The invention relates to a method for preparing 3apos; , 5apos; method for preparing 2, 2, 2-trifluoroacetophenone

Abstract

The invention discloses a synthesis method of an important intermediate 3 ', 5'-dichloro-2, 2, 2-trifluoroacetophenone of fluralana, and the synthesis route is as follows: # imgabs0 #. The preparation method has the advantages of short steps, low price of reaction raw materials, milder process conditions, small amount of three wastes, high reaction yield and good product quality, has better competitive advantages, and meets the requirements of modern industrial mass production.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing an important intermediate of flurana, 3', 5'-dichloro-2,2, 2-trifluoroacetophenone. Background Art

[0002] Fluoranab is mainly used for the treatment of animal parasites. It has similar targets to insecticides such as phenylpyrazoles, cyclopentadienes and macrolides. It is a γ-aminobutyric acid-gated chloride channel interferor. Its mechanism of action is mainly to interfere with γ-aminobutyric acid-gated chloride channels to achieve insecticidal effects. According to relevant literature reports, as a broad-spectrum insecticide, fluoranab has good insecticidal activity against most agricultural pests in addition to animal parasites. Compared with other insecticides on the market, fluoranab has comparable or higher insecticidal activity, especially against pests such as Pediculus, Ovaries, Hemiptera, Diptera and Lepidoptera. Therefore, fluoranab is expected to be developed as a pesticide for the prevention and control of agricultural pests. There are currently many methods for the synthesis of fluoranab, among which 3', 5'-dichloro-2,2, 2-trifluoroacetophenone is an important intermediate for the synthesis of fluoranab. There are many methods for synthesizing 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone in the prior art.

[0003] US9006447B2 uses CF3TMS to trifluoromethylate 3,5-dichlorobenzoic acid methyl ester to prepare 3', 5'-dichloro-2,2, 2-trifluoroacetophenone, but CF3TMS is expensive. The synthesis route is as follows:

[0004] .

[0005] WO2010125130A1 uses 2,4-dichlorobromobenzene and trifluoroacetyl chloride to prepare 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone. However, trifluoroacetyl chloride has great environmental hazards and a highly dangerous catalyst, diisobutylaluminum hydride DIBAL-H, is used. The synthesis route is as follows:

[0006] .

[0007] Master's thesis (Study on the Synthesis of Fluralaner, a New Veterinary Drug, Huang Daoyou) uses 2,4-dichlorobromobenzene and ethyl trifluoroacetate to prepare 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone, but the raw material price is high and it is not suitable for industrial production. The public synthesis route is as follows:

[0008] .

[0010] IN202021021840A prepares a 1-trifluoroacetylpiperidine intermediate by reacting piperidine with ethyl trifluoroacetate, and then reacts with 2,4-dichlorobromobenzene to prepare 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone. The reaction is multi-step, and the raw materials are expensive and difficult to produce. The disclosed synthesis route is as follows:

[0011] .

[0012] The following synthetic route is disclosed in WO2018009751A1:

[0013] ,

[0014] The yield of the synthesis method reported in this document is 36%, but there are problems such as high raw material prices and low yields, making it unsuitable for industrial production.

[0015] JP2008133242 A discloses the following synthesis route:

[0016] ,

[0017] This reaction route requires minus 80 o C range, which is difficult to operate industrially, consumes a lot of energy, and is not convenient for industrial production.

[0018] CN116535298A uses 3,5-dichlorobenzoic acid methyl ester as a raw material and trifluoromethane as a trifluoromethylation reagent to prepare 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone. Gaseous trifluoromethane can cause headaches, nausea and vomiting in humans, and has an anesthetic effect on humans. Therefore, large-scale use in industry poses a safety hazard. At the same time, the specific base used in the reaction also leads to high production costs. Summary of the invention

[0019] In order to solve the above-mentioned defects existing in the prior art, the present application provides a method for preparing 3', 5'-dichloro-2, 2,2-trifluoroacetophenone with short steps, cheap reaction raw materials, milder process conditions, high reaction yield, good product quality and good competitive advantage.

[0020] Specifically, the present invention provides a method for preparing a compound of formula III, which comprises the following steps:

[0021] Step 1), the compound of formula I reacts with magnesium metal in a solvent to generate a corresponding Grignard reagent;

[0022] Step 2), the Grignard reagent obtained in step 1) reacts with the compound of formula II to obtain the compound of formula III, and its synthesis route is as follows:

[0023] .

