A method for preparing a meta-substituted acetophenone coupled compound in one pot

Abstract

This invention relates to a one-pot method for preparing m-substituted acetophenone coupling compounds. The technical solution of this invention provides a one-pot synthetic method for preparing m-substituted acetophenone coupling compounds, enabling qualitative and quantitative analysis of impurities during the preparation of oxime esters. By monitoring the production process, identifying impurity sources, and reducing impurity formation, the method improves raw material utilization and enhances product quality.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a one-pot method for preparing meta-substituted acetophenone coupling compounds. Background Technology

[0002] Azoxystrobin, an important methoxyacrylate fungicide, is an inhibitor of mitochondrial respiration. Its advantages include a broad fungicidal spectrum, high activity, low residue, and resistance to disease and rain washout. Currently, numerous azoxystrobin compound formulations are available on the market. Due to its combined protective and curative effects, it is suitable for crops such as wheat, barley, rice, sugar beets, rapeseed, legumes, vegetables, grapes, and apples, showing significant efficacy against powdery mildew, leaf spot, rust, and fruit tree diseases. Since its market launch, azoxystrobin has become one of Bayer's key fungicide products, holding a significant position in the soybean and grain fungicide market.

[0003] The key intermediate of oxime ester, m-trifluoromethylacetophenone, contains a trifluoromethyl group. Trifluoromethyl groups containing a CF bond exhibit high lipid solubility, high electronegativity, good metabolic stability, and bioavailability, and are widely found in pharmaceuticals, pesticides, and functional materials. In 1928, Lehmann et al. studied the biological activities of some trifluoromethyl-containing compounds, finding that compounds with different substituents had different effects on the central nervous system of frogs, thus exhibiting stimulant or sedative effects. In 1959, Yale et al. reported the biological activities of approximately 50 trifluoromethyl-containing compounds. These included aliphatic compounds with anesthetic effects, phenothiazine sedatives and antiemetics, benzothiadiazine diuretics, and some unevaluated antihistamines, anti-asthmatics, antimalarial, and anti-Staphylococcus aureus compounds, all of which contained trifluoromethyl groups.

[0004] The compounds of this invention contain two trifluoromethyl groups; therefore, compounds containing two trifluoromethyl groups cannot be ignored when assessing the risk of m-trifluoromethylacetophenone. Furthermore, the content of the compounds of this invention directly affects the yield of the oxime ester intermediate m-trifluoromethylacetophenone. Therefore, in the synthesis of m-trifluoromethylacetophenone, it is crucial to study the synthetic route of this coupling impurity and prepare standards for qualitative and quantitative analysis of its content in m-trifluoromethylacetophenone. Summary of the Invention

[0005] The main objective of this invention is to provide a one-pot synthesis method for preparing meta-substituted acetophenone coupling compounds and its application, so as to perform qualitative and quantitative analysis of impurities during the preparation of oxime esters, improve raw material utilization and enhance product quality by detecting the production process, identifying the source of impurities, reducing impurity generation, and improving the production process.

[0006] To achieve the above-mentioned technical objectives, the present invention provides the following technical solution: a one-pot method for preparing meta-substituted acetophenone coupling compounds, specifically comprising the following steps:

[0007]

[0008]

[0009] In Formulas I to IV, X is a halogen, and R1 is a halogen-substituted or unsubstituted C. 1-6 alkyl;

[0010] Magnesium and compound (IV) were added to a polar aprotic solvent, and the reaction yielded compound (III). An acylation reagent was added, and the reaction yielded compound (II). Compound (II) was then reacted with compound (III) in a one-pot reaction and post-treated to obtain product compound (I).

[0011] Further, the polar aprotic solvent is any one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, butanone, toluene, xylene, chlorobenzene, pyridine, acetonitrile, propionitrile, butyronitrile, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, chloromethane, chloroform, and dichloromethane; preferably, the polar aprotic solvent is any one selected from tetrahydrofuran, methyltetrahydrofuran, toluene, or a mixture of tetrahydrofuran and toluene.

