CN118851894A - A preparation method of 4-halogenated-2-trifluoromethylacetophenone - Google Patents

Abstract

The present invention discloses a method for preparing a compound of formula IV, which comprises the following steps: step 1), reacting a compound of formula I with a compound II to generate a compound of formula III; step 2), reacting a compound of formula III with an oxidant to generate a compound of formula IV. The synthetic route of the present invention is as follows: wherein X, Y and Z are as defined in the specification. The raw materials used in the above method provided by the present invention are low in cost, and compared with the existing process raw materials and preparation process, the reaction conditions are mild, the process pollution is small, the safety is high, and green industrialization is achieved, which is more suitable for industrial production.

Description

A preparation method of 4-halogenated-2-trifluoromethylacetophenone

Technical Field

The invention relates to the synthesis of pesticide intermediates, and in particular to a method for preparing a clofoconazole intermediate 4-halogenated-2-trifluoromethylacetophenone.

Background Art

Mefentrifluconazole (generic name: Mefentrifluconazole) is a new triazole fungicide developed by BASF with epoch-making significance. It was officially launched in 2019 and is expected to have a market value of more than US$1 billion per year in the future. Mefentrifluconazole has broad-spectrum, high efficiency, systemic, eradication and protection effects, especially outstanding biological activity against a variety of fungal diseases that are difficult to control. It can significantly enhance the prevention and control of more than 60 crop diseases, such as field crops such as corn, grains, and soybeans, as well as cash crops such as green peppers and grapes. It can also be used for lawn and seed treatment. It not only has higher biological activity, but also has good environmental characteristics, low toxicity to mammals, bees, etc., and high safety.

The chlorpyrifos intermediate 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone is mainly prepared through two routes: 4-fluoro-2-trifluoromethylacetophenone (route one) and 4-nitro-2-trifluoromethylacetophenone (route two).

Route 1:

Route 2

In route 1, 4-fluoro-2-trifluoromethylacetophenone is currently mainly prepared from 5-fluoro-2-bromo-trifluoromethylbenzene in the industry. The raw material cost is high, and the preparation process requires Grignard reaction and acylation reaction. The reaction conditions are harsh, and a large amount of magnesium-containing wastewater is generated after the reaction, which is difficult to treat. Refer to patents CN103649057A and WO2015091045A1 (see route 3):

Route 3:

In route 2, the preparation of 4-nitro-2-trifluoromethylacetophenone is to synthesize 4-nitro-2-trifluoromethylacetophenone by substitution reaction of 5-nitro-2-chloro-trifluorotoluene with nitroethane, and then oxidize 4-nitro-2-trifluoromethylacetophenone and etherify it with p-chlorophenol. This route will produce a large amount of waste water and nitrite, which will make post-treatment difficult. Refer to patents, EP3670491A1, US6229051B1 and CN114478259A (see route 4):

Route 4:

At present, route 1 using 5-fluoro-2-bromotrifluoromethylbenzene as an intermediate raw material to prepare the chlorfluanidazole intermediate 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone is better than route 2 and is also the preferred technical solution in this field.

Summary of the invention

In view of the problems that 5-fluoro-2-bromo-trifluoromethylbenzene is used as a raw material in the preparation process of 4-halogenated-2-trifluoromethylacetophenone in the prior art, the raw material cost is high, and the preparation process requires Grignard reaction and acylation reaction, the reaction conditions are harsh, and a large amount of magnesium-containing wastewater is generated after the reaction, which is difficult to treat. The applicant provides a preparation method of 4-halogenated-2-trifluoromethylacetophenone with low production cost and environmentally friendly process.