[0025] Preferably, the present invention further comprises step 3) a post-processing step.

[0026] Beneficial effects of the present invention:

[0027] 1. The preparation method of the present invention has a short number of steps, the price of the reaction raw materials is cheap, the process conditions are milder, and it is more suitable for process production;

[0028] 2. The preparation method of the present invention has good selectivity, high reaction yield, good product quality, low production cost and strong competitive advantage. DETAILED DESCRIPTION

[0029] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "including" will be understood to include the stated components or steps, without excluding other material components or steps.

[0030] In addition, in order to better illustrate the present invention, numerous specific details are given in the following detailed description.

[0031] Those skilled in the art will appreciate that the present invention can be implemented without certain specific details. In some embodiments, raw materials, methods, means, etc. that are well known to those skilled in the art are not described in detail in order to highlight the main purpose of the present invention.

[0032] In addition, it should be noted that the numerical ranges in this application include the end values ​​and any point values ​​between the end values. For example, the numerical range of 1 to 10 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; the numerical range of 0.1 to 0.9 includes 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9; the numerical range of 0.01 to 0.09 includes 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09; the numerical range of 0.08 to 0.21 includes 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21.

[0033] The present invention first provides a method for preparing a compound of formula III, which comprises the following steps:

[0034] Step 1), the compound of formula I reacts with magnesium metal in a solvent to generate a corresponding Grignard reagent;

[0035] Step 2) The reaction product obtained in step 1) is reacted with the compound of formula II to obtain the compound of formula III, and its synthesis route is as follows:

[0036] .

[0038] In the above preparation method, the reaction temperature in step 1) is between 10°C and 90°C, preferably 50-90 o C. More preferably 70-80 o C, the reaction time is 1-5 h, preferably 2-3 h; the solvent is one or more of tetrahydrofuran, ethyl ether, dibutyl ether, 2-methyltetrahydrofuran, tert-butyl methyl ether, toluene or hexane.

[0039] In the above preparation method, preferably, in step 1), an initiator is added when the compound of formula I reacts with metal magnesium in a solvent; the initiator is iodine or 1,2-dibromoethane. The molar ratio of metal magnesium to 3,5-dichlorobromobenzene is 0.9-1.2:1, preferably 1.1:1; the metal magnesium is preferably magnesium chips. The weight ratio of the solvent to 3,5-dichlorobromobenzene is 1-3:1, preferably 1.5:1.

[0040] In the above preparation method, the reaction temperature in step 2) is -15-5 o C. Preferred -10- o C, the reaction time is 0.5-2h, preferably 1 h.

[0041] Preferably, the molar ratio of the compound of formula II in step 2) of the above preparation method to the compound of formula I in step 1) is 0.5-1.5:1, preferably 1:1. Preferably, the reaction in step 2) is carried out in a solvent, and the solvent is the same as the solvent in step 1).

[0042] Preferably, the preparation method of the present invention further comprises step 3) a post-treatment step, wherein the post-treatment step comprises the steps of distilling off the reaction solvent of step 2) under reduced pressure, adding an organic solvent and an acid to extract the product. The solvent is preferably 1,2-dichloroethane, and the acid is preferably 10% hydrochloric acid.

[0043] Under the preferred conditions of the present invention, the method has excellent selectivity and yield.

[0044] In this application, unless otherwise specified, room temperature refers to "25 o C”.

[0045] The present application will be described below in conjunction with the examples. The following examples are exemplary and are only used to explain the present application, and should not be construed as limiting the spirit, purpose and scope of protection of the present application. Those who do not indicate specific techniques or conditions in the examples are carried out according to the techniques or conditions described in the literature in this area, or according to the product instructions. Those who do not indicate the manufacturer of the reagents or instruments used are all conventional products that can be purchased through regular channels.

[0046] The contents (purity) of reactants and products in the examples were measured by liquid chromatography (Agilent HPLC 1260).

[0047] The conversion rate and yield of the reaction were calculated by the following formula:

[0048] Conversion rate = (molar amount of raw material input - molar amount of raw material remaining in the product) / molar amount of raw material input × 100%.

