Preparation method of aromatic ring carboxylic acid intermediate

Abstract

The invention relates to a preparation method of an aromatic cyclic carboxylic acid intermediate compound I. The preparation method comprises the following steps: S1, reacting with a ketal reagent under the catalysis of acid to prepare a compound as shown in a formula II; s2, reacting under an alkaline condition, and treating with acid to obtain a compound I; wherein X is an optionally substituted aromatic ring, and the aromatic ring is selected from a benzene ring, a thiophene ring and a naphthalene ring; the substituent group of the aromatic ring is selected from methyl, ethyl, propyl, butyl, amyl and isopropyl, preferably methyl; aromatic rings are selected from R1 and are independently selected from carbonyl protecting groups; or in the formula II, R1-R1 and atoms connected with the R1-R1 form a ring, and-R1-R1-is selected from carbonyl protecting groups; r1 is independently selected from a methyl group, an ethyl group, a benzyl group, a propyl group, a butyl group, a amyl group, an isopropyl group and a methylthio group; or R1-R1 cyclizes together with the atom to which they are attached, selected from the group consisting of R1-R1

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of an aromatic ring carboxylic acid intermediate, belonging to the technical field of medicine and chemistry. BACKGROUND

[0002] The aromatic ring carboxylic acid is a key intermediate of isoxazoline antiparasitic drugs (such as Lotilaner, Afoxolaner, Fluralaner).

[0003] For example, Fluralaner exhibits broad-spectrum insecticidal properties, and exhibits significant biological activity on arthropod pests such as ticks (Ixodida), fleas (Siphonaptera), lice (Anoplura), stink bugs (Hemiptera), and mosquitoes and flies (Diptera), with an LC50 value superior to or comparable to mainstream commercial insecticides. Notably, the compound has no cross-resistance with existing insecticides, and still maintains high efficiency on certain drug-resistant pest strains, making it a highly valuable agricultural chemical. Accordingly, the key intermediate 2-methyl-4-acetylbenzoic acid has important industrialization significance in the chemical industry.

[0004] 2-methyl-4-acetylbenzoic acid, as a key intermediate in the synthesis of Fluralaner, is important due to the excellent insecticidal performance of the target product. Currently, there are several main synthesis methods for 2-methyl-4-acetylbenzoic acid:

[0005] In patent CN109553528A, 2-fluorotoluene is used as the raw material, and the target product is obtained through acetylation, cyanation and hydrolysis in three steps, with a reaction yield of 54%, and the reaction route is as follows:

[0006]

[0007] In patent CN117510428A, 2-bromotoluene is used as the raw material, and the target product is obtained through acetylation, cyanation and hydrolysis in three steps, with a reaction yield of 72%, and the reaction route is as follows:

[0008]

[0009] The reaction steps in the prior art are long, the yield is not high, and hydrolysis produces a large amount of acidic wastewater. Therefore, it is of great practical significance to further explore new preparation processes to improve the yield, reduce impurity generation, and reduce production costs, thereby expanding the production scale and improving economic efficiency. Therefore, there is a need to develop a new preparation method for synthesizing 2-methyl-4-acetylbenzoic acid. SUMMARY

[0010] The present application provides a preparation method of an aromatic ring carboxylic acid intermediate compound I, comprising the following steps S1 and S2:

[0011]

[0012] S1 : preparing compound of formula II by reacting with ketal reagent under acid catalysis;

[0013] S2: reacting under basic condition, treating with acid to obtain compound I;

[0014] wherein X is an optionally substituted aromatic ring, the aromatic ring is selected from benzene ring, thiophene ring, naphthalene ring;

[0015] Further, the substituent of the aromatic ring is selected from methyl, ethyl, propyl, butyl, pentyl, isopropyl, preferably methyl;

[0016] Further, the aromatic ring is selected from

[0017] Further, each R1is independently selected from carbonyl protecting group; or R1-R1together with the atom to which they are attached form a ring, -R1-R1- is selected from carbonyl protecting group;

[0018] Further, each R1is independently selected from methyl, ethyl, benzyl, propyl, butyl, pentyl, isopropyl, methylthio; or R1-R1together with the atom to which they are attached form a ring, is selected from

[0019] Further, a dehydrating agent is optionally added in step S1 ;