The present invention provides a method for preparing 4-halogenated-2-trifluoromethylacetophenone (compound of formula IV), which comprises the following steps:

Step 1), reacting the compound of formula I with compound II to generate a compound of formula III;

Step 2), the compound of formula III is oxidized with an oxidant to generate a compound of formula IV;

The synthetic route is as follows:

in,

X is a halogen;

Y and Z may be the same or different and are independently selected from hydrogen, halogen, optionally substituted alkyl, -NO ₂ , -COOR, CN, -CONH ₂ , R ₁ -CO- and pyridyl, R and R ₁ are independently H or alkyl,

Provided that Y and Z are not simultaneously alkyl, nitro, halogen, pyridyl or hydrogen.

Preferably, in step 1), the reaction is carried out in the presence of an acid-binding agent, and the acid-binding agent is selected from an organic base or an inorganic base.

Preferably, the reaction in step 2) is an oxidation reaction of the compound of formula III under metal catalysis.

Beneficial Effects

The preparation method provided by the present invention has low raw material cost. Compared with the harsh reaction conditions in the raw material preparation process of the existing process, the reaction conditions of the present invention are milder and less polluting, thus realizing green industrialization. The production process is safer and more suitable for industrial production. At the same time, since the process conditions of the present invention are suitable for industrial production and the production cost is low, it has strong competitiveness.

DETAILED DESCRIPTION

The specific implementation methods of the present invention are further described in detail below in conjunction with the examples. 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 in 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 "including" or its variations such as "comprising" or "including" will be understood to include the stated components and steps, without excluding the presence of other material components or steps.

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

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.

Hereinafter, embodiments of the present invention are described in detail. However, these embodiments are exemplary, the present invention is not limited thereto, and the present invention is defined by the scope of the claims.

In the present invention, the percentage content, unless otherwise specified, generally refers to the percentage content by weight.

In the present invention, unless otherwise specified, room temperature refers to about "20°C-25°C".

In the present invention, when indicating that a certain temperature is within a range of about, about means within a range of ±5° C. of the relevant temperature.

As used herein, the following terms used in the specification and claims have the following meanings when specific definitions are not otherwise provided.

In the present invention, halogen means fluorine, chlorine, bromine and iodine.

The term "alkyl" as used herein (and in other groups containing alkyl, e.g. the alkyl moiety of alkoxy, the alkyl moiety of arylalkyl) denotes in each case a straight-chain or branched alkyl group having usually 1 to 20 carbon atoms, frequently 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, in particular 1 to 3 carbon atoms. Examples of _C1 - _C4 -alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl). Examples of C ₁ -C ₆ -alkyl radicals are, in addition to the radicals mentioned for C ₁ -C ₄ -alkyl radicals, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl. Examples of the C ₁ -C ₁₀ alkyl group include, in addition to the groups mentioned for the C ₁ -C ₆ alkyl group, n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 1-ethylhexyl, 2-ethylhexyl, 1,2-dimethylhexyl, 1-propylpentyl, 2-propylpentyl, nonyl, decyl, 2-propylheptyl, and 3-propylheptyl, but are not limited thereto. The alkyl group may be substituted with, but is not limited to, halogen, cyano, nitro, aryl, cycloalkyl, heterocyclic, acylamino, ester, and the like.

In the present invention, "alkali metal or alkaline earth metal" has the conventional meaning in the art. Alkali metal elements refer to the six metal elements in Group IA of the periodic table except hydrogen (H), including lithium (Li), sodium (Na), potassium (K), rubidium (Rb), cesium (Cs), and francium (Fr); alkaline earth metals refer to the elements in Group IA of the periodic table, which are adjacent to Group IA where alkali metals are located, including six elements: beryllium (Be), magnesium (Mg), calcium (Ca), strontium (Sr), barium (Ba), and radium (Ra).

Examples of the "inorganic base which is a hydroxide of an alkali metal or an alkaline earth metal" of the present invention include potassium hydroxide and sodium hydroxide, but are not limited thereto.

Exemplary compounds of the "carbonate of an alkali metal or an alkaline earth metal" of the present invention include sodium carbonate, potassium carbonate, calcium carbonate and the like, but are not limited thereto.

