A process for the synthesis of a multivirin intermediate

Abstract

The present application provides a kind of preparation of doravirine intermediate 3-chloro-5-[[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy]benzonitrile synthesis method, the method includes from formula D compound and 3-chloro-5-hydroxybenzonitrile in the presence of base, catalyst coupling to obtain formula E compound, formula E compound is cyclized to obtain 3-chloro-5-[[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy]benzonitrile in the presence of acid.The method uses cheap starting material, avoids the use of noble metal catalyst and expensive material fragment, process operation and post-processing are simple, suitable for industrial scale production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, specifically to a method for synthesizing the doravirine intermediate 3-chloro-5-[[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy]benzonitrile. Background Technology

[0002] Doravirine is an oral medication used to treat HIV infection. It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that can be used in combination with other antiretroviral drugs for adult HIV-1 infected patients with no prior history of antiretroviral therapy.

[0003] Currently, there are many reported synthetic routes for doravirine, but few can be scaled up for practical application. The main method involves synthesizing the key intermediate 3-chloro-5-[[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy]benzonitrile (CAS: 1155846-86-8), followed by docking with a triazole fragment to obtain doravirine. The structure of the intermediate 3-chloro-5-[[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy]benzonitrile is as follows:

[0004]

[0005] The first synthetic route for this intermediate is as follows: It is obtained from m-chloroiodobenzene via a 5-step reaction.

[0006]

[0007] This route has been scaled up to the hundred-kilogram level and is currently the only route that can be mass-produced, but the materials used are expensive and the production cost is relatively high.

[0008] Synthetic Route 2: Synthesized using a continuous flow reaction method, the specific synthetic route is as follows:

[0009]

[0010] Using 3-chloro-5-hydroxybenzonitrile as a starting material, ethyl 2-bromoethyl acetate undergoes a substitution reaction with N,N-diisopropylethylamine to yield ethyl 2-(3-chloro-5-cyanophenoxy)ethyl acetate. This ethyl acetate is then reacted with 4-ethoxy-1,1,1-trifluoro-3-buten-2-one in a flow reactor with triethylamine, potassium tert-pentoxy, and trifluoroacetic anhydride to yield ethyl 2-(3-chloro-5-cyanophenoxy)-5-ethoxy-3-(trifluoromethyl)-2,4-pentadienoate. This ethyl acetate is then reacted directly with ammonia without separation to give the intermediate 3-chloro-5-[[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy]benzonitrile. The overall yield of both steps is 68%. Although this method uses readily available raw materials and has a short procedure, it requires a high degree of precision in continuous reaction and precise control of the reaction points; otherwise, the yield will vary greatly. Currently, only a one-kilogram scale preparation has been achieved. Summary of the Invention

[0011] To address the problems of high raw material costs and low overall yield in existing methods for synthesizing doravirine intermediate 3-chloro-5-[[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy]benzonitrile, this invention provides a method for synthesizing this intermediate. Using ethyl 2-fluoro-2-bromoacetate and 4-ethoxy-1,1,1-trifluoro-3-buten-2-one as raw materials, the method involves halogenation, ammonolysis, dehydroxylation, coupling, and cyclization steps to finally obtain the doravirine intermediate 3-chloro-5-[[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy]benzonitrile. This method uses low-cost raw materials, has a short process cycle, is environmentally friendly, and is suitable for large-scale production.

[0012] The first aspect of the present invention is to provide a preparative F compound. The method is characterized by:

[0013] Step 1, Compound D Coupling with 3-chloro-5-hydroxybenzonitrile in the presence of a base and a catalyst yields compound E. ,

[0014] Step 2: The compound E obtained in Step 1 is cyclized in the presence of acid to obtain compound F. The synthetic route is shown below:

[0015]

[0016] Among them, R1 is selected from H, C 1-6 Alkyl groups, C substituted with one or more halogen, hydroxyl, or phenyl substituents. 1-6 Alkyl, C 2-6 alkenyl, C 4-8 cycloalkyl, C 6-14Aromatic group, with one or more C 1-6 Alkyl-substituted C 6-14 Aromatic group, C 1-6 Alkyl carbonyl, C 1-6 alkyloxycarbonyl, C substituted with one or more phenyl or fused ring groups 1-6 Alkyloxycarbonyl; preferably, R1 is selected from H, C 1-6 Alkyl groups, C substituted with one or more halogen, hydroxyl, or phenyl groups. 1-6 Alkyl, phenyl, with one or more C 1-6 Alkyl-substituted phenyl, C 1-6 alkyl carbonyl, C 1-6 Alkyloxycarbonyl, or methyloxycarbonyl substituted with a phenyl or fluorenyl group; more preferably, R1 is H, triphenylmethyl, benzyl, tert-butyl, acetyl, benzyloxycarbonyl, or fluorenylmethyloxycarbonyl.