[0012] Further, the acylation reagent is selected from formic acid, glacial acetic acid, sulfonyl chloride, acetyl chloride, oxalate acetyl chloride, dichloroacetyl chloride, acetamide, acetic anhydride, and maleic anhydride.

[0013] Furthermore, the acylation reagent is selected from either acetyl chloride or acetic anhydride.

[0014] Furthermore, the reaction temperature of magnesium and the (IV) compound is 30–40 °C, and the reaction time is 2–5 hours.

[0015] Furthermore, the reaction temperature of the compound of formula (III) and the acylation reagent is -10 to 5°C, and the reaction time is 2 to 5 hours.

[0016] Furthermore, the post-treatment involves distilling the crude product using a post-treatment solvent; the post-treatment solvent includes one or more of benzene, toluene, xylene, o-xylene, trimethylbenzene, ethylbenzene, diethylbenzene, chlorobenzene, dichloromethane, dichloroethane, and trichloromethane.

[0017] Furthermore, the molar ratio of the compound of formula (Ⅳ) to magnesium is 1:1.05 to 1:3.

[0018] Furthermore, the molar ratio of the compound of formula (Ⅳ) to magnesium is 1:1.05.

[0019] Furthermore, the molar ratio of the compound of formula (Ⅳ) to the acylation reagent is 1:0.5 to 1:2.

[0020] Furthermore, the molar ratio of the compound of formula (Ⅳ) to the acylation reagent is 1:0.5 to 0.6;

[0021] Furthermore, the molar ratio of the compound of formula (Ⅳ) to the acylation reagent is 1:0.5 or 1:0.6.

[0022] Due to the adoption of the above technologies, the significant advantages of this invention compared with the prior art are as follows:

[0023] 1) This invention uses the compound of formula (IV) as a reactant to prepare meta-substituted acetophenone coupling compounds in a one-pot process, which has the advantages of high product yield and high purity compared with the multi-step method for preparing meta-substituted acetophenone coupling compounds.

[0024] 2) This invention achieves high yield and high purity preparation of meta-substituted acetophenone coupling compounds by using specific solvents and acylation reagents. The reaction is mild and easy to control, the operation is simple, and the product quality is high. It can provide testing standards for subsequent process optimization and product quality management, and can also provide a reference for product toxicity and toxicological studies. Attached Figure Description

[0025] Figure 1 This is the HPLC chromatogram of the product prepared in Example 1 of this invention;

[0026] Figure 2 This is an MS image of the product prepared in Example 1 of the present invention;

[0027] Figure 3 This is the product prepared in Example 1 of the present invention. 1 H NMR spectrum. Detailed Implementation

[0028] To make the technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to specific embodiments, but this does not limit the scope of the present invention.

[0029] Example 1

[0030] Preparation of 3,3'-(vinyl-1,1-yl)-((trifluoromethyl)benzene) (Compound I):

[0031] Under a nitrogen atmosphere, 2.54 g (0.105 mol, 1.05 eq) of magnesium shavings and 75 g of tetrahydrofuran were added to a four-necked flask. 22.4 g (0.1 mol, 1.0 eq) of m-bromotrifluorotoluene was added dropwise. The mixture was kept at 30 °C for 2 h, then cooled to 0 °C. 5.1 g (0.05 mol, 0.5 eq) of acetic anhydride was added dropwise, and the mixture was kept at 30 °C for 3 h. 40 g of water was added dropwise, and the mixture was stirred at 30 °C. The mixture was separated, and the aqueous phase was extracted with 10 g of toluene. The organic phases were then separated and combined. Simple distillation was performed under a negative pressure of -0.09 MPa using a 20 cm distillation column to obtain 12 g of a pale yellow liquid with a purity of 97.2% and a yield of 73.8%.

[0032] The prepared product underwent structural confirmatory testing, and the results are as follows: Figure 3 As shown, specifically as follows:

[0033] 1 H NMR (400MHz, Chloroform-d) δ7.81-7.60(m,4H),7.64-7.43(m,2H),7.32-7.01(m,2H),5.31(d,J=2.9Hz,1H),5.13(d,J=2.9Hz,1H).

