Synthesis method of 2, 2, 2-trifluoro-1-(3, 4, 5-trichlorobenzene) ethanone

Abstract

The invention discloses a synthesis method of 2, 2, 2-trifluoro-1-(3, 4, 5-trichlorobenzene) ethanone, and belongs to the field of medical intermediates. The method comprises the following steps that 2, 6-dichloroaniline serves as a raw material, 3, 4, 5-trichlorobromobenzene is obtained through continuous bromination / oxidation and diazotization / chlorination, 2, 2, 2-trifluoro-1-(3, 4, 5-trichlorobenzene) ethanone is obtained through Grignard / acylation reaction, and the total yield is 65% or above. The process has the advantages of easily available raw materials, short period, mild conditions, high yield, less three wastes and low requirements on equipment, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone, belonging to the field of synthesis of pharmaceutical intermediates. Background Art

[0002] 2,2,2-Trifluoro-1-(3,4,5-trichlorophenyl)ethanone, molecular formula: C8H2Cl3F3O, molecular weight: 277.46, CAS number: 158401-00-4, and its chemical structural formula is as follows:

[0003]

[0004] 2,2,2-Trifluoro-1-(3,4,5-trichlorophenyl)ethanone is an intermediate for the anthelmintic lotilaner. As an important fine chemical raw material and intermediate, the current main synthesis methods are as follows:

[0005] A. Using 2,6-dichloro-4-bromoaniline as the raw material, synthesizing the product through diazotization chlorination and Grignard reaction. There are many literatures on Grignard reaction (CN112876345A, CN102414202A, CN117447459A, CN109328017A, WO2017196607 A1, etc.). The trifluoroacetyl compounds coupled with 3,4,5-trichlorophenylmagnesium bromide mainly include trifluoroacetyl diethylamine, trifluoroacetyl dimethylamine, N-trifluoroacetylpiperidine, N-trifluoroacetylpyrrolidine, ethyl trifluoroacetate, trifluoroacetyl chloride, trifluoroacetic anhydride, etc., and the highest yield is about 70%. The reaction yield is low, there is a lot of wastewater, the preparation conditions of Grignard reagent are harsh, and isopropylmagnesium bromide which is expensive and difficult to store needs to be purchased for Grignard exchange at low temperature, which is not conducive to industrialization. When preparing Grignard reagent under reflux conditions, the practical result of the applicant according to this method is that there is a large amount of tar, it is difficult to be completely converted, and the subsequent Grignard reaction is difficult with low yield.

[0006] B. Using 2,6-dichloroaniline as the raw material, obtaining the product through amino protection, Friedel-Crafts acylation, deprotection, and diazotization chlorination (CN113651710A). This method requires protection and deprotection of amino groups, and both acyl chloride and acyl fluoride as acylating reagents are gases, which are not easy to operate in storage, transportation, and feeding. The yields of other acylating reagents such as esters, acid anhydrides, and carboxylic acids in Friedel-Crafts reactions are low.

[0007] C. Using 3,4,5-trichlorobromobenzene as the raw material to exchange with n-butyllithium, and then coupling with ethyl trifluoroacetate to obtain the product (CN103502246A). This method needs to be carried out at a relatively low temperature, with harsh conditions and is not easy to industrialize. Summary of the Invention

[0008] In view of the above disadvantages, the present invention provides a milder and more environmentally friendly method for synthesizing 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone. This method uses a bromination / oxidation method to synthesize the intermediate, with mild conditions, saving the unit consumption of bromine and reducing costs. The product can directly undergo the next diazotization chlorination reaction without post-treatment. It greatly reduces wastewater, reduces unit consumption, energy consumption and equipment, and improves the reaction yield. The Grignard reaction greatly improves the reaction activity in the presence of a catalyst, with mild conditions, increased conversion rate, reduced formation of tar, and improved reaction yield. This process has mild conditions, high yield, low unit consumption, less three wastes, and low requirements for equipment, and is suitable for industrial production.

[0009] The synthesis method of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone according to the present invention comprises the following steps: using 2,6-dichloroaniline as a raw material, through bromination / oxidation, diazotization, and Grignard / acylation reactions to obtain 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone.

[0010] Furthermore, the technical solution of the present invention mainly includes three-step reactions, and the specific conditions for each step are as follows:

[0011] First step: React 2,6-dichloroaniline with a brominating agent and an oxidizing agent in an organic solvent to obtain 2,6-dichloro-4-bromoaniline;

[0012] Second step: Mix 2,6-dichloro-4-bromoaniline with hydrochloric acid, then dropwise add a diazotizing reagent to form a diazonium salt; then add it to a chlorinating agent for reaction to obtain 3,4,5-trichlorobromobenzene;

[0013] Third step: React 3,4,5-trichlorobromobenzene with metallic magnesium to form a Grignard reagent, and then react it with an acylating agent in the presence of a catalyst and hydrolyze to obtain 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone.