[0020] Further, the ketal reagent in step S1 is selected from methanol, ethanol, benzyl alcohol, 1-propanol, 1-butanol, 1-pentanol, isopropanol, methyl mercaptan, ethylene glycol, 1,3-propanediol, 1,2-propanediol, 1,3-butanediol, 2-methyl-1,3-butanediol, 1,3-pentanediol, 2,4-pentanediol, 2-methyl-1,3-propanediol, 2,2-dimethyl-1,3-propanediol, ethanedithiol, propanedithiol;

[0021] Further, the dehydrating agent in step S1 is selected from trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate, tributyl orthoformate, triamyl orthoformate, triisopropyl orthoformate;

[0022] Further, the acid in step S1 is selected from scandium triflate, bismuth triflate, iron triflate, aluminum triflate, boron trifluoride, boron trifluoride etherate, trifluoroacetic acid, p-toluenesulfonic acid, tin dichloride, iron chloride, aluminum trichloride, zinc chloride, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid or oxalic acid, preferably scandium triflate;

[0023] Further, the molar ratio of compound III to the ketal reagent in step S1 is 1:(1.5-3), and can be 1:1.5, 1:2, 1:2.5, 1:3, or a value between any two of them;

[0024] Further, the molar ratio of compound III to the acid in step S1 is 1:(0.005-0.1), and can be 1:0.005, 1:0.01, 1:0.015, 1:0.02, 1:0.025, 1:0.03, 1:0.035, 1:0.04, 1:0.045, 1:0.05, 1:0.055, 1:0.06, 1:0.065, 1:0.07, 1:0.075, 1:0.08, 1:0.085, 1:0.09, 1:0.095, 1:0.1, or a value between any two of them;

[0025] Further, the reaction in step S1 needs to be heated to reflux for 5-48h, preferably 6-24h;

[0026] Further, the reaction solvent in step S1 is selected from any one or a mixture of any proportion of toluene, xylene, ethylbenzene, styrene, cyclohexane, n-hexane, dichloromethane, methyl ethyl ketone, methanol, ethanol, ethylene glycol.

[0027] Further, the volume of the reaction solvent in step S1 is 1-20 times, preferably 1-10 times, more preferably 2-8 times the mass of compound III.

[0028] Further, the base in step S2 is selected from inorganic or organic base.

[0029] Further, the inorganic base in step S2 is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and calcium carbonate, potassium phosphate, sodium phosphate, potassium hydrogen phosphate and sodium hydrogen phosphate.

[0030] Further, the organic base in step S2 is selected from triethylamine, diethylamine, pyridine, diisopropyl ethylamine.

[0031] Further, the acid in step S2 is selected from hydrochloric acid, sulfuric acid.

[0032] Further, the molar ratio of compound II to the base in step S2 is 1:(1.5-5), and can be 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:4.5, 1:5, or a value between any two of them.

[0033] Further, the acid treatment in step S2 includes adjusting the pH value to 3-4 by adding acid.

[0034] Further, the step S2 is carried out in a solvent selected from water or a mixture of water and an organic solvent, and the organic solvent is selected from one or any combination of toluene, xylene, ethylbenzene, cyclohexane, n-hexane, n-heptane, methyl ethyl ketone;

[0035] Further, the reaction temperature in the step S2 is 95-100°C, and specifically can be 95°C, 96°C, 97°C, 98°C, or a value between any two values;

[0036] Further, the volume of the solvent used in the step S2 is 1-20 times, preferably 5-10 times, and more preferably 5 times, the mass of the compound II;

[0037] The second aspect of the present application provides an intermediate compound of formula II, as shown in the structure below:

[0038]

[0039] In the formula, X is an optionally substituted aromatic ring, and the aromatic ring is selected from a benzene ring, a thiophene ring, and a naphthalene ring;

[0040] Further, the substituent of the aromatic ring is selected from methyl, ethyl, propyl, butyl, pentyl, and isopropyl, and preferably methyl;

[0041] Further, the aromatic ring is selected from

[0042] Further, each R1 is independently selected from a carbonyl protecting group, or R1-R1 in formula II, together with the atoms to which they are attached, forms a ring, and -R1-R1- is selected from a carbonyl protecting group;

[0043] Further, each R1 is independently selected from methyl, ethyl, benzyl, propyl, butyl, pentyl, and isopropyl, and isopropyl, or R1-R1 in formula II, together with the atoms to which they are attached, forms a ring, and is selected from

[0044] Further, the intermediate compound is preferably compound II-1, II-2, II-3, or II-4, as shown in the structure below:

[0045]

[0046] The third aspect of the present application, as a further improvement of the present application, provides a method for preparing Lotilaner, Afoxolaner, or Fluralaner, which comprises using the preparation method of any one of the first aspect of the present application, and / or using the compound of formula II of the second aspect of the present application as a raw material or intermediate.