[0017] According to the present invention, the R1 group can be an amino protecting group, and thus, conventional amino protecting groups can be used, such as alkyl, benzyl, substituted alkyloxycarbonyl, alkylacyl, etc. included in the aforementioned definition of the R1 group, but the yield of different groups will have some differences.

[0018] In step one, the base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide, preferably potassium carbonate; the catalyst is selected from any one or a combination of TBAF, TBAC, TBAB, and TBAI, preferably TBAB; preferably, the reaction in step one is carried out in the presence of base, catalyst, and solvent D, wherein solvent D is selected from DMF, NMP, DMAc, and DMSO, preferably NMP.

[0019] In step two, the acid is selected from hydrochloric acid and hydrobromic acid; preferably, the reaction in step two is carried out in an acid and solvent E, wherein solvent E is selected from 1,4-dioxane and toluene.

[0020] Furthermore, if necessary, when R1 in compound F is not H, compound F with R1 being H can be obtained by deprotection. The deprotection can be performed using conventional methods, such as reacting in the presence of an acid to remove the R1 group; the acid may be selected from, for example, trifluoroacetic acid and trifluoromethanesulfonic acid.

[0021] According to the present invention, in the aforementioned method for preparing compound F, compound D is prepared from compound C. The reaction is carried out in the presence of a base to obtain the product, wherein R1 is defined as before, that is, R1 is selected from H, C 1-6 Alkyl groups, C substituted with one or more halogen, hydroxyl, or phenyl substituents. 1-6 Alkyl, C 2-6 alkenyl, C 4-8cycloalkyl, C 6-14 Aromatic group, with one or more C 1-6 Alkyl-substituted C 6-14 Aromatic group, C 1-6 Alkyl carbonyl, C 1-6 alkyloxycarbonyl, C substituted with one or more phenyl or fused ring groups 1-6 Alkyloxycarbonyl; preferably, R1 is selected from H, C 1-6 Alkyl groups, C substituted with one or more halogen, hydroxyl, or phenyl groups. 1-6 Alkyl, phenyl, with one or more C 1-6 Alkyl-substituted phenyl, C 1-6 alkyl carbonyl, C 1-6 Alkyloxycarbonyl, or methyloxycarbonyl substituted with a phenyl or fluorenyl group; more preferably, R1 is H, triphenylmethyl, benzyl, tert-butyl, acetyl, benzyloxycarbonyl, or fluorenylmethyloxycarbonyl.

[0022] Preferably, the preparation method of the compound of formula D is carried out in the presence of a base and a solvent C, wherein the solvent C is selected from MTBE, THF, EtOH or 1,4-dioxane, preferably THF. The base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, preferably sodium hydroxide.

[0023] Furthermore, compound C is prepared by reacting ethyl 2-bromo-2-fluoroacetate with 4-ethoxy-1,1,1-trifluoro-3-buten-2-one to yield compound B. Compound B then reacts with R1NH2 to obtain compound C.

[0024] R1 is defined as before, that is, R1 is selected from H, C 1-6 Alkyl groups, C substituted with one or more halogen, hydroxyl, or phenyl substituents. 1-6 Alkyl, C 2-6 alkenyl, C 4-8 cycloalkyl, C 6-14 Aromatic group, with one or more C 1-6 Alkyl-substituted C 6-14 Aromatic group, C 1-6 Alkyl carbonyl, C 1-6 alkyloxycarbonyl, C substituted with one or more phenyl or fused ring groups 1-6 Alkyloxycarbonyl; preferably, R1 is selected from H, C 1-6 Alkyl groups, C substituted with one or more halogen, hydroxyl, or phenyl groups. 1-6 Alkyl, phenyl, with one or more C 1-6 Alkyl-substituted phenyl, C 1-6 alkyl carbonyl, C 1-6Alkyloxycarbonyl, or methyloxycarbonyl substituted with a phenyl or fluorenyl group; more preferably, R1 is H, triphenylmethyl, benzyl, tert-butyl, acetyl, benzyloxycarbonyl, or fluorenylmethyloxycarbonyl.

