Method for synthesizing 5-halogenated-2-methylbenzoic acid

Abstract

The present invention relates to a method for the highly selective synthesis of 5-halogenated 2-methylbenzoic acid, belonging to the field of medicinal chemistry. The preparation method can obtain 5-halogenated 2-methylbenzoic acid by using p-toluenesulfonic acid as a starting material through acylation, substitution, and haloform reaction. Compared with the prior art, this method has the advantages of mild and easily controllable reaction conditions, high yield, high purity, environmental friendliness, and suitability for industrial scale-up.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a method for synthesizing 5-halogenated-2-methylbenzoic acid with high selectivity. Background Art

[0002] 5-Halo-2-methylbenzoic acid is an important organic synthesis intermediate and pharmaceutical intermediate, widely used in laboratory research and development processes and chemical production processes. 5-Bromo-2-methylbenzoic acid is a key intermediate in the oral hypoglycemic drug canagliflozin. Its chemical structure is shown in Formula I below:

[0003]

[0004] Patent WO2006116157 discloses a method for preparing 5-fluoro-2-methylbenzoic acid: Using 2-bromo-4-fluorotoluene as the raw material and diethyl ether as the solvent, the Grignard reagent 5-fluoro-2-methylmagnesium bromide is first prepared. Carbon dioxide is then introduced, and the pH is adjusted to acidic with hydrochloric acid to obtain 5-fluoro-2-methylbenzoic acid. The preparation of the Grignard reagent requires strict anhydrous and oxygen-free conditions, resulting in harsh conditions and cumbersome procedures. Furthermore, diethyl ether has a low flash point and is a highly hazardous solvent, making it unsuitable for scale-up production.

[0005] Patent CN108929217 discloses a method for preparing 5-fluoro-2-methylbenzoic acid: 2-halogenated 4-fluorotoluene is reacted with magnesium turnings to form a Grignard reagent, which is then converted to 5-halogenated 2-methylbenzoic acid. However, the preparation of the Grignard reagent requires anhydrous and oxygen-free conditions, resulting in harsh and cumbersome procedures, making it unsuitable for industrial scale-up.

[0006] Justus Liebigs Annalen der Chemie, 1893, vol. 274, p. 308 discloses a method for preparing 5-chloro-2-methylbenzoic acid: using o-methylbenzoic acid as a raw material, iron powder as a catalyst, and chloroform as a solvent, chlorine gas is introduced to obtain a mixture of 5-chloro-2-methylbenzoic acid and 3-chloro-2-methylbenzoic acid. This method does not perform an isomer separation operation, and the resulting product is of insufficient purity.

[0007] The document J.Org.Chem. 2008, 73, 5, 1732-1744 also discloses a method similar to the above patent for preparing 5-bromo-2-methylbenzoic acid, but no isomer separation operation is performed, and a mixture is obtained.

[0008] Patents WO2005100351 and US2007203116 report a solvent-free reaction using o-methylbenzoic acid as the raw material, bromine as the brominating agent, and iron powder as the catalyst. The reaction was reported to be so viscous that the reactants formed lumps in the late stages of the reaction and could not be stirred. The resulting product was a 6:4 mixture of 5-bromo-2-methylbenzoic acid and 3-bromo-2-methylbenzoic acid. Although a single isomer of 5-bromo-2-methylbenzoic acid was obtained after post-treatment, the yield was only 54.5%. This method not only has a low yield, but also cannot be applied to large-scale production due to the lumps in the system.

[0009] Patent JP2021127332 uses o-methylbenzoic acid as raw material, sulfuric acid as solvent, and bromine is added dropwise. After the reaction is completed, the crude product obtained is a mixture of 5-bromo-2-methylbenzoic acid and 3-bromo-2-methylbenzoic acid in a ratio of 62:38. After refining, a mixture of the two isomers with a ratio of 91:9 is obtained, and the yield is only 38.5%.

[0010] Patents US6414126 and US2003114390 use o-methylbenzoic acid as a raw material and iron powder as a catalyst to react with bromic acid at 0°C. When the substrate conversion is 40%, dichloromethane is added, and the reactants are stirred and kept at 45°C for reaction. After the reaction is completed, the crude product obtained is a mixture of 5-bromo-2-methylbenzoic acid and 3-bromo-2-methylbenzoic acid in a ratio of 2:1. After purification, the yield is only 32.5%.