[0014] The synthesis method of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone according to the present invention is represented by the following synthetic route:

[0015]

[0016] Furthermore, in the first step of the above technical solution, the brominating agent is selected from bromine or hydrobromic acid, the oxidizing agent is chlorine; the organic solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, and water.

[0017] Furthermore, in the first step of the above technical solution, the molar ratio of the brominating reagent to 2,6-dichloroaniline is 0.51 - 1.05:1, and the molar ratio of the oxidizing agent to 2,6-dichloroaniline is 0.51 - 1.05:1.

[0018] Further, in the first step of the above technical solution, the feeding sequence is to add the brominating agent first and then introduce the oxidizing agent; the reaction temperature is 10 - 50°C.

[0019] Further, in the second step of the above technical solution, the diazotizing reagent is sodium nitrite, the diazotization reaction temperature is -10 - 10°C; the molar ratio of sodium nitrite to 2,6-dichloroaniline is 1.1 - 1.4:1.

[0020] Further, in the second step of the above technical solution, the chlorinating agent is hydrochloric acid / cuprous chloride or hydrochloric acid / cupric oxide.

[0021] Further, in the third step of the above technical solution, the catalyst is anhydrous lithium chloride or lanthanum(III) bis(lithium chloride); the acylating reagent is selected from dimethyl(trifluoroacetyl)amine, diethyl(trifluoroacetyl)amine, piperidyl(trifluoroacetyl) or N-methoxy-N-methyltrifluoroacetamide.

[0022] Further, in the third step of the above technical solution, the molar ratio of 3,4,5-trichlorobromobenzene, metallic magnesium to the acylating reagent is 1:1.1 - 1.2:0.9 - 1.1. Specific Embodiments

[0023] The following non-limiting embodiments can enable those of ordinary skill in the art to more comprehensively understand the present invention, but do not limit the present invention in any way.

[0024] In the following embodiments, the test methods are conventional methods unless otherwise specified; the reagents and materials can be obtained from commercial sources unless otherwise specified.

[0025] Example 1

[0026] In a four-necked flask equipped with a reflux pipe, add 162 g (1 mol) of 2,6-dichloroaniline and 82 g of water, control the temperature at 30 - 40°C, start to dropwise add 83 g of bromine (0.52 mol), and keep warm for 0.5 h after the addition; open the ventilation valve, slowly introduce 37 g of chlorine gas, keep warm for 1 h after completion, and end the reaction when the raw materials in the middle control are ≤ 0.2%, control the kettle temperature at 60 - 80°C and distill and recover chloroform.

[0027] Add 162 g of 30% hydrochloric acid to the reaction flask, stir and cool down to -10°C, dropwise add 449 g of 20% sodium nitrite solution, control the reaction temperature at -10 - 0°C, and keep warm for 1 h after the addition.

[0028] Add 40 g (0.4 mol) of cuprous chloride and 243 g of 30% hydrochloric acid to a four-necked flask. Control the temperature of the kettle at 0 ± 5 °C and dropwise add the diazonium solution. After addition, keep the temperature for 1 h, then raise the temperature to 10 - 15 °C and keep the temperature for 1 h. Add an organic solvent for extraction and layering. After distilling and recovering the organic solvent, rectify to obtain 214 g of 3,4,5-trichlorobromobenzene, with a purity of 99.3% and a yield of 81.6%.

[0029] Example 2

[0030] In a four-necked flask equipped with a reflux pipe, add 162 g (1 mol) of 2,6-dichloroaniline and 162 g of water. Control the temperature at 20 - 30 °C and dropwise add 177 g (1.05 mol) of 48% hydrobromic acid. After addition, keep the temperature for 0.5 h. Open the ventilation valve and slowly introduce 76 g of chlorine gas. After completion, keep the temperature for 1 h. When the intermediate control of the raw materials is ≤ 0.2%, the reaction ends.

[0031] Add 243 g of 30% hydrochloric acid to the reaction flask, stir and cool down to -5 °C, then dropwise add 386 g of 25% sodium nitrite solution, control the reaction temperature at -5 to 5 °C. After addition, keep the temperature for 1 h.