[0049] Yield = actual mass of target product / theoretical mass of target product × 100%

[0050] Example 1 Preparation of 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone

[0051] Add 11.66g magnesium chips to a 500ml reaction bottle, add 45g tetrahydrofuran and start stirring, protect with nitrogen, dissolve 3,5-dichlorobromobenzene in 92g tetrahydrofuran and add to a constant pressure dropping funnel, first drop 3-5g of 3,5-dichlorobromobenzene solution, then add 1,2-dibromoethane to initiate, release heat violently to reflux, react with a lot of foam, wait for the foam to disappear and then drop the remaining 3,5-dichlorobromobenzene solution, it takes 1h to drop, reflux reaction for 1.5h and take samples for testing, the reaction is complete, The reaction solution was cooled to -10 to -15°C and 2,2,2-trifluoro-N-dimethylacetamide was added dropwise for 2 hours. The reaction was carried out for 0.5-1 hour and sampling was performed for detection. The raw materials were reacted and the reaction was stopped. After the reaction was completed, tetrahydrofuran was recovered under reduced pressure, and 1,2-dichloroethane was added. The temperature was lowered and the solution was quenched with hydrochloric acid. 1,2-dichloroethane 90gX2 was added and extracted twice. The organic phases were combined and the solvent was evaporated. The product was distilled under reduced pressure at 130-140°C with a 15-20 cm column. The yield was 95% and the purity was 99.5%.

[0052] Example 2 Preparation of 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone

[0053] 11.66g magnesium chips were added to a 500ml reaction bottle, 45g 2-methyltetrahydrofuran was added and stirring was started. Under nitrogen protection, 3,5-dichlorobromobenzene was dissolved in 92g 2-methyltetrahydrofuran and added to a constant pressure dropping funnel. 3-5g 3,5-dichlorobromobenzene solution was first added dropwise, and then 1,2-dibromoethane was added to initiate. Exothermic heat was violently released and reflux was reached. A large amount of foam was generated in the reaction. After the foam disappeared, the remaining 3,5-dichlorobromobenzene solution was added dropwise. The dripping time was 1h. After reflux reaction for 1.5h, sampling and detection were performed. The reaction was complete. After that, the reaction solution was cooled to -10 to -15 ° C and 2,2,2-trifluoro-N-dimethylacetamide was added dropwise. The dripping time was 2 h. The reaction was 0.5-1 h and the sampling was tested. The raw materials were reacted and the reaction was stopped. After the reaction was over, 2-methyltetrahydrofuran was recovered under reduced pressure, and 1,2-dichloroethane was added. The temperature was lowered and quenched with hydrochloric acid. 1,2-dichloroethane 90gX2 was added and extracted twice. The organic phases were combined and the solvent was evaporated. The product was distilled out under reduced pressure at 130-140 ° C with a 15-20 cm column. The yield was 90% and the purity was 99.3%.

[0054] Example 3 Preparation of 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone

[0055] Add 11.66g magnesium chips to a 500ml reaction bottle, add 45g tetrahydrofuran and start stirring, protect with nitrogen, dissolve 3,5-dichlorobromobenzene in 92g tetrahydrofuran and add to a constant pressure dropping funnel, first drop 3-5g of 3,5-dichlorobromobenzene solution, then add 1,2-dibromoethane to initiate, release heat violently to reflux, react with a lot of foam, wait for the foam to disappear and then drop the remaining 3,5-dichlorobromobenzene solution, take 1h to complete the drop, react at 40-50 degrees for 1.5h, take samples for testing, the reaction is complete, The reaction solution was cooled to -5 to 0°C and 2,2,2-trifluoro-N-dimethylacetamide was added dropwise for 2 hours. The reaction was carried out for 0.5-1 hour and sampling was performed. After the reaction was completed, the reaction was stopped. After the reaction was completed, tetrahydrofuran was recovered under reduced pressure, and 1,2-dichloroethane was added. The temperature was lowered and the solution was quenched with hydrochloric acid. 1,2-dichloroethane 90gX2 was added and extracted twice. The organic phases were combined and the solvent was evaporated. The product was distilled under reduced pressure at 130-140°C with a 15-20 cm column. The yield was 80% and the purity was 98.7%.

