Preparation method of fluralana intermediate impurity

Abstract

The invention relates to the technical field of organic synthesis of fluralana, in particular to the field of IPC C07D317 / 20, and more particularly relates to a preparation method of a fluralana intermediate impurity. Comprising the following steps: S1, adding 3 ', 5'-dichloro-2, 2, 2-trifluoroacetophenone and acetic acid into an organic solvent A, and then adding a catalyst; s2, stirring and heating, and carrying out heat preservation reaction for the first time; s3, adding a dehydrating agent, and carrying out a second heat preservation reaction; s4, pouring the reaction liquid obtained in the step S2 into an ice-water mixture, and performing extraction concentration and column separation by using an organic solvent B to obtain a crude product; and S5, recrystallizing the crude product by using an organic solvent C, so as to obtain the intermediate impurity 3-(3, 5-dichlorophenyl)-4, 4, 4-trifluorobutyl-2-olefine acid. The preparation method is simple, the purity of the obtained product is high, and the method has great benefits of effectively improving the quality of the fluralana bulk drug product.

Description

Technical Field

[0001] The invention relates to the technical field of flurellane organic synthesis, in particular to the field of IPC C07D317 / 20, and more specifically to a method for preparing a flurellane intermediate impurity. Background Art

[0002] Flurella, CAS No. 864731-61-3, is a broad-spectrum insecticide with good insecticidal activity against pests such as ticks, siphonaptera, pedicels, hemiptera and diptera, and its toxicity is higher than or equivalent to that of commonly used insecticides. Flurella mainly acts by interfering with the chloride ion channels of the γ-aminobutyric acid receptors (GABA receptors) and glutamate receptors in the nervous system of invertebrates, and its targets are similar to those of insecticides such as cyclopentadiene, phenylpyrazoles and macrolides. It not only has no cross-resistance with existing GABA receptor-type insecticides, but is also safe for non-target organisms such as mammals, zebrafish and poultry.

[0003] Patent EP2172462A1 reports in detail the preparation method of the flurana intermediate 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid, wherein 4-acetyl-2-methylbenzoic acid and 3',5'-dichloro-2,2,2-trifluoroacetophenone are reacted with toluene and triethylamine to generate the intermediate 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutane)-2-methylbenzoic acid, and then acetic anhydride and 4-dimethylaminopyridine are subjected to a dehydration reaction to prepare 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid. The synthesis route is as follows:

[0004]

[0005] In the experiment, it was found that in the process of preparing 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid (M2), a specific impurity would be generated. After subsequent structural confirmation, it was found that 3',5'-dichloro-2,2,2-trifluoroacetophenone reacted with acetic acid to undergo aldol condensation and dehydrated under the action of acetic anhydride to form Michael acceptor 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid. This impurity is easy to further derive a series of impurities in the next reaction, which seriously affects the purity and quality of subsequent products. It needs to be strictly controlled to ensure the safety of medication, but there is currently a lack of preparation methods for related impurities. Summary of the invention

[0006] The present invention provides a method for preparing a fluororana intermediate impurity, and the preparation reaction formula is shown in Formula 1:

[0007]

[0008] The method for preparing the fluororana intermediate impurity comprises the following steps:

[0009] S1, adding 3',5'-dichloro-2,2,2-trifluoroacetophenone and acetic acid to organic solvent A, and then adding a catalyst;

[0010] S2, stirring and heating, and performing the first heat preservation reaction;

[0011] S3, adding a dehydrating agent and performing a second heat preservation reaction;

[0012] S4, pouring the reaction solution obtained in step S2 into an ice-water mixture, extracting and concentrating with an organic solvent B, and performing column separation to obtain a crude product;

[0013] S5, recrystallizing the crude product using organic solvent C to obtain the intermediate impurity 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid.

[0014] The organic solvent A includes at least one of N,N-dimethylformamide, N,N-dimethyl sulfoxide, dichloromethane, dioxane, and toluene.

[0015] The solvents used for column separation are ethyl acetate and petroleum ether, and the mass ratio of ethyl acetate to petroleum ether is (1-5):1.

[0016] The concentration includes vacuum distillation, and the temperature of the vacuum distillation is 45-55°C.

[0017] The catalyst comprises at least one of triethylamine, DBU (1,8-diazacyclo[5,4,0]undecene-7), DMAP (4-dimethylaminopyridine), and tributylamine.

[0018] The temperature of the first insulation reaction is 0-80°C.

[0019] Preferably, the temperature of the first insulation reaction is 60-75°C.

[0020] The dehydrating agent includes at least one of acetic anhydride, propionic anhydride, succinic anhydride, acetyl chloride, propionyl chloride, butyryl chloride and oxalyl chloride.

[0021] The organic solvent B includes at least one of toluene, dichloromethane, chloroform, ethyl acetate, isopropyl acetate, n-heptane and petroleum ether.

[0022] The organic solvent C includes at least one of acetonitrile, ethyl acetate, isopropyl acetate, acetone, butanone, dichloromethane, ethanol, methanol, isopropanol, n-heptane, n-hexane, and petroleum ether.