[0011] Patent CN103980263 discloses the preparation of 5-bromo-2-methylbenzoic acid using o-methylbenzoic acid as a raw material, catalyzed by the metal reagent ferric bromide and the superacid p-toluenesulfonic acid, with the addition of 1.25 equivalents of bromine, in a yield exceeding 85%. We repeated the reaction conditions and found that in addition to the two isomers of 5-bromo-2-methylbenzoic acid and 3-bromo-2-methylbenzoic acid, the reaction also contained 3,5-dibromo-2-methylbenzoic acid as an impurity. This system was more complex than the one using iron powder as a catalyst, making it impossible to isolate 5-bromo-2-methylbenzoic acid alone.

[0012] Patent WO2006117669 uses 5-amino-2-methylbenzoic acid as a starting material. It undergoes a diazotization reaction to obtain a diazonium salt at the 5-position, which is then reacted with potassium iodide to produce 5-iodo-2-methylbenzoic acid. This reaction offers good selectivity and is free of isomeric impurities. However, the diazotization reaction is a hazardous chemical reaction, as the diazonium salt is unstable and can easily release nitrogen gas at elevated temperatures, leading to explosions.

[0013] Patent EP1642881 uses o-methylbenzoic acid as the raw material and acetic acid as the solvent. Acetic anhydride, iodine, 70% hydroiodic acid, and H-β-molecular sieve are added, heated to 122°C for 4 hours, and post-processed to produce 5-iodo-2-methylbenzoic acid. Disadvantages of this method include the high availability of H-β-molecular sieves, the high reaction temperature of 122°C, high energy consumption, and the generation of large amounts of acidic wastewater, resulting in significant environmental pollution.

[0014] Therefore, there is still a need to study the preparation method of 5-halogenated-2-methylbenzoic acid to obtain a preparation method with high yield, high purity, environmental protection, mild reaction conditions, less three wastes, and suitable for industrial scale-up production. Summary of the Invention

[0015] The above-mentioned preparation method of 5-halogeno-2-methylbenzoic acid has the technical problems of harsh reaction conditions, high risk factor, isomer impurities in the product, low yield, material plate formation in the reactor, difficulty in obtaining raw materials, high energy consumption or severe environmental pollution. The present invention provides a preparation method of 5-halogeno-2-methylbenzoic acid, which has the characteristics of mild and easy-to-control reaction conditions, high yield, high purity, environmental protection, and suitability for industrial scale-up.

[0016] The present invention provides a method for preparing 5-halogenated 2-methylbenzoic acid. 5-halogenated 2-methylbenzoic acid, referred to as Compound I, has a structure shown below:

[0017]

[0018] The preparation method provided by the present invention can use compound A as the starting material, undergo a Friedel-Crafts acylation reaction to obtain compound B, compound B undergoes a substitution reaction to obtain compound C, compound C undergoes a halogenation reaction to obtain compound D, and compound D undergoes hydrolysis and elimination reactions to obtain compound I. The specific reaction route is as follows:

[0019]

[0020] Wherein, X1 is selected from at least one of F, Cl, Br or I; X2 is selected from at least one of Cl, Br or I.

[0021] In one aspect, the present invention provides a method for preparing Compound I, comprising the following steps:

[0022] Step a: Compound A undergoes Friedel-Crafts acylation reaction with acetyl chloride in a reaction solvent at reaction temperature in the presence of a catalyst. After the reaction is complete, compound B is obtained.

[0023]

[0024] Step b: Compound B undergoes a substitution reaction with a metal halide in a reaction solvent at a reaction temperature. After the reaction is complete, compound C is obtained.

[0025]

[0026] Step c: Compound C reacts with halogen in a reaction solvent at the reaction temperature. After the reaction is complete, compound D is obtained.

[0027]

[0028] Step d: Compound D is hydrolyzed and eliminated in the presence of an aqueous base solution at the reaction temperature to obtain compound I.

[0029]

[0030] Wherein, X1 is selected from at least one of F, Cl, Br or I; X2 is selected from at least one of Cl, Br or I.

[0031] In step a, the reaction solvent is an organic solvent, which can be selected from at least one of dichloromethane, dichloroethane, nitromethane, nitrobenzene and carbon disulfide. In some embodiments, the reaction solvent is dichloromethane, which is conducive to the reaction and post-processing.

[0032] In step a, the reaction temperature is -10°C-25°C. In some embodiments, in step a, the reaction temperature is 20°C-25°C.