[0025] In the method for preparing compound C, solvent B is more effective, and solvent B is selected from methanol or ethanol.

[0026] In one embodiment of the present invention, a method for preparing a compound of structural formula F is provided, characterized in that the method includes the following steps:

[0027] S1: Ethyl 2-bromo-2-fluoroacetate (compound A) is added to 4-ethoxy-1,1,1-trifluoro-3-buten-2-one to give compound B, which is then reacted with R1NH2 and methanol to give compound C.

[0028] S2: Compound C is dehydroxylated in the presence of solvent C and a base to give compound D;

[0029] S3: Compound D is coupled with 3-chloro-5-hydroxybenzonitrile to give compound E.

[0030] S4: Compound E is cyclized to obtain compound F;

[0031] The synthesis circuit is shown below:

[0032]

[0033] Among them, R1 is selected from H, C 1-6 Alkyl groups, C substituted with one or more halogen, hydroxyl, or phenyl substituents. 1-6 Alkyl, phenyl, with one or more C 1-6 Alkyl-substituted phenyl, C 1-6 alkyl carbonyl, C 1-6 The alkyloxycarbonyl group is a methyloxycarbonyl group substituted with a phenyl or fluorenyl group; more preferably, R1 is H, triphenylmethyl, benzyl, tert-butyl, acetyl, benzyloxycarbonyl or fluorenylmethyloxycarbonyl.

[0034] Preferably, in step S2, compound C is dissolved in solvent C, and a base is added to react and give compound D; the solvent C is selected from MTBE, THF, EtOH or 1,4-dioxane, preferably THF; the base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, preferably sodium hydroxide.

[0035] Preferably, in step S3, compound D is dissolved in solvent D, and a base and catalyst are added to react and yield compound E; the base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide, preferably potassium carbonate. Solvent D is selected from DMF, NMP, DMAc, and DMSO, preferably NMP. The catalyst is selected from TBAF, TBAC, TBAB, and / or TBAI, preferably TBAB.

[0036] Preferably, in step S4, compound E is cyclized in the presence of an acid and solvent E to obtain compound F, wherein the acid is HCl or HBr; and solvent E is selected from 1,4-dioxane or toluene.

[0037] In one specific embodiment of the present invention, the reaction route and conditions are as follows:

[0038] .

[0039] According to the present invention, the preparation method may further include:

[0040] S5. If R1 of compound F is not H, convert compound F obtained in step S4 into a compound with R1 of H, i.e., obtain 3-chloro-5-[[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy]benzonitrile. React compound F with an acid to obtain 3-chloro-5-[[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy]benzonitrile, wherein the acid is trifluoroacetic acid or trifluoromethanesulfonic acid.

[0041] Definitions:

[0042] Alkali: In the broadest sense, alkali includes substances that form an alkaline environment through hydrolysis or solvation, and is not limited to metal hydroxides, such as carbonates, bicarbonates, ammonia, ammonium salts, organic amine compounds, alkoxides, etc.

[0043] Acids include organic acids and inorganic acids.

[0044] The following abbreviations are used in the instructions and examples: TBAF: tetrabutylammonium fluoride; TBAC: tetrabutylammonium chloride; TBAB: tetrabutylammonium bromide; TBAI: tetrabutylammonium iodide; MTBE: methyl tert-butyl ether; THF: tetrahydrofuran; EtOH: ethanol; DMF: N,N-dimethylformamide; NMP: N-methylpyrrolidone; DMAc: N,N-dimethylacetamide; DMSO: dimethyl sulfoxide. Attached Figure Description

[0045] Figure 1 Compound C, where R1 is H, was prepared in Example 1. 1 HNMR spectrum.

[0046] Figure 2 Compound E, where R1 is H, was prepared in Example 1. 1 HNMR spectrum.

[0047] Figure 3 Compound F, where R1 is H, was prepared in Example 1. 1 HNMR spectrum. Detailed Implementation

[0048] The present invention will be further described below with reference to embodiments. It should be noted that the embodiments are not intended to limit the scope of protection of the present invention, and those skilled in the art will understand that any improvements and variations made based on the present invention are within the scope of protection of the present invention.