[0023] Preferably, the organic solvent C comprises ethyl acetate and n-heptane, and the mass ratio of ethyl acetate to n-heptane is 1:(1-5).

[0024] The present application study found that by selecting specific organic solvents A, B and C, the purity of the intermediate impurity 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid can reach 98%, which may be due to avoiding the dissolution and precipitation of side reaction products.

[0025] The recrystallization temperature is 0-5°C.

[0026] The weight ratio of the 3',5'-dichloro-2,2,2-trifluoroacetophenone to acetic acid is 1:(1.2-3).

[0027] Preferably, the weight ratio of the 3',5'-dichloro-2,2,2-trifluoroacetophenone to acetic acid is 1:(1.2-3).

[0028] Beneficial Effects

[0029] 1. This application provides the structural characteristics and preparation method of the fluororana intermediate impurity 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid.

[0030] 2. The preparation method provided in this application has a short synthetic route and is easy to operate.

[0031] 3. The preparation method provided in this application has mild reaction conditions and short reaction time.

[0032] 4. The present application selects specific organic solvent A, organic solvent B and organic solvent C, which can make the purity of the intermediate impurity 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid reach 98%.

[0033] 5. This application can provide technical support for the preparation of high-purity flurellana by performing spectral characterization on 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid, which has positive significance for improving the quality standard of flurellana and ensuring the safety of veterinary drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 It is the purity of the reaction solution of 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid in Example 1.

[0035] Figure 2 It is the purity of 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid after recrystallization in Example 1.

[0036] Figure 33-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid in Example 1 1 H NMR.

[0037] Figure 4 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid in Example 1 13 C NMR.

[0038] Figure 5 This is the MS spectrum of 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid in Example 1.

[0039] Figure 6 It is 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid HH COSY in Example 1.

[0040] Figure 7 This is the DEPT 90 spectrum of 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid in Example 1.

[0041] Figure 8 This is the DEPT 135 spectrum of 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid in Example 1. DETAILED DESCRIPTION

[0042] Example 1

[0043] A method for preparing a fluororana intermediate impurity [3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid] comprises the following steps:

[0044] Add 5.0 g of 3',5'-dichloro-2,2,2-trifluoroacetophenone to a 500 mL three-necked flask, add 2.0 g of triethylamine (Shandong Kunda Biotechnology Co., Ltd., batch number: 2024030104001), add 2.0 g of acetic acid (Shenyang Chemical Reagent Factory, batch number: 202404011), heat to 60 ° C, react for 2 hours, add 2.0 g of acetic anhydride (Sinopharm Chemical Reagent Co., Ltd., batch number: 20200722), keep warm for 2 hours, pour the reaction solution into 100 g of ice-water mixture and stir for 30 minutes, add 200 mL of toluene (Northern Huajin Chemical Industry Co., Ltd., batch number: 20230318) for extraction, separate the liquids, add 100 mL of toluene to the aqueous phase for extraction again, separate the liquids, combine the organic phases, and concentrate under reduced pressure at 50 ° C to obtain a dark oil with a purity of 87.95% (HPLC analysis). Figure 1), add dichloromethane (Shandong Dongyue Fluorosilicon Material Co., Ltd., batch number: 240301) 200 mL, silica gel 40 g, stir evenly and concentrate to dryness, ethyl acetate (Tangshan Zhongrong Technology Co., Ltd., batch number: 20240220): petroleum ether (Dongying Yongxin Fine Chemical Co., Ltd., batch number: 20240305) = 3:1 for column separation to obtain 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid (2.6 g). The above solid was added to 10 mL of ethyl acetate, heated to dissolve, and 30 mL of n-heptane (Shanxi Yueanda New Energy Co., Ltd., batch number: 20231121) was added. The mixture was refluxed for 2 h, cooled to room temperature (25°C), and a solid was precipitated. The solid was crystallized at 3°C ​​for 5 h, filtered, and the filter cake was rinsed with n-heptane = 1:3 to obtain a light yellow solid. The solid was dried to obtain 1.8 g of 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid.

[0045] Example 2

[0046] A method for preparing a fluororana intermediate impurity [3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid] comprises the following steps:

[0047] To a 500mL three-necked flask, 5.0g of 3',5'-dichloro-2,2,2-trifluoroacetophenone, 2.0g of 4-dimethylaminopyridine and 2.0g of acetic acid were added, the temperature was raised to 60°C, the reaction was continued for 2h, 3.0g of acetic anhydride was added, the reaction mixture was kept warm for 2h, the reaction solution was poured into 100g of ice-water mixture and stirred for 30min, 200mL of toluene was added for extraction, the liquids were separated, 100mL of toluene was added to the aqueous phase for extraction again, the liquids were separated, the organic phases were combined, and the mixture was concentrated under reduced pressure at 50°C to obtain a dark oily substance. 150mL of dichloromethane and 40g of silica gel were added, the mixture was stirred evenly and then concentrated to dryness. Column separation was performed with ethyl acetate: petroleum ether = 3:1 to obtain 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid (3.3g). The above solid was added with 15 mL of ethyl acetate, heated to dissolve, 50 mL of n-heptane was added, refluxed for 2 h, cooled to room temperature (25°C), solid was precipitated, and crystallized at 3°C ​​for 5 h. The filter cake was rinsed with n-heptane = 1:3 to obtain a light yellow solid, which was dried to obtain 2.4 g of 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid.