[0034] GC-MS:316.1.

[0035] Example 2

[0036] Preparation of 3,3'-(vinyl-1,1-yl)-((trifluoromethyl)benzene) (Compound I):

[0037] Under a nitrogen atmosphere, 2.54 g of magnesium shavings (0.105 mol, 1.05 eq) and 75 g of methyltetrahydrofuran were added to a four-necked flask. 22.4 g of m-bromotrifluorotoluene (0.1 mol, 1.0 eq) was added dropwise. The mixture was kept at 30 °C for 2 h, then cooled to 0 °C. 5.1 g of acetic anhydride (0.05 mol, 0.5 eq) was added dropwise, and the mixture was kept at 30 °C for 3 h. 40 g of water was added dropwise, and the mixture was stirred at 30 °C. The mixture was separated, and the aqueous phase was extracted with 10 g of dichloroethane. The organic phases were then separated and combined. Simple distillation was performed under a negative pressure of -0.09 MPa using a 20 cm distillation column to obtain 11.8 g of a pale yellow liquid with a purity of 96.3% and a yield of 71.9%.

[0038] Example 3

[0039] Preparation of 3,3'-(vinyl-1,1-yl)-((trifluoromethyl)benzene) (Compound I):

[0040] Under a nitrogen atmosphere, 2.54 g (0.105 mol, 1.05 eq) of magnesium shavings and 75 g of tetrahydrofuran were added to a four-necked flask. 22.4 g (0.1 mol, 1.0 eq) of m-bromotrifluorotoluene was added dropwise. The mixture was kept at 30 °C for 2 h, then cooled to -5 °C. 4.7 g (0.06 mol, 0.6 eq) of acetyl chloride was added dropwise, and the mixture was kept at this temperature for 2 h. 40 g of water was added dropwise, and the mixture was stirred at 30 °C. The mixture was separated, and the aqueous phase was extracted with 10 g of dichloromethane. The organic phases were then separated and combined. Simple distillation was performed under a negative pressure of -0.09 MPa using a 20 cm distillation column to obtain 12.1 g of a pale yellow liquid with a purity of 97.8% and a yield of 74.9%.

[0041] Example 4

[0042] Preparation of 3,3'-(vinyl-1,1-yl)-((trifluoromethyl)benzene) (Compound I):

[0043] Under a nitrogen atmosphere, 2.54 g of magnesium shavings (0.105 mol, 1.05 eq), 50 g of tetrahydrofuran, and 25 g of toluene were added to a four-necked flask. 22.4 g of m-bromotrifluorotoluene (0.1 mol, 1.0 eq) was added dropwise. The mixture was kept at 30 °C for 2 h, then cooled to -5 °C. 4.7 g of acetyl chloride (0.06 mol, 0.6 eq) was added dropwise, and the mixture was kept at this temperature for 2 h. 40 g of water was added dropwise, and the mixture was stirred at 30 °C. The mixture was separated, and the aqueous phase was extracted with 10 g of o-xylene. The organic phases were then separated and combined. Simple distillation was performed under a negative pressure of -0.09 MPa using a 20 cm distillation column to obtain 12.6 g of a pale yellow liquid with a purity of 98.7% and a yield of 78.7%.

[0044] Example 5

[0045] Preparation of 3,3'-(vinyl-1,1-yl)-((trifluoromethyl)benzene) (Compound I):

[0046] Under a nitrogen atmosphere, 2.54 g of magnesium shavings (0.105 mol, 1.05 eq), 50 g of tetrahydrofuran, and 25 g of toluene were added to a four-necked flask. 22.4 g of m-bromotrifluorotoluene (0.1 mol, 1.0 eq) was added dropwise. The mixture was kept at 30 °C for 2 h, then cooled to -5 °C. 8.8 g of dichloroacetyl chloride (0.06 mol, 0.6 eq) was added dropwise, and the mixture was kept at this temperature for 4 h. 40 g of water was added dropwise, and the mixture was stirred at 30 °C. The mixture was separated, and the aqueous phase was extracted with 10 g of dichloroethane. The organic phases were then separated and combined. Simple distillation was performed under a negative pressure of -0.09 MPa using a 20 cm distillation column to obtain 11.5 g of a pale yellow liquid with a purity of 96.7% and a yield of 70.3%.