[0032] Add 50 g (0.5 mol) of cuprous chloride and 243 g of 30% hydrochloric acid to a four-necked flask. Control the temperature of the kettle at 0 ± 5 °C and dropwise add the diazonium solution. After addition, keep the temperature for 1 h, then raise the temperature to 10 - 15 °C and keep the temperature for 1 h. Add an organic solvent for extraction and layering. After distilling and recovering the organic solvent, rectify to obtain 221 g of 3,4,5-trichlorobromobenzene, with a purity of 99.1% and a yield of 84.1%.

[0033] Example 3

[0034] In a four-necked flask equipped with a reflux pipe, add 162 g (1 mol) of 2,6-dichloroaniline and 162 g of water. Control the temperature at 30 - 40 °C and dropwise add 186 g (1.1 mol) of 48% hydrobromic acid. After addition, keep the temperature for 0.5 h. Open the ventilation valve and slowly introduce 82 g of chlorine gas. After completion, keep the temperature for 1 h. When the intermediate control of the raw materials is ≤ 0.2%, the reaction ends.

[0035] Add 243 g of 30% hydrochloric acid to the reaction flask, stir and cool down to -10 °C, then dropwise add 414 g of 25% sodium nitrite solution, control the reaction temperature at -10 to 5 °C. After addition, keep the temperature for 1 h.

[0036] Add 72 g (0.5 mol) of cuprous oxide and 243 g of 30% hydrochloric acid to a four-necked flask. Control the temperature of the kettle at 0 - 10 °C and dropwise add the diazonium solution. After addition, keep the temperature for 1 h, then raise the temperature to 15 - 25 °C and keep the temperature for 1 h. Add an organic solvent for extraction and layering. After distilling and recovering the organic solvent, rectify to obtain 209 g of 3,4,5-trichlorobromobenzene, with a purity of 99.4% and a yield of 79.8%.

[0037] Example 4

[0038] Under nitrogen protection, 8.64 g (0.36 mol) of magnesium chips and 240 g of tetrahydrofuran were added to a four-necked flask. The mixture was stirred and heated to 25 - 30 °C. 2 grains of iodine and 4 g of isopropyl bromide were added. When an obvious temperature rise was observed, it was considered as initiation. After the temperature in the kettle naturally dropped below 30 °C, the temperature was lowered, and the reaction temperature was controlled at 10 - 20 °C. 1.6 g of anhydrous lithium chloride was added, and a solution of 78.5 g (0.3 mol) of 3,4,5-trichlorobromobenzene and 80 g of tetrahydrofuran was added dropwise. After addition, the mixture was kept warm for 2 h. The reaction was completed when the content of 3,4,5-trichlorobromobenzene in the in-process control sample was ≤0.5%. The temperature was lowered to -5 - 5 °C, and 54.35 g (0.3 mol) of N-trifluoroacetylpiperidine was added dropwise. After addition, the mixture was kept warm for 2 h, and the reaction ended.

[0039] 10% hydrochloric acid was added to the four-necked flask, and the temperature was lowered to 0 ± 5 °C. The temperature was controlled at ≤30 °C, and the Grignard reaction solution was added dropwise. The pH was adjusted to acidic, and the layers were separated. The aqueous layer was extracted with toluene. After the oil layers were combined, the oil layer was washed with water. The solvents toluene and tetrahydrofuran were recovered by distillation, and 67.7 g of the product was obtained by rectification. The purity was 99.6%, and the yield was 81.01%.

[0040] Example 5

[0041] Under nitrogen protection, 7.92 g (0.33 mol) of magnesium chips and 160 g of tetrahydrofuran were added to a four-necked flask. The mixture was stirred and heated to 25 - 30 °C. 2 grains of iodine and 3 g of dibromoethane were added. When an obvious temperature rise was observed, it was considered as initiation. After the temperature in the kettle naturally dropped below 30 °C, the temperature was lowered, and the reaction temperature was controlled at 5 - 20 °C. 2 g of lanthanum(III) bis(lithium chloride) reagent was added, and a solution of 78.3 g (0.3 mol) of 3,4,5-trichlorobromobenzene and 120 g of toluene was added dropwise. After addition, the mixture was kept warm for 2 h. The reaction was completed when the content of 3,4,5-trichlorobromobenzene in the in-process control sample was ≤0.5%. The temperature was lowered to -5 - 5 °C, and 54 g (0.32 mol) of N,N-diethyltrifluoroacetamide was added dropwise. After addition, the mixture was kept warm for 2 h, and the reaction ended.