Exemplary compounds of the "bicarbonate of an alkali metal or alkaline earth metal" of the present invention include sodium bicarbonate, potassium bicarbonate, calcium bicarbonate and the like, but are not limited thereto.

The NBS described in the present invention is N-bromosuccinimide, and the NCS described in the present invention is N-chlorosuccinimide.

The present invention provides a method for preparing 4-halogenated-2-trifluoromethylacetophenone (Formula IV), which comprises the following steps:

Step 1), reacting the compound of formula I with compound II to generate a compound of formula IV;

Step 2), the compound of formula III is oxidized with an oxidant to generate a compound of formula IV;

The synthetic route is as follows:

in,

X is halogen, preferably fluorine, chlorine, bromine and iodine;

Y and Z may be the same or different and are selected from hydrogen, halogen, substituted alkyl, -NO ₂ , -COOR, CN, -CONH ₂ , R ₁ -CO- and pyridyl, R and R ₁ are H or alkyl, respectively.

Provided that Y and Z are not simultaneously alkyl, nitro, halogen, pyridyl or hydrogen.

Preferably, the alkyl group is methyl, ethyl and propyl.

Preferably, formula II is nitroethane, 2-cyanopropionic acid, methyl 2-cyanopropionate, dimethyl methylmalonate, methyl lactate, ethyl lactate, 2-pyridinepropionic acid, methyl 2-pyridinepropionate, 2-halopropionic acid and methyl 2-halopropionate.

Preferably, in step 1), the reaction is carried out in the presence of an acid-binding agent, and the acid-binding agent is selected from an organic base or an inorganic base; the inorganic base is an alkali metal or alkaline earth metal hydroxide, an alkali metal or alkaline earth metal carbonate, an alkali metal or alkaline earth metal bicarbonate and sodium hydrogen, preferably one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate, and particularly preferably potassium carbonate; the organic base is one or more of triethylamine, pyridine and DBU, and the molar ratio of the compound of formula I to the compound of formula II and the acid-binding agent is 1:(1-1.5):(1-2).

Preferably, in the above preparation method, the reaction temperature in step 1) is 50°C to 110°C, preferably 75°C to 95°C; the reaction time is 1-8h, preferably 3-4h.

Preferably, in the above preparation method, the reaction temperature in step 2) is 40°C to 110°C, preferably 50°C to 70°C; the reaction time is 3-12h, preferably 6-8h.

Preferably, in the above preparation method, the reaction in step 2) is an oxidation reaction of the compound of formula III under metal catalysis, and the oxidant is selected from air, oxygen, ozone, _chlorine , bromine, iodine, NCS, _NBS , dichlorohydantoin _, sodium trichloroisocyanurate, KMnO4, _MnO2 , _Cr2O3 , _K2Cr2O7 , _ferric chloride, sodium tungstate, _ferric nitrate, _H2O2 , thiourea or urea of hydrogen peroxide, hypochlorous acid, sodium hypochlorite, chloric acid, sodium chlorate, hypobromous acid, sodium hypobromite, bromic acid, sodium bromate, peroxyformic acid, peracetic acid, peroxydichloroacetic acid, perfluoro or trifluoroacetic acid, sodium percarbonate, sulfur trioxide, sulfuric acid, sodium persulfate, potassium persulfate, ammonium persulfate, ammonium cerium nitrate, and at least one of meta-chlorobenzoic acid; preferably one of oxygen, air, and sodium persulfate, the metal catalyst is one of the simple substances or salts of copper, nickel, iron, cobalt, vanadium, chromium, manganese, tungsten, osmium, molybdenum, ruthenium, palladium, platinum, silver, gold, and cerium, the salt can be an organic acid salt or an inorganic acid salt, the organic acid is exemplified by formic acid, acetic acid, propionic acid, etc., but not limited thereto, the inorganic acid is exemplified by sulfuric acid, hydrochloric acid, nitric acid, etc., but not limited thereto. The metal salt is exemplified by copper sulfate, copper nitrate, copper acetate, etc., but not limited thereto.