[0056] Example 4 Preparation of 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone

[0057] Add 11.66g magnesium chips to a 500ml reaction bottle, add 45g 2-methyltetrahydrofuran and start stirring, protect with nitrogen, dissolve 3,5-dichlorobromobenzene with 92g 2-methyltetrahydrofuran and add to a constant pressure dropping funnel, first drop 3-5g of 3,5-dichlorobromobenzene solution, then add 1,2-dibromoethane to initiate, release heat violently to reflux, react with a lot of foam, wait for the foam to disappear and then drop the remaining 3,5-dichlorobromobenzene solution, take 1h to complete the drop, keep the temperature at 40-50 degrees for 1.5h, take samples for testing, the reaction is complete, The reaction solution was cooled to -5 to 0°C and 2,2,2-trifluoro-N-dimethylacetamide was added dropwise. The dripping time was 2h. The reaction was performed for 0.5-1h and sampling was performed for detection. When the raw material remained about 6-8%, the reaction was stopped. After the reaction was completed, 2-methyltetrahydrofuran was recovered under reduced pressure, and 1,2-dichloroethane was added. The temperature was lowered and quenched with hydrochloric acid. 1,2-dichloroethane 90gX2 was added and extracted twice. The organic phases were combined and the solvent was evaporated. The product was evaporated under reduced pressure at 130-140°C with a 15-20 cm column. The yield was 76% and the purity was 98.5%.

[0058] Comparative Example 1 Preparation of 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone

[0059] The preparation was carried out according to the reaction conditions of Example 1, except that N,N-dimethyltrifluoroacetamide was replaced by trifluoroacetyl chloride, with a yield of 53% and a purity of 97%.

[0060] Comparative Example 2 Preparation of 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone

[0061] The preparation was carried out according to the reaction conditions of Example 1, except that N,N-dimethyltrifluoroacetamide was replaced by methyl trifluoroacetate, with a yield of 60% and a purity of 97.5%.

[0062] Comparative Example 3 Preparation of 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone

[0063] The preparation was carried out according to the reaction conditions of Example 1, except that N,N-dimethyltrifluoroacetamide was replaced by trifluoroacetylpyridine, with a yield of 45% and a purity of 95.8%.

[0064] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing a compound of formula III, characterized in that: The steps include: Step 1), the compound of formula I reacts with magnesium metal in a solvent to generate a corresponding Grignard reagent; Step 2), the Grignard reagent obtained in step 1) reacts with the compound of formula II to obtain the compound of formula III, and its synthesis route is as follows: 。 2. The preparation method according to claim 1, characterized in that: In step 1), the reaction temperature is between 10°C and 90°C, preferably between 50-90 o C. More preferably 70-80 o C, the reaction time is 1-5 h, preferably 2-3 h.

3. The method according to claim 1 or 2, characterized in that: In the step 1), the solvent is one or more of tetrahydrofuran, ethyl ether, dibutyl ether, 2-methyltetrahydrofuran, tert-butyl methyl ether, toluene or hexane.

4. The method according to claim 3, characterized in that: Step 1) adding an initiator when the compound of formula I reacts with magnesium metal in a solvent; preferably, the initiator is iodine or 1,2-dibromoethane.

5. The method according to claim 4, characterized in that In step 1), the molar ratio of the metal magnesium to 3,5-dichlorobromobenzene is 0.9-1.2:1, preferably 1.1:1; the metal magnesium is preferably magnesium chips.

6. The method according to claim 5, characterized in that In the reaction of step 1), the weight ratio of the solvent to 3,5-dichlorobromobenzene is 1-3:1, preferably 1.5:

1.

7. The preparation method according to claim 1, characterized in that: Step 2) The reaction temperature is -15-5 o C. Preferred -10- o C, the reaction time is 0.5-2 h, preferably 1 h.

8. The method according to claim 7, characterized in that The molar ratio of the compound of formula II in step 2) to the compound of formula I in step 1) is 0.5-1.5:1, preferably 1:

1.

9. The method according to claim 8, characterized in that The reaction in step 2) is carried out in a solvent, which is the same as the solvent in step 1).

10. The preparation method according to claim 9, characterized in that: The method further comprises a post-treatment step in step 3), wherein the post-treatment step comprises the steps of distilling off the reaction solvent in step 2) under reduced pressure, and adding an organic solvent and an acid to extract the product; the solvent is preferably 1,2-dichloroethane, and the acid is hydrochloric acid, preferably 10% hydrochloric acid.

Images