comparative Example 2:

[0057] Under a nitrogen atmosphere, 2,6-dichlorobenzaldehyde (17.5 g, 0.1 mol), acetone oxime (8.4 g, 0.115 mol), sodium hydroxide (0.2 g, 0.05 mol) and ethanol (40 g) were added to a four-necked bottle reaction device. The reaction solution was stirred and heated to 79-82 ° C and kept at reflux for 8 hours. After the reaction was completed, ethanol was directly removed by distillation. Then 30 g of dichloroethane was used for extraction, the organic layer was collected, and dried with anhydrous sodium sulfate, cooled to 5 ° C to precipitate crystals, filtered, and dried to obtain the target product of 4-(2,6-dichlorophenyl)-3-butene-2-one oxime (E configuration) 15.329 g, with a yield of 55% and a purity of 82.52%.

[0058] Comparative Example 3:

[0059] Under a nitrogen atmosphere, 2,6-dichlorobenzaldehyde (17.5 g, 0.1 mol), acetone oxime (8.4 g, 0.115 mol), piperidine (0.4257 g, 0.005 mol) and n-butanol (40 g) were added to a four-necked bottle reaction device. The reaction solution was stirred and heated to 79-82 ° C and kept at reflux for 8 hours. After the reaction was completed, n-butanol was directly removed by distillation. Then 30 g of dichloroethane was used for extraction, the organic layer was collected, and dried over anhydrous sodium sulfate, cooled to 5 ° C to precipitate crystals, filtered, and dried to obtain the target product of 4-(2,6-dichlorophenyl)-3-butene-2-one oxime (E configuration) 16.306 g, with a yield of 59% and a purity of 83.22%.

[0060] The reaction steps of the present invention are simple, the equipment requirements are low, and a high yield of 74% and a high purity can be achieved. Compared with comparative examples 1-3, the reaction efficiency of the present invention is significantly improved, and the yield in the comparative example is low (52% to 59%), and the purity is also low (53% to 83%). By comparing the reaction conditions and yields of different experimental groups, it can be seen that the selection of the catalyst, solvent and reaction conditions of the present invention makes the reaction more efficient and simple, and the yield and purity are better than the prior art.

Claims

1. A method for preparing a ketoxime compound containing a substituted phenyl group, characterized in that: The substituted benzaldehyde shown in formula II and the ketoxime shown in formula III are reacted in the presence of an organic base catalyst and a solvent to generate a ketoxime compound containing a substituted phenyl group shown in formula I; In the formula, X is a halogen; n is 1 or 2; R is a C1-C4 alkyl group.

2. The preparation method according to claim 1, characterized in that: Under a nitrogen atmosphere, the substituted benzaldehyde represented by formula II and the ketoxime represented by formula III are heated in the presence of an organic base catalyst and a solvent to generate a ketoxime compound containing a substituted phenyl group represented by formula (I); In the formula, X is chlorine; n is 1 or 2; R is methyl, ethyl, n-propyl or isopropyl.

3. The preparation method according to claim 1, characterized in that: The organic base is one or more of piperidine, diethylamine, triethylamine and piperazine; the molar ratio of the organic base to the compound of formula II is 0.05-0.1:

1.

4. The preparation method according to claim 1, characterized in that: The solvent is one or more of methanol, ethanol and isobutanol.

5. The preparation method according to claim 1, characterized in that: The molar ratio of the compound of formula II to the compound of formula III is 1:1 to 1.

2.

6. The preparation method according to claim 2, characterized in that: The reaction time is 8-10h and the heating temperature is 65-85℃.

7. The preparation method according to any one of claims 1 or 2, characterized in that: After the reaction is completed, the reaction solution is distilled to remove the solvent, extracted with dichloroethane, dried, cooled to precipitate crystals, and filtered to obtain the ketoxime compound containing a substituted phenyl group as shown in formula I.

8. The preparation method according to claim 7, characterized in that: The cooling to precipitate crystals is to cool the reaction solution to -5°C for crystallization.

9. The preparation method according to claim 1, characterized in that: The purity of the ketoxime compound containing substituted phenyl represented by formula (I) is ≥90%.

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