[0049] Example 1: Preparation method of F with R1 being hydrogen

[0050] EX1.1 Preparation of ethyl 5-ethoxy-2-fluoro-3-hydroxy-3-(trifluoromethyl)pent-4-enoate (Formula B)

[0051] In a 250ml reaction flask, add 100ml of tetrahydrofuran, then add 10g of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one and 13g of ethyl 2-bromo-2-fluoroacetate (Formula A), and stir until dissolved. Add 8g of zinc powder activated with hydrochloric acid in portions, controlling the temperature below 30°C. After the addition is complete, heat to 60-65°C and react for 4 hours until the starting material is completely converted. Cool to room temperature, filter, and evaporate the filtrate under reduced pressure to remove the solvent, obtaining the product, which is then directly added to the next reaction step.

[0052] EX1.2 Preparation of 5-ethoxy-2-fluoro-3-hydroxy-3-(trifluoromethyl)pent-4-enamide (R1 is hydrogen in formula C)

[0053] The product from the previous step was added to 100 ml of a 25% ammonia-methanol solution and reacted overnight at room temperature (20-25°C) until the starting material was completely converted. The solvent was removed by vacuum evaporation, and the residue was added to 100 ml of ethyl acetate and 60 ml of water. After stirring, the mixture was allowed to stand. The ethyl acetate layer was separated, washed once with 10% citric acid aqueous solution, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Further purification with isopropyl ether yielded the final product. The overall yield of the two steps (EX1.1 and EX1.2) was 71%.

[0054] EX1.3 Preparation of 5-ethoxy-2-fluoro-3-(trifluoromethyl)pentane-2,4-dieneamide (R1 is hydrogen in formula D)

[0055] 8 g of 5-ethoxy-2-fluoro-3-hydroxy-3-(trifluoromethyl)pent-4-enamide was added to 30 ml of tetrahydrofuran, followed by 1.6 g of a pre-prepared sodium hydroxide solution in 16 ml of water. The reaction was carried out at room temperature for 1 hour until the starting material was completely converted. Hydrochloric acid (1N) was slowly added to adjust the pH to 6-7; 20 ml of ethyl acetate was added, and the mixture was stirred and allowed to stand. The organic layer was separated, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain the product, with a yield of 82%.

[0056] EX1.4 Preparation of 2-(3-chloro-5-cyanophenoxy)-5-ethoxy-3-(trifluoromethyl)pent-2,4-dieneamide (R1 is hydrogen in formula E)

[0057] 6 g of 5-ethoxy-2-fluoro-3-(trifluoromethyl)pentane-2,4-dieneamide and 3.8 g of 3-chloro-5-hydroxybenzonitrile were sequentially added to 50 ml of N-methylpyrrolidone. While stirring, 9 g of tetrabutylammonium bromide and 6 g of potassium carbonate were added. The mixture was heated to 100°C and reacted until the starting material was completely converted. After cooling to room temperature, 150 ml of water and 40 ml of toluene were added, and the mixture was stirred and allowed to stand. The toluene layer was separated, washed once with 1N hydrochloric acid, once with water, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Further purification with isopropyl ether yielded the final product (76%).

[0058] EX1.5 Preparation of 3-chloro-5-((2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxy)benzonitrile (R1 is hydrogen of formula F)

[0059] 5 g of 2-(3-chloro-5-cyanophenoxy)-5-ethoxy-3-(trifluoromethyl)pentane-2,4-dieneamide was added to 30 ml of 1,4-dioxane, along with 0.3 ml of hydrochloric acid (2N). The mixture was heated to 90°C and reacted overnight until the starting material was completely converted. The solvent was removed by vacuum distillation, and the residue was added to methanol. The mixture was stirred and dispersed at -20°C to obtain the solid. The solid was filtered and dried under reduced pressure to obtain the product, with a yield of 84%.

[0060] Example 2: Preparation method of formula F with R1 being benzyl

[0061] EX2.1: Same as EX1.1 in Example 1.

[0062] EX2.2 Preparation of N-benzyl-5-ethoxy-2-fluoro-3-hydroxy-3-(trifluoromethyl)pent-4-enamide (R1 is benzyl group of formula C)

[0063] 10 g of ethyl 5-ethoxy-2-fluoro-3-hydroxy-3-(trifluoromethyl)pent-4-enoate was added to 100 ml of methanol solution, followed by 6 g of benzylamine. The reaction was carried out overnight at room temperature (20-25°C) until the starting material was completely converted. The temperature was lowered to 0-5°C, and water was added dropwise to quench the reaction. Then, 25 ml of ethyl acetate was added, and the organic layer was separated. The aqueous layer was extracted once more with 15 ml of ethyl acetate. The organic layers were combined, and the pH was adjusted to 3-4 with 2M hydrochloric acid. The mixture was extracted twice, washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by silica gel column chromatography to obtain the product in 75% yield.