[0047] The present application has the beneficial technical effects:

[0048] 1. The present application provides a novel preparation method of aromatic ring carboxylic acid intermediate compound I, by introducing ketal protecting group and optimizing the cyanide hydrolysis process, the stability of intermediate II, reaction yield and subsequent reaction efficiency are significantly improved.

[0049] 2. In the prior art, the intermediate I is usually prepared by cyanide hydrolysis method, but different reaction systems have obvious shortcomings. In acidic system, even if the reaction time is prolonged or the temperature is increased, it is still difficult to completely inhibit the generation of amide by-product; although the raw materials can be fully reacted and mainly generate target product in alkaline system, due to the difficulty in separating the generated polar impurities from the product carboxylic acid, it is easy to cause single impurity exceeding the standard.

[0050] 3. The present application protects the unstable carbonyl functional group to prepare intermediate compound II. In step S1, triflate is used as catalyst, the product yield can reach 94%, and the purity is 99.4%, which is more suitable for large-scale production than the prior art. BRIEF DESCRIPTION OF DRAWINGS

[0051] Figure 1 HPLC spectrum of compound I-1 in Example 1 of the present application;

[0052] Figure 2 HPLC spectrum of the middle control reaction in Example 3 of the present application when the catalyst is p-toluenesulfonic acid;

[0053] Figure 3 HPLC spectrum of the middle control reaction in Example 3 of the present application when the catalyst is 0.005 eq of scandium triflate;

[0054] Figure 4 HPLC spectrum of the middle control in Comparative Example 1 of the present application;

[0055] Figure 5 HPLC spectrum of the middle control in Comparative Example 3 of the present application;

[0056] Figure 6 HPLC spectrum of the finished product after treatment in Comparative Example 3 of the present application. DETAILED DESCRIPTION

[0057] The preparation method of the present application will be further described in detail below in conjunction with specific examples. It should be understood that the following examples are only illustrative and explanatory of the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope intended to be protected by the present application.

[0058] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0059] Example

[0060]

[0061] Example 1

[0062] Compound III-1 (10 g, 62.82 mmol), 50 ml toluene, 7.8 g ethylene glycol (2.0 eq), and 0.155 g scandium trifluoromethanesulfonate were added to a three-necked flask. The mixture was refluxed at 110–115 °C for 16 h to remove water. The reaction was stopped, 50 ml of water was added, and the mixture was separated. The organic phase was concentrated to dryness to give a yellow oily compound II-1.

[0063] 1 H NMR (400MHz, CD3OD) δ7.62(d,J=8.0Hz,1H),7.50(d,J=0.6Hz,1H),7.42(dd,J=8.0,1.2Hz ,1H),4.02(td,J=6.1,4.2Hz,2H),3.73(td,J=6.1,4.2Hz,2H),2.52(s,3H),1.57(s,3H).

[0064] Add all the above oily substance to a three-necked flask, add 50 ml of water, add sodium hydroxide (5 g, 2.0 eq), and react at 95–100 °C for 16 h. Stop the reaction, add DCM for extraction, discard the DCM phase, adjust the pH of the aqueous phase to 3–4 with hydrochloric acid, and stir for 6 h. Filter, dry, and obtain 10.52 g of off-white solid with a purity of 99.44%, a two-step yield of 94%, and an HPLC purity of 99.4%. The HPLC chromatogram is shown below. Figure 1 As shown.

[0065] 1 H NMR (400MHz, DMSO) δ13.18(s,1H),7.89(d,J=8.0Hz,1H),7.86(m,1H),7.82(dd,J=8.1,1.4Hz,1H),2.60(s,3H),2.57(s,3H).

[0066] Example 2

[0067] Compound III-1 (10 g, 62.82 mmol), 50 ml of ethylene glycol, and sulfuric acid (0.314 g, 3.14 mmol) were added to a three-necked flask. The mixture was refluxed at 105–115 °C for 16 h to remove water. The reaction was then stopped. After the reaction solution was concentrated, 50 ml of toluene and 50 ml of water were added. The mixture was separated, and the organic phase was concentrated to dryness to obtain a yellow oily substance, II-1.