[0033] In step a, the catalyst is selected from at least one of anhydrous aluminum trichloride, anhydrous zinc chloride, ferric chloride and titanium tetrachloride.

[0034] In step a, the molar ratio of acetyl chloride to compound A may be 1.2:1-3:1. In some embodiments, the molar ratio of acetyl chloride to compound C is 1.5:1-2:1, which is conducive to the formation and acquisition of the product.

[0035] In step a, the reaction time may be 3 h to 9 h. In some embodiments, in step a, the reaction time is 4 h to 8 h; or in step a, the reaction time is 5 h to 7 h; or in step a, the reaction time is 6 h.

[0036] In step a, after the reaction is complete, post-treatment is optionally performed. In some embodiments, the post-treatment comprises: slowly pouring the reaction solution into ice water, stirring, standing, separating the liquid, collecting the organic layer, adding dichloromethane to the aqueous layer for extraction, combining the organic layers, drying, filtering, removing the organic solvent, and adding ethanol for recrystallization to obtain compound B.

[0037] In some embodiments, in step a, compound A is reacted in dichloromethane at -10°C-25°C, with the addition of anhydrous aluminum chloride, and then with the addition of acetyl chloride. After completion of the reaction, optional post-treatment is performed to obtain compound B; the post-treatment comprises: slowly pouring the reaction solution into ice water, stirring, standing, separating the liquids, collecting the organic layer, adding dichloromethane to the aqueous layer for extraction, combining the organic layers, drying, filtering, removing the organic solvent, and adding ethanol for recrystallization.

[0038] In step b, the reaction solvent is an organic solvent, which can be selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide. In some embodiments, the reaction solvent is tetrahydrofuran, which is conducive to the reaction and post-processing.

[0039] In step b, the metal halide is at least one of potassium fluoride, lithium chloride, cuprous chloride, potassium bromide, cuprous bromide, potassium iodide and cuprous iodide.

[0040] In step b, the reaction temperature is 40° C.-120° C. In some embodiments, in step b, the reaction temperature is 70° C.-110° C.

[0041] In step b, the molar ratio of the metal halide to compound B may be 1.2:1-5:1. In some embodiments, the molar ratio of the metal halide to compound B is 1.5:1-3:1, which is conducive to the formation and acquisition of the product.

[0042] In step b, the reaction time may be 4 h to 18 h. In some embodiments, in step b, the reaction time is 6 h to 12 h.

[0043] In step b, after the reaction is complete, post-treatment is optionally performed. In some embodiments, the post-treatment comprises: concentrating the reaction solution, cooling to room temperature, adding water, then adding ethyl acetate, extracting, combining the organic phases, drying, filtering, removing the organic solvent, and recrystallizing from a mixed solvent of ethyl acetate and isopropanol to produce compound C.

[0044] In some embodiments, in step b, compound A is reacted in dichloromethane at -10°C-25°C, with the addition of anhydrous aluminum chloride and then acetyl chloride. After completion of the reaction, optional post-treatment is performed to obtain compound B; the post-treatment comprises: slowly pouring the reaction solution into ice water, stirring, standing, separating the liquids, collecting the organic layer, adding dichloromethane to the aqueous layer for extraction, combining the organic layers, drying, filtering, removing the organic solvent, and adding ethanol for recrystallization.

[0045] In step c, the reaction solvent is an organic solvent, which can be selected from at least one of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, toluene and xylene. In some embodiments, the reaction solvent is dichloromethane, which is conducive to the reaction and post-processing.

[0046] In step c, the reaction temperature is -10°C to 40°C. In some embodiments, the reaction temperature is 0°C.

[0047] In step c, the halogen is selected from at least one of a concentrated sodium hydroxide solution of Br2, bromine, chlorine and iodine.

[0048] In step c, the molar ratio of the halogen to compound C may be 5:1-20:1. In some embodiments, the molar ratio of the halogen to compound C is 5:1-10:1, which is conducive to the formation and acquisition of the product.

[0049] In step c, the reaction time may be 2 h to 24 h. In some embodiments, in step c, the reaction time is 5 h to 20 h; or in step c, the reaction time is 8 h to 12 h; or in step c, the reaction time is 10 h.

[0050] In step c, after the reaction is complete, the next step of reaction is directly carried out without separation.