[0047] Example 6

[0048] Preparation of 3,3'-(vinyl-1,1-yl)-((trifluoromethyl)benzene) (Compound I):

[0049] Under a nitrogen atmosphere, 2.54 g (0.105 mol, 1.05 eq) of magnesium shavings and 75 g of tetrahydrofuran were added to a four-necked flask, followed by the dropwise addition of 22.4 g (0.1 mol, 1.0 eq) of m-bromotrifluorotoluene. The mixture was kept at 30 °C for 2 h to prepare the Grignard reagent. Under a nitrogen atmosphere, 5.1 g (0.05 mol, 0.5 eq) of acetic anhydride was added to the four-necked flask. The prepared Grignard reagent was added dropwise to the acetic anhydride using a bidirectional transfer needle. After the addition was complete, the mixture was kept at 3 h, followed by the addition of 40 g of water. The mixture was stirred at 30 °C, and the liquid was separated. The aqueous phase was extracted with 10 g of toluene, and the liquid was separated again. The organic phases were combined. The product was obtained by simple distillation under a negative pressure of -0.09 MPa and a 20 cm distillation column. The product was a light yellow liquid, weighing 11.4 g, with a purity of 91.8% and a yield of 66.2%.

[0050] Example 7

[0051] Preparation of 3,3'-(vinyl-1,1-yl)-((trifluoromethyl)benzene) (Compound I):

[0052] Under a nitrogen atmosphere, 2.54 g (0.105 mol, 1.05 eq) of magnesium shavings and 75 g of methanol were added to a four-necked flask, followed by the dropwise addition of 22.4 g (0.1 mol, 1.0 eq) of m-bromotrifluorotoluene. The mixture was kept at 30 °C for 2 h, then cooled to -5 °C, and 4.7 g (0.06 mol, 0.6 eq) of acetyl chloride was added dropwise. The mixture was kept at this temperature for 3 h, and the reaction was monitored. No target product was found.

[0053] Example 8

[0054] Preparation of 3,3'-(vinyl-1,1-yl)-((trifluoromethyl)benzene) (Compound I):

[0055] Under a nitrogen atmosphere, 2.54 g of magnesium shavings (0.105 mol, 1.05 eq), 50 g of tetrahydrofuran, and 25 g of toluene were added to a four-necked flask. 22.4 g of m-bromotrifluorotoluene (0.1 mol, 1.0 eq) was added dropwise. The mixture was kept at 50 °C for 4 h, then cooled to 25 °C. 5.1 g of acetic anhydride (0.05 mol, 0.5 eq) was added dropwise, and the mixture was kept at this temperature for 6 h. 40 g of water was added dropwise, and the mixture was stirred at 30 °C. The mixture was separated, and the aqueous phase was extracted with 10 g of dichloromethane. The organic phases were then separated and combined. Simple distillation was performed under a negative pressure of -0.09 MPa using a 20 cm distillation column to obtain 8.3 g of an orange-yellow liquid with a purity of 72.8% and a yield of 38.2%.

[0056] Example 9

[0057] Preparation of 3,3'-(vinyl-1,1-yl)-((trifluoromethyl)benzene) (Compound I):

[0058] Under a nitrogen atmosphere, 2.54 g (0.105 mol, 1.05 eq) of magnesium shavings and 75 g of tetrahydrofuran were added to a four-necked flask. 22.4 g (0.1 mol, 1.0 eq) of m-bromotrifluorotoluene was added dropwise. The mixture was kept at 30 °C for 2 h, then cooled to 0 °C. 4.7 g (0.06 mol, 0.6 eq) of acetyl chloride was added dropwise, and the mixture was kept at 30 °C for 3 h. 40 g of water was added dropwise, and the mixture was stirred at 30 °C. The mixture was separated, and the aqueous phase was extracted with 10 g of ethyl acetate. The organic phases were then separated and combined. Simple distillation was performed under a negative pressure of -0.09 MPa using a 20 cm distillation column to obtain 11.2 g of a pale yellow liquid with a purity of 96.3% and a yield of 68.2%.