[0068] Add all the above oily substance to a three-necked flask, add 50 ml of water, add sodium hydroxide (5 g, 2.0 eq), and react at 95–100 °C for 16 h. Stop the reaction, add DCM for extraction, discard the DCM phase, adjust the pH of the aqueous phase to 3–4 with hydrochloric acid, and keep warm and stir for 6 h. Filter, dry, and obtain 9.5 g of off-white solid. The two-step yield is 85%.

[0069] Example 3: Reaction under other conditions using ethylene glycol to protect aldehyde groups

[0070]

[0071] Example 4

[0072]

[0073] Compound III-1 (10 g, 62.82 mmol), 50 ml toluene, 9.56 g 1,2-propanediol (2.0 eq), and 0.155 g scandium trifluoromethanesulfonate were added to a three-necked flask. The mixture was refluxed at 110–115 °C for 16 h to remove water. The reaction was stopped, 50 ml of water was added, and the mixture was separated. The organic phase was concentrated to dryness to give a yellow oily compound II-2.

[0074] Add all the above oily substance to a three-necked flask, add 50 ml of water, add sodium hydroxide (5 g, 2.0 eq), and react at 95–100 °C for 16 h. Stop the reaction, add DCM for extraction, discard the DCM phase, adjust the pH of the aqueous phase to 3–4 with hydrochloric acid, and keep it warm and stirred for 6 h. Filter, dry, and obtain 9.51 g of off-white solid. The two-step yield is 85%.

[0075] Example 5

[0076]

[0077] Compound III-1 (10 g, 62.82 mmol), 50 ml toluene, 9.56 g 1,3-propanediol (2.0 eq), and 0.155 g scandium trifluoromethanesulfonate were added to a three-necked flask. The mixture was refluxed at 110–115 °C for 16 h to remove water. The reaction was stopped, 50 ml of water was added, and the mixture was separated. The organic phase was concentrated to dryness to give a yellow oily substance, II-3.

[0078] Add all the above oily substance to a three-necked flask, add 50 ml of water, add sodium hydroxide (5 g, 2.0 eq), and react at 95–100 °C for 16 h. Stop the reaction, add DCM for extraction, discard the DCM phase, adjust the pH of the aqueous phase to 3–4 with hydrochloric acid, and keep it warm and stirred for 6 h. Filter, dry, and obtain 8.06 g of light yellow solid. The two-step yield is 72%.

[0079] Example 6:

[0080]

[0081] Compound III-1 (10 g, 62.82 mmol), trimethyl orthoformate (20.0 g), methanol (50 ml), and p-toluenesulfonic acid (0.6 g) were added to a three-necked flask. The mixture was reacted at 65-70 °C for 6 hours. After the reaction was deemed satisfactory, the mixture was concentrated under reduced pressure until no residue was observed. Toluene and a 10% sodium carbonate aqueous solution were added, and the mixture was stirred and separated. The organic phase was concentrated to dryness to give a yellow oily compound, II-4.

[0082] Add all the above oily substance to a three-necked flask, add 50 ml of water, add sodium hydroxide (5 g, 2.0 eq), and react at 95–100 °C for 16 h. Stop the reaction, add DCM for extraction, discard the DCM phase, adjust the pH of the aqueous phase to 3–4 with hydrochloric acid, and keep it warm and stirred for 6 h. Filter, dry, and obtain 8.40 g of light yellow solid. The two-step yield is 75%.

[0083] Comparative Example:

[0084]

[0085] Comparative Example 1:

[0086] The preparation method of three acids in duplicate patent CN109553528A

[0087] Method 1: Sulfuric acid

[0088] Compound IV (5 g, 31.41 mmol) and 30 ml of 80% sulfuric acid were added to a three-necked flask and refluxed at 100 ± 3 °C for 12 h. HPLC analysis showed that 49.3% of the starting material, 34.9% of the intermediate amide, and 7.7% of compound I remained. The HPLC chromatogram is shown below. Figure 4 show.

[0089] Method 2: Concentrated hydrochloric acid

[0090] Compound IV (5g, 31.41mmol) and 30ml of concentrated hydrochloric acid were added to a three-necked flask and reacted at 100±3℃ for 12h. Samples were taken for testing. HPLC analysis showed that 98.9% of the raw material remained, and no intermediate amide or product was detected.

[0091] Method 3: Trifluoroacetic acid

[0092] Compound IV (5g, 31.41mmol) and 30ml of trifluoroacetic acid were added to a three-necked flask and refluxed at 60±3℃ for 12h. HPLC analysis showed that the remaining raw material was 6.8%, the intermediate amide was 8.7%, and the product was 1.4%.