[0051] In some embodiments, in step c, compound C is reacted with a halogenation reagent in a reaction solvent at -10°C to 40°C. After the reaction is complete, the compound is directly subjected to the next reaction without isolation. The halogen is at least one of Br2 in a concentrated sodium hydroxide solution, bromine, chlorine, and iodine; and the reaction solvent is at least one of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, toluene, and xylene.

[0052] In step d, the aqueous alkali solution is selected from a sodium hydroxide aqueous solution or a potassium hydroxide aqueous solution. In some embodiments, in step d, the aqueous alkali solution has a mass fraction of 10% to 50% alkali, which is conducive to the reaction and treatment.

[0053] In step d, the reaction temperature of the hydrolysis and elimination reaction may be 25° C.-50° C. In some embodiments, in step d, the reaction temperature of the hydrolysis and elimination reaction is 30° C.-40° C.

[0054] In step d, the reaction time of the hydrolysis and elimination reaction can be 4 hours to 20 hours. In some embodiments, in step d, the reaction time of the hydrolysis and elimination reaction is 6 hours to 16 hours; or in step d, the reaction time of the hydrolysis and elimination reaction is 8 hours to 12 hours; or in step d, the reaction time of the hydrolysis and elimination reaction is 10 hours.

[0055] In step d, after the reaction is complete, post-treatment is optionally performed. In some embodiments, the post-treatment comprises: separating the liquids, collecting the aqueous layer, washing the organic layer with water, combining the organic layer with the aqueous layer, adding acid to adjust the pH to 1-2, filtering, and recrystallizing the resulting filter cake from ethanol or an ethanol-water mixed solvent to produce Compound I.

[0056] In some embodiments, in step d, compound D is hydrolyzed and eliminated by adding an aqueous base solution at 25°C-50°C. After completion of the reaction, optional post-treatment is performed to obtain compound I; the aqueous base solution is selected from a sodium hydroxide aqueous solution or a potassium hydroxide aqueous solution; the post-treatment comprises: liquid separation, collecting the aqueous layer, washing the organic layer with water, combining the organic layer with the aqueous layer, adding acid to adjust the pH to 1-2, filtering, and recrystallizing the resulting filter cake with ethanol or an ethanol-water mixed solvent.

[0057] The inventors have discovered that the preparation method of Compound I, using the above-mentioned method, produces unexpected technical effects, with high product purity, high yield, and few impurities. The present invention uses inexpensive and readily available p-toluenesulfonic acid as a starting material, selectively introduces an acetyl group at the ortho position of the methyl group, and then replaces the easily departed sulfonic acid group with a more nucleophilic halide anion. This process does not produce positional isomers of the halogen, reduces the generation of isomeric impurities, and has good positional selectivity. The acetyl group is then converted into a carboxyl group through halogenation and hydrolysis, thereby obtaining the target product, 5-halo-2-methylbenzoic acid.

[0058] In another aspect, the present invention provides a compound having the following structure:

[0059]

[0060] Wherein, when X1=F, X2=at least one of Br or I;

[0061] When X1=Cl, X2=at least one of Br or I;

[0062] When X1=Br, X2=at least one of Cl, Br or I;

[0063] When X1=I, X2=at least one of Cl, Br or I.

[0064] In summary, the present invention has the following beneficial technical effects:

[0065] 1. The preparation method of 5-halogenated-2-methylbenzoic acid provided by the present invention can avoid the use of Grignard reagent, uses cheap and readily available raw materials, has mild reaction conditions, is simple and safe to operate, and is suitable for industrial scale-up production;

[0066] 2. The preparation method of 5-halogenated-2-methylbenzoic acid provided by the present invention has good positional selectivity of the reaction, does not produce isomer impurities, and greatly improves the purity and yield of the product;

[0067] 3. The preparation method of 5-halogenated-2-methylbenzoic acid provided by the present invention uses a small amount of solvent, generates less three wastes, and is more environmentally friendly. This method is more suitable for industrial production with increasingly stringent safety and environmental protection requirements.

[0068] In the description of the present invention, it should be understood that the terms "first" and "second" are used for descriptive purposes only and should not be understood to indicate or imply relative importance or implicitly specify the number of the technical features indicated. Therefore, a feature specified as "first" or "second" may explicitly or implicitly include one or more of the features. In the description of the present invention, "plurality" means two or more, unless otherwise specifically defined.

[0069] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0070] In the present invention, expressions such as "compound A