[0042] The temperature was controlled at ≤30 °C, and an aqueous ammonium chloride solution was added dropwise. The pH was adjusted to acidic, and the layers were separated. The aqueous layer was extracted with toluene. After the oil layers were combined, the oil layer was washed with water. The solvents toluene and tetrahydrofuran were recovered by distillation, and 70.6 g of the product was obtained by rectification. The purity was 99.5%, and the yield was 84.4%.

[0043] Example 6

[0044] Under nitrogen protection, 9.2 g (0.38 mol) of magnesium chips and 160 g of 2-methyltetrahydrofuran were added to a four-necked flask. The mixture was stirred and heated to 25 - 30 °C. 2 grains of iodine and 5 g of isopropyl bromide were added. When an obvious temperature increase was observed, it was considered as initiation. After the temperature of the reactor naturally dropped below 30 °C, the temperature was decreased, and the reaction temperature was controlled at 5 - 15 °C. 3 g of anhydrous lithium chloride was added, and a solution of 78.3 g (0.3 mol) of 3,4,5-trichlorobromobenzene and 80 g of 2-methyltetrahydrofuran was added dropwise. After the addition, the mixture was kept warm for 2 h. The reaction was completed when the content of 3,4,5-trichlorobromobenzene in the in-process control sample was ≤ 0.5%. The temperature was decreased to -5 - 5 °C, and 47.5 g (0.3 mol) of N-methoxy-N-methyltrifluoroacetamide was added dropwise. After the addition, the mixture was kept warm for 2 h, and the reaction ended.

[0045] The temperature was controlled ≤ 30 °C, and 15% aqueous hydrochloric acid solution was added dropwise to adjust the pH to acidic. The layers were separated, and the aqueous layer was extracted with 2-methyltetrahydrofuran. The organic layers were combined and washed with water, and the solvent was recovered by distillation. The product was obtained by rectification, with a mass of 71.7 g, a purity of 99.4%, and a yield of 85.6%.

[0046] As described above, it is only the preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, makes equivalent substitutions or changes, and all should be covered within the protection scope of the present invention.

Claims

1. A method for synthesizing 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone, characterized in that, It includes the following steps: Using 2,6-dichloroaniline as a raw material, through bromination / oxidation, diazotization, Grignard / acylation reactions, 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone is obtained.

2. The synthesis method of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone according to claim 1, characterized in that: In the first step, 2,6-dichloroaniline is reacted with a brominating agent and an oxidizing agent in an organic solvent to obtain 2,6-dichloro-4-bromoaniline; In the second step, 2,6-dichloro-4-bromoaniline is mixed with hydrochloric acid, and then a diazotizing reagent is added dropwise to generate a diazonium salt; then it is reacted in a chlorinating agent to obtain 3,4,5-trichlorobromobenzene; In the third step, 3,4,5-trichlorobromobenzene reacts with metallic magnesium to form a Grignard reagent, and then it is reacted with an acylating reagent in the presence of a catalyst and hydrolyzed to obtain 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone.

3. The synthesis method of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone according to claim 2, characterized in that: In the first step, the brominating agent is selected from bromine or hydrobromic acid, the oxidizing agent is chlorine; the organic solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, and water.

4. The synthesis method of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone according to claim 2, wherein: In the first step, the molar ratio of the brominating reagent to 2,6-dichloroaniline is 0.51-1.05:1, and the molar ratio of the oxidizing agent to 2,6-dichloroaniline is 0.51-1.05:

1.

5. The synthesis method of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone according to claim 2, characterized in that: In the first step, the feeding order is to add the brominating agent first and then introduce the oxidizing agent; the reaction temperature is 10-50°C.

6. The synthesis method of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone according to claim 2, wherein: In the second step, the diazotizing reagent is sodium nitrite, and the diazotization reaction temperature is -10-10°C; the molar ratio of sodium nitrite to 2,6-dichloroaniline is 1.1-1.4:

1.

7. The synthesis method of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone according to claim 2, characterized in that: In the second step, the chlorinating agent is hydrochloric acid / cuprous chloride or hydrochloric acid / cupric oxide.

8. The synthesis method of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone according to claim 2, wherein: In the third step, the catalyst is anhydrous lithium chloride or lanthanum(III) bis(lithium chloride); the acylating reagent is selected from trifluoroacetyl dimethylamine, trifluoroacetyl diethylamine, trifluoroacetyl piperidine, or N-methoxy-N-methyl trifluoroacetamide.

9. The synthesis method of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone according to claim 2, characterized in that: In the third step, the molar ratio of 3,4,5-trichlorobromobenzene, metallic magnesium to the acylating reagent is 1:1.1-1.2:0.9-1.1.

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