[0059] Example 10

[0060] Preparation of 3,3'-(vinyl-1,1-yl)-((trifluoromethyl)benzene) (Compound I):

[0061] Under a nitrogen atmosphere, 7.2 g (0.3 mol, 3 eq) of magnesium shavings and 75 g of methyltetrahydrofuran were added to a four-necked flask, followed by dropwise addition of 22.4 g (0.1 mol, 1.0 eq) of m-bromotrifluorotoluene. The mixture was kept at 30 °C for 2 h, then cooled to 0 °C. 40.8 g (0.4 mol, 4 eq) of acetic anhydride was added dropwise, and the mixture was kept at 3 h. 40 g of water was added dropwise, and the mixture was stirred at 30 °C. The mixture was separated, and the aqueous phase was extracted with 10 g of toluene. The organic phases were then separated and combined. Simple distillation was performed under a negative pressure of -0.09 MPa using a 20 cm distillation column to obtain 10.2 g of a pale yellow liquid with a purity of 91.6% and a yield of 59.1%.

[0062] The above embodiments are merely preferred technical solutions of the present invention and should not be regarded as limitations on the present invention. The scope of protection of the present invention should be the technical solution described in the claims, including equivalent substitutions of the technical features described in the claims. That is, equivalent substitutions and improvements within this scope are also within the scope of protection of the present invention.

Claims

1. A one-pot method for preparing meta-substituted styrene coupling compounds, characterized in that, Specifically, the steps include the following: ， In Formulas I to IV, X is bromine and R1 is trifluoromethyl. Magnesium and compound (IV) are added to a polar aprotic solvent, and the reaction yields compound (III). An acylation reagent is added, and the reaction yields compound (II). The product compound (I) is then obtained by a one-pot reaction and post-treatment. The acylation reagent is any one of acetyl chloride, acetic anhydride, and dichloroacetyl chloride.

2. The method according to claim 1, characterized in that, The polar aprotic solvent is any one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, butanone, toluene, xylene, chlorobenzene, pyridine, acetonitrile, propionitrile, butyronitrile, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, chloromethane, chloroform, and dichloromethane.

3. The method according to claim 2, characterized in that, The polar aprotic solvent is selected from any one of tetrahydrofuran, methyltetrahydrofuran, toluene, or a mixture of tetrahydrofuran and toluene.

4. The method according to claim 1, characterized in that, The reaction temperature of magnesium with compound (IV) is 30–40 °C and the reaction time is 2–5 hours.

5. The method according to claim 1, characterized in that, The reaction temperature of compound (III) and acylation reagent is -10 to 5℃, and the reaction time is 2 to 5 hours.

6. The method according to claim 1, characterized in that, The post-treatment involves distilling the crude product using a post-treatment solvent; the post-treatment solvent includes one or more of benzene, toluene, o-xylene, trimethylbenzene, ethylbenzene, diethylbenzene, chlorobenzene, dichloromethane, dichloroethane, and trichloromethane.

7. The method according to claim 1, characterized in that, The molar ratio of the compound of formula (Ⅳ) to magnesium is 1:1.05 to 1:

3.

8. The method according to claim 7, characterized in that, The molar ratio of the compound of formula (Ⅳ) to magnesium is 1:1.

05.

9. The method according to claim 1, characterized in that, The molar ratio of the compound of formula (Ⅳ) to the acylation reagent is 1:0.5 to 1:

2.

10. The method according to claim 9, characterized in that, The molar ratio of the compound of formula (Ⅳ) to the acylation reagent is 1:0.5 to 0.6.

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