[0064] EX2.3 Preparation of N-benzyl-5-ethoxy-2-fluoro-3-(trifluoromethyl)pentane-2,4-dieneamide (R1 is benzyl of formula D)

[0065] 8 g of N-benzyl-5-ethoxy-2-fluoro-3-hydroxy-3-(trifluoromethyl)pent-4-enamide was added to 30 ml of tetrahydrofuran, followed by 1.5 g of a pre-prepared sodium hydroxide solution in 15 ml of water. The reaction was carried out at room temperature for 1 hour until the starting material was completely converted. Hydrochloric acid (1N) was slowly added to adjust the pH to 6-7; 20 ml of ethyl acetate was added, and the mixture was stirred and allowed to stand. The organic layer was separated, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain the product, with a yield of 81%.

[0066] EX2.4 Preparation of N-benzyl-2-(3-chloro-5-cyanophenyl)-5-ethoxy-3-(trifluoromethyl)pent-2,4-dieneamide (R1 is benzyl of formula E)

[0067] 5 g of N-benzyl-5-ethoxy-2-fluoro-3-(trifluoromethyl)pentane-2,4-dieneamide and 2.4 g of 3-chloro-5-hydroxybenzonitrile were sequentially added to 50 ml of N-methylpyrrolidone. While stirring, 8 g of tetrabutylammonium bromide and 5 g of potassium carbonate were added. The mixture was heated to 100°C and reacted until the starting material was completely converted. After cooling to room temperature, 150 ml of water and 40 ml of toluene were added, and the mixture was stirred and allowed to stand. The toluene layer was separated, washed once with 1N hydrochloric acid, once with water, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Further purification with isopropyl ether yielded the final product (73%).

[0068] EX2.5 Preparation of 3-((1-benzyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxy)-5-chlorobenzonitrile (R1 is benzyl of formula F)

[0069] 4.5 g of N-benzyl-2-(3-chloro-5-cyanophenyl)-5-ethoxy-3-(trifluoromethyl)pentane-2,4-dieneamide was added to 30 ml of 1,4-dioxane, along with 0.2 ml of hydrochloric acid (2N). The mixture was heated to 90°C and reacted overnight until the starting material was completely converted. The solvent was removed by vacuum distillation, and the residue was added to methanol. The mixture was stirred and dispersed at -20°C to obtain the solid. The solid was filtered and dried under reduced pressure to obtain the product, with a yield of 85%.

[0070] EX2.6 Preparation of 3-chloro-5-((2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxy)benzonitrile

[0071] 3.5 g of 3-((1-benzyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxy)-5-chlorobenzonitrile was added to 50 ml of trifluoroacetic acid, followed by 7 g of trifluoromethanesulfonic acid. The mixture was heated to 60-65 degrees Celsius and reacted for 4 hours until the starting material was completely converted. The mixture was then cooled to 5-10 degrees Celsius, and ice water was added. Solid sodium bicarbonate was slowly added to adjust the pH to 8-9, followed by the addition of more ice water. The mixture was stirred until a solid precipitated, filtered, the filter cake was washed with water, and dried under vacuum. The solid was then added to methanol, stirred and dispersed at 0 degrees Celsius, filtered, and dried under reduced pressure to obtain the product, with a yield of 74%.

[0072] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing compound F, characterized in that: Step 1: Compound D is coupled with 3-chloro-5-hydroxybenzonitrile in the presence of a base and a catalyst to obtain compound E; Step 2: The compound E obtained in Step 1 is cyclized in the presence of an acid to obtain compound F; Among them, R1 is selected from H, C 1-6 Alkyl groups, C substituted with one or more halogen, hydroxyl, or phenyl substituents. 1-6 Alkyl, C 2-6 alkenyl, C 4-8 cycloalkyl, C 6-14 Aromatic group, with one or more C 1-6 Alkyl-substituted C 6-14 Aromatic group, C 1-6 Alkyl carbonyl, C 1-6 alkyloxycarbonyl, C substituted with one or more phenyl or fused ring groups 1-6 Alkyloxycarbonyl; preferably, R1 is selected from H, C 1-6 Alkyl groups, C substituted with one or more halogen, hydroxyl, or phenyl groups. 1-6 Alkyl, phenyl, with one or more C 1-6 Alkyl-substituted phenyl, C 1-6 alkyl carbonyl, C 1-6 Alkyloxycarbonyl, or methyloxycarbonyl substituted with a phenyl or fluorenyl group; more preferably, R1 is H, triphenylmethyl, benzyl, tert-butyl, acetyl, benzyloxycarbonyl, or fluorenylmethyloxycarbonyl; In step one, the alkali is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide, preferably potassium carbonate; the catalyst is selected from any one or a combination of TBAF, TBAC, TBAB, and TBAI, preferably TBAB; In step two, the acid is selected from hydrochloric acid and hydrobromic acid; preferably, the reaction in step two is carried out in an acid and solvent E, wherein solvent E is selected from 1,4-dioxane and toluene.