[0048] Comparative Example 1

[0049] A method for preparing a fluororana intermediate impurity [3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid] comprises the following steps:

[0050] 4.46 g of 4-acetyl-2-methylbenzoic acid, 6.08 g of 3',5'-dichloro-2,2,2-trifluoroacetophenone, 18.2 g of toluene and 3.79 g of triethylamine were stirred at 60°C for 13 hours. 12.2 g of toluene was added to the slurry reaction solution and cooled to room temperature (25°C). The reaction solution was filtered under reduced pressure and the solid was washed with a small amount of toluene. 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanyl)-2-methylbenzoic acid was a white solid, and 11.3 g of triethylamine salt was obtained by drying under reduced pressure.

[0051] Add 3.0 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutyl)-2-methylbenzoic acid, 7.5 g of toluene and 87 mg of 4-dimethylaminopyridine, and heat to 80°C. Then add 1.16 g of acetic anhydride and 0.86 g of triethylamine. After the addition, stir at 80°C for 4 hours. Add 7.5 g of toluene to the reaction solution and cool to room temperature (25°C). Add 0.77 g of sodium hydroxide in water (8.1 g) to the reaction solution and separate the mixture. The organic phase is concentrated under reduced pressure to obtain 2.3 g of a light yellow solid. The solid is separated by column, ethyl acetate: n-heptane = 3:1, and 0.13 g of a light yellow solid is obtained.

[0052] Performance Testing Methods and Data

[0053] The purity (HPLC) test was carried out in the examples and comparative examples, and the test data are listed in Table 1, wherein the purity of 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid prepared in Example 1 is as follows: Figure 2 shown.

[0054] The 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid prepared in Example 1 was characterized by its structure: Figure 3 As shown, the NMR carbon spectrum is Figure 4 As shown, mass spectrometry Figure 5 As shown, the two-dimensional NMR spectrum of hydrogen-hydrogen correlation Figure 6 As shown, DEPT 90 carbon spectrum Figure 7 As shown, DEPT 135 carbon spectrum Figure 8 shown.

[0055] Table 1

[0056] 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid purity / % Example 1 98.61 Example 2 98.82 Comparative Example 1 95.8

Claims

1. A method for preparing a fluororana intermediate impurity, characterized in that: The reaction formula of the preparation is shown in Formula 1:

2. The method for preparing the fluororana intermediate impurity according to claim 1, characterized in that: The following steps are involved: S1, adding the reaction raw materials 3',5'-dichloro-2,2,2-trifluoroacetophenone and acetic acid into organic solvent A, and then adding a catalyst; S2, stirring and heating, and performing the first heat preservation reaction; S3, adding a dehydrating agent and performing a second heat preservation reaction; S4, pouring the reaction solution obtained in step S2 into an ice-water mixture, extracting and concentrating with an organic solvent B, and performing column separation to obtain a crude product; S5, recrystallizing the crude product using organic solvent C to obtain the intermediate impurity 3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoic acid.

3. The method for preparing the fluororana intermediate impurity according to claim 2, characterized in that: The organic solvent A includes at least one of N,N-dimethylformamide, N,N-dimethyl sulfoxide, dichloromethane, dioxane, and toluene.

4. The method for preparing the fluororana intermediate impurity according to claim 2 or 3, characterized in that: The catalyst includes at least one of triethylamine, DBU, DMAP and tributylamine.

5. The method for preparing the fluororana intermediate impurity according to claim 4, characterized in that: The temperature of the first insulation reaction is 0-80°C.

6. The method for preparing the fluororana intermediate impurity according to claim 2, characterized in that: The temperature of the first insulation reaction is 60-75°C.

7. The method for preparing the fluororana intermediate impurity according to claim 6, characterized in that: The dehydrating agent includes at least one of acetic anhydride, propionic anhydride, succinic anhydride, acetyl chloride, propionyl chloride, butyryl chloride and oxalyl chloride.

8. The method for preparing the fluororana intermediate impurity according to claim 7, characterized in that: The organic solvent B includes at least one of toluene, dichloromethane, chloroform, ethyl acetate, isopropyl acetate, n-heptane and petroleum ether.

9. The method for preparing the fluororana intermediate impurity according to claim 8, characterized in that: The organic solvent C includes at least one of acetonitrile, ethyl acetate, isopropyl acetate, acetone, butanone, dichloromethane, ethanol, methanol, isopropanol, n-heptane, n-hexane, and petroleum ether.

10. The method for preparing the fluororana intermediate impurity according to claim 9, characterized in that: The weight ratio of the 3',5'-dichloro-2,2,2-trifluoroacetophenone to acetic acid is 1:(1.2-3).

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