[0093] Comparison Example 2:

[0094] The preparation method in patent CN102822168A is repeated.

[0095] Compound IV (5g, 31.41mmol), 50ml water, 50ml acetic acid, and 50ml sulfuric acid were added to a three-necked flask and refluxed at 105-110℃ for 5h. HPLC analysis showed that 46.2% of the raw material, 19.6% of the intermediate amide, and 22.5% of the product remained.

[0096] Comparative Example 3:

[0097] The preparation method in patent CN117776924A is repeated.

[0098] Compound IV (5 g, 31.41 mmol), 25 ml acetonitrile, and 12.5 ml 4 mol / L sodium hydroxide solution were added to a three-necked flask. The mixture was reacted at 90 ± 3 °C for 3 h. HPLC control analysis showed that the starting material was 0.4%, the intermediate amide was 0.2%, and the product was 76.9%. The control HPLC chromatogram is shown below. Figure 5 The process involved concentrating the acetonitrile, extracting with 50 ml of dichloromethane, washing once with 20 ml of water, concentrating the organic phase to dryness, and obtaining an off-white solid with a purity of 96.2% and a yield of 89%. The HPLC chromatogram is shown below. Figure 6 show.

[0099] The comparison results above show that in the acid system, the actual repeated process suffers from incomplete reaction, with a large amount of residual raw materials and only some intermediate amide and a small amount of target product generated. Particularly in the trifluoroacetic acid system, the product stability is poor, making effective accumulation difficult. In the alkaline system, the raw materials react more completely, mainly generating the target product. However, because acetyl groups are unstable under alkaline conditions, various difficult-to-remove impurities are easily produced, ultimately resulting in a product that fails to meet quality standards.

[0100] Comparative Example 4:

[0101]

[0102] Compound III-1 (10 g, 62.82 mmol), 50 g methanol, 5 g DMSO, and 8.4 g 30% sodium hydroxide solution were added to a three-necked flask. 21.4 g 30% hydrogen peroxide was added dropwise at a controlled temperature of 20-30℃, and the reaction was maintained at this temperature for 2 hours. HPLC analysis showed that compound III-1 was 2.92% and amide V was 96.17%. 7.5 g concentrated hydrochloric acid was added, and the mixture was quenched with 25 g sodium sulfite. The mixture was concentrated under reduced pressure to remove methanol, and 50 g water was added. The mixture was filtered to obtain a wet product of compound V. HPLC analysis showed that compound III-1 was 0.50% and amide V was 99.06%.

[0103] All the wet product of compound V was added to a three-necked flask, along with 80g of water, 42g of acetic acid, and 45g of sulfuric acid. The mixture was reacted at 100±5℃ for 20 hours. HPLC analysis showed that compound V was 2.05% and compound I-1 was 94.35%. The mixture was cooled, filtered, and dried to obtain 8.95g of compound I-1 as an off-white solid. The two-step yield was 80%, and the purity was 98.6% as determined by HPLC, with a maximum single impurity of 0.25%.

[0104] The experimental results show that when the first step reaction is carried out in the H2O2-DMSO system, the reaction process is normal and feasible. However, the use of hydrogen peroxide in this system poses a significant safety risk in large-scale commercial production. When the second step uses the sulfuric acid-acetic acid system for amide hydrolysis, the reaction produces a large amount of waste acid, resulting in high levels of waste, serious environmental pollution, and failing to meet the requirements of green production.

Claims

1. A method for preparing an aromatic cyclic carboxylic acid intermediate compound I, characterized in that, Includes the following steps S1 and S2: S1: Compound of formula II is prepared by reacting with a ketal reagent under acid catalysis; S2: The reaction proceeds under alkaline conditions, and the compound I is obtained by acid treatment. Wherein, X is an optional substituted aromatic ring, which is selected from benzene ring, thiophene ring, and naphthalene ring; The substituents of the aromatic ring are selected from methyl, ethyl, propyl, butyl, pentyl, and isopropyl, with methyl being preferred; Aromatic rings selected from R1 is independently selected from carbonyl protecting groups; or in Formula II, R1-R1 forms a ring with the atoms attached to it, and -R1-R1- is selected from carbonyl protecting groups; R1 is independently selected from methyl, ethyl, benzyl, propyl, butyl, pentyl, isopropyl, and methylthio; or R1-R1 together with the atoms attached to them form a ring, selected from...