2. The method as described in claim 1, characterized in that, The reaction in step one is carried out in the presence of a base, a catalyst, and solvent D, wherein solvent D is selected from DMF, NMP, DMAc, and DMSO, with NMP being preferred.

3. The method as described in claim 1 or 2, characterized in that, When R1 of compound F is not H, compound F with R1 is obtained by deprotection, wherein the deprotection method removes the R1 group in the presence of an acid selected from trifluoroacetic acid and trifluoromethanesulfonic acid.

4. The method according to any one of claims 1-3, characterized in that, Compound D is derived from compound C. The reaction is carried out in the presence of a base and a solvent C, wherein the solvent C is selected from MTBE, THF, EtOH or 1,4-dioxane, preferably THF; and the base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, preferably sodium hydroxide.

5. The method as described in claim 4, characterized in that, Compound C was prepared by reacting ethyl 2-bromo-2-fluoroacetate with 4-ethoxy-1,1,1-trifluoro-3-buten-2-one to give compound B. Compound B then reacts with R1NH2 to obtain compound C.

6. The method as described in claim 5, characterized in that, In the method for preparing compound C, solvent B is used, which is selected from methanol or ethanol.

7. A method for preparing a compound with structural formula F, characterized in that, The method includes the following steps: S1: Ethyl 2-bromo-2-fluoroacetate reacts with 4-ethoxy-1,1,1-trifluoro-3-buten-2-one to give compound B, which then reacts with R1NH2 and methanol to give compound C. S2: Compound C is dehydroxylated in the presence of solvent C and a base to give compound D; S3: Compound D is coupled with 3-chloro-5-hydroxybenzonitrile to obtain compound E; S4: Compound E is cyclized to obtain compound F; Among them, R1 is selected from H, C 1-6 Alkyl groups, C substituted with one or more halogen, hydroxyl, or phenyl substituents. 1-6 Alkyl, phenyl, with one or more C 1-6 Alkyl-substituted phenyl, C 1-6 alkyl carbonyl, C 1-6 Alkyloxycarbonyl, a methyloxycarbonyl group substituted with a phenyl or fluorenyl group; more preferably, R1 is H, triphenylmethyl, benzyl, tert-butyl, acetyl, benzyloxycarbonyl or fluorenylmethyloxycarbonyl; Preferably, in step S2, compound C is dissolved in solvent C, and a base is added to react and give compound D; the solvent C is selected from MTBE, THF, EtOH, or 1,4-dioxane, preferably THF; the base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, preferably sodium hydroxide; or, Preferably, in step S3, compound D is dissolved in solvent D, and a base and catalyst are added to react and obtain compound E; the base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide, preferably potassium carbonate; the solvent D is selected from DMF, NMP, DMAc, or DMSO, preferably NMP; the catalyst is selected from TBAF, TBAC, TBAB, or TBAI, preferably TBAB; or, Preferably, in step S4, compound E is cyclized in the presence of an acid and solvent E to obtain compound F, wherein the acid is HCl or HBr; and solvent E is selected from 1,4-dioxane or toluene.

8. The method as described in claim 7, characterized in that, The preparation method further includes: S5. If R1 is not H, convert the compound F obtained in step S4 into a compound where R1 is H, that is, to obtain 3-chloro-5-[[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy]benzonitrile.

9. The method as described in claim 7 or 8, characterized in that, When a compound of formula F, where R1 is not H, reacts with an acid, it yields 3-chloro-5-[[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy]benzonitrile, wherein the acid is trifluoroacetic acid or trifluoromethanesulfonic acid.

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