Particularly preferably, in the above preparation method, the oxidant in step 2) is air and/or oxygen, and the metal catalyst copper acetate is particularly preferably copper acetate.

Preferably, the reaction of the above reaction step 1) and step 2) is carried out in an organic solvent, and the organic solvent is selected from one of acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone.

The present invention will be described in detail below by way of examples. In the following examples:

The amounts of reactants and products were determined by liquid chromatography (Agilent HPLC 1260).

The conversion and selectivity of the reaction were calculated by the following formula:

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

Selectivity = actual molar amount of target product/theoretical molar amount of target product × 100%

Unless otherwise specified, all raw materials used were commercially available products.

Example 14 Preparation of chloro-2-trifluoromethylacetophenone

In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, 16.7 g (0.08 mol) of the compound 2-fluoro-5-chlorotrifluorotoluene, 60 g of DMF and 17.4 g of potassium carbonate were added in sequence, the temperature was kept at 80°C, 12.9 g (0.11 mol) of methyl 2-cyanopropionate was added dropwise, and the reaction was stirred for 3 h. After HPLC detection showed that the raw materials were complete, the temperature was lowered to 60°C, copper acetate was added, and air was slowly introduced. The reaction was stirred at about 60°C for 7 h. When the raw materials were complete, acid water was added to adjust the pH, and extraction and desolventization were performed to obtain 4-chloro-2-trifluoromethylacetophenone with a content of 97% and a yield of 89%.

Example 2 Preparation of 4-chloro-2-trifluoromethylacetophenone

The difference from Example 1 is that dimethyl methylmalonate replaces methyl 2-cyanopropionate, and the other conditions remain unchanged. The compound 4-chloro-2-trifluoromethylacetophenone is obtained by reaction, with a content of 95% and a yield of 88%.

Example 3 Preparation of 4-chloro-2-trifluoromethylacetophenone

The difference from Example 1 is that methyl 2-chloropropionate replaces methyl 2-cyanopropionate, the molar ratio remains unchanged, and the reaction produces the compound 4-chloro-2-trifluoromethylacetophenone with a content of 95% and a yield of 86%.

Example 4 Preparation of 4-chloro-2-trifluoromethylacetophenone

The difference from Example 1 is that cuprous iodide replaces cupric acetate. Other conditions remain unchanged. The reaction produces the compound 4-chloro-2-trifluoromethylacetophenone with a content of 96% and a yield of 80%.

Example 54 Preparation of 4-fluoro-2-trifluoromethylacetophenone

The difference from Example 1 is that 2-fluoro-5-fluoro-trifluorotoluene is used instead of 2-fluoro-5-chlorotrifluorotoluene. The other conditions remain unchanged. The compound 4-fluoro-2-trifluoromethylacetophenone is obtained by reaction with a content of 96% and a yield of 86%.

Comparative Example 1 Preparation of 4-chloro-2-trifluoromethylacetophenone

21.7 g of 2,5-dichlorotrifluorotoluene (0.1 mol, 99%, purchased from Aladdin) was added to a four-necked bottle, and 17.4 g of potassium carbonate and 60 g of DMF were added. The mixture was kept at 150°C, and 12.9 g of methyl 2-cyanopropionate was added dropwise. The mixture was stirred for 10 h. HPLC detection showed that no reaction occurred and no 4-chloro-2-trifluoromethylacetophenone was prepared.

Comparative Example 2 Preparation of 4-chloro-2-nitroacetophenone

19.2g of 2,5-dichloronitrotoluene (0.1mol, 99%, purchased from Aladdin) was added to a four-necked bottle, and 17.4g of potassium carbonate and 60g of DMF were added. The mixture was kept at 60°C, and 12.9g of methyl 2-cyanopropionate was added dropwise. The mixture was stirred and reacted for 6h. HPLC detected that the raw materials had reacted completely. The temperature was lowered to 50°C, and copper acetate was added. Air was slowly introduced, and the temperature was maintained and stirred for 7h. When the raw materials were complete, acid water was added to adjust the pH, and the mixture was extracted and desolvated to obtain 18.9g of 4-chloro-2-nitroacetophenone with a content of 95% and a yield of 90%.