2. The preparation method according to claim 1, characterized in that, A dehydrating agent may be selectively added in step S1.

3. The preparation method according to claim 1, characterized in that, The ketal reagent in step S1 can be selected from methanol, ethanol, benzyl alcohol, 1-propanol, 1-butanol, 1-pentanol, isopropanol, methanethiol, ethylene glycol, 1,3-propanediol, 1,2-propanediol, 1,3-butanediol, 2-methyl-1,3-butanediol, 1,3-pentanediol, 2,4-pentanediol, 2-methyl-1,3-propanediol, 2,2-dimethyl-1,3-propanediol, ethylene dithiol, and propylene dithiol.

4. The preparation method according to claim 2, characterized in that, In step S1, the dehydrating agent is selected from trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate, tributyl orthoformate, tripentyl orthoformate, and triisopropyl orthoformate.

5. The preparation method according to any one of claims 1 to 4, characterized in that, The reaction conditions in step S1 must satisfy at least one of the following conditions: In step S1, the acid is selected from scandium trifluoromethanesulfonate, bismuth trifluoromethanesulfonate, ferric trifluoromethanesulfonate, aluminum trifluoromethanesulfonate, boron trifluoride, boron trifluoride ether, trifluoroacetic acid, p-toluenesulfonic acid, tin dichloride, ferric chloride, aluminum trichloride, zinc chloride, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, or oxalic acid. The molar ratio of compound III to the ketal reagent is 1:(1.5-3), preferably 1:2; In step S1, the molar ratio of compound III to acid is 1:(0.005-0.1), preferably 1:(0.005-0.01), and more preferably 1:0.

01. The reaction in step S1 requires heating under reflux for 5 to 48 hours, preferably 6 to 24 hours; The reaction solvent in step S1 is selected from any one or a mixture of any proportion of toluene, xylene, ethylbenzene, styrene, cyclohexane, n-hexane, dichloromethane, methyl ethyl ketone, methanol, ethanol, and ethylene glycol. In step S1, the volume of the reaction solvent (mL) is 1 to 20 times the mass (g) of compound III, preferably 1 to 10 times, and more preferably 2 to 8 times.

6. The preparation method according to claim 1, characterized in that, In step S2, the base is selected from inorganic or organic bases.

7. The preparation method according to any one of claims 1 or 6, characterized in that, The reaction conditions in step S2 must satisfy at least one of the following conditions: In step S2, the inorganic base is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, tripotassium phosphate, trisodium phosphate, dipotassium hydrogen phosphate, and disodium hydrogen phosphate. In step S2, the organic base is selected from triethylamine, diethylamine, pyridine, and diisopropylethylamine; In step S2, the acid is selected from hydrochloric acid and sulfuric acid; In step S2, the molar ratio of compound II to the base is 1:(1.5-5), preferably 1:2; The acid treatment in step S2 includes adding acid to adjust the pH value to 3-4. Step S2 is carried out in a solvent selected from water or a mixture of water and an organic solvent; the organic solvent is selected from one or any combination of toluene, xylene, ethylbenzene, cyclohexane, n-hexane, n-heptane, and methyl ethyl ketone. The reaction temperature in step S2 is 95–100°C; In step S2, the volume of solvent used (mL) is 1 to 20 times the mass of compound II (g), preferably 5 to 10 times, and more preferably 5 times.

8. An intermediate compound of Formula II, having the following structure: in, X is an optional substituted aromatic ring, selected from benzene ring, thiophene ring, and naphthalene ring; The substituents of the aromatic ring are selected from methyl, ethyl, propyl, butyl, pentyl, and isopropyl, with methyl being preferred; Aromatic rings can be selected from R1 is independently selected from carbonyl protecting groups; or in Formula II, R1-R1 forms a ring with the atoms attached to it, and -R1-R1- is selected from carbonyl protecting groups; R1 is independently selected from methyl, ethyl, benzyl, propyl, butyl, pentyl, isopropyl, and methylthio; or R1-R1 in Formula II forms a ring with the atoms attached to them, selected from... The intermediate compounds II-1, II-2, II-3, and II-4 have the following structures:

9. A method for preparing Lotilaner, Afoxolaner, or Fluralaner, characterized in that: The method comprises the preparation method according to any one of claims 1 to 7.

10. Use of a compound of formula II as described in claim 8 in the preparation of Lotilaner, Afoxolaner, or Fluralaner.

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