Comparison of Examples 1 and 2 shows that the activity of trifluoromethyl is worse than that of nitro. The trifluoromethyl group can only react to prepare the compound of Formula IV if it is ortho to a fluorine atom, while the nitro group can. Moreover, the comparative example does not react at high temperature, while the comparative example 2 can react at a lower temperature.

The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims (7)

1. A process for the preparation of a compound of formula IV, comprising the steps of:

Step one), reacting a compound of formula I with a compound of formula II to form a compound of formula III;

Step two), oxidizing the compound of the formula III with an oxidant to generate a compound of the formula IV;

The synthetic route is as follows:

Wherein,

X is halogen;

y and Z may be the same or different and are each selected from hydrogen, halogen, optionally substituted alkyl, -NO ₂、-COOR、CN、-CONH₂、R₁ -CO-and pyridinyl, R and R ₁ are each H or alkyl,

With the proviso that Y and Z are not simultaneously alkyl, nitro, halogen, pyridinyl or hydrogen.

2. The process according to claim 1, wherein in step one) the reaction is carried out in the presence of an acid-binding agent selected from organic or inorganic bases; the inorganic base is one or more of hydroxide of alkali metal or alkaline earth metal, carbonate of alkali metal or alkaline earth metal, bicarbonate of alkali metal or alkaline earth metal and sodium hydrogen, preferably potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate, particularly preferably potassium carbonate; the organic base is one or more of triethylamine, pyridine and DBU, and the molar ratio of the compound of the formula I to the compound of the formula II to the acid binding agent is 1: (1-1.5): (1-2).

3. The preparation process according to any one of claims 1 or 2, wherein in step one) the reaction temperature is 50 ℃ to 110 ℃, preferably 75 ℃ to 95 ℃; the reaction time is 1 to 8 hours, preferably 3 to 4 hours.

4. A process according to any one of claims 1 to 3, wherein in step two) the reaction temperature is from 40 ℃ to 110 ℃, preferably from 50 ℃ to 70 ℃; the reaction time is 3 to 12 hours, preferably 6 to 8 hours.

5. The method according to claim 4, wherein the reaction in the second step) is an oxidation reaction of the compound of formula III with an oxidizing agent under the catalysis of a metal catalyst, wherein the oxidizing agent is one or more selected from the group consisting of air, oxygen, ozone, chlorine, bromine, iodine, NCS, NBS, dichlorohydantoin, sodium trichloroisocyanuric acid, KMnO ₄、MnO₂、Cr₂O₃、K₂Cr₂O₇, ferric chloride, sodium tungstate, ferric nitrate, H ₂O₂, thiourea or urea of hydrogen peroxide, hypochlorous acid, sodium hypochlorite, chloric acid, sodium chlorate, hypobromous acid, sodium hypobromite, bromous acid, peroxyformic acid, peroxyacetic acid, peroxydichloroacetic acid, peroxydifluoro or trifluoroacetic acid, sodium percarbonate, sulfur trioxide, sulfuric acid, sodium persulfate, potassium persulfate, ammonium cerium nitrate, and m-chlorobenzoic acid; preferably one of air and sodium persulfate.

6. The method according to claim 5, wherein the metal catalyst is one of simple substances or salts of copper, nickel, iron, cobalt, vanadium, chromium, manganese, tungsten, osmium, molybdenum, ruthenium, palladium, platinum, silver, gold, cerium; the salt is an inorganic salt or an organic salt, and acetate is particularly preferred.

7. The method of claim 5 or 6, wherein the oxidizing agent is air and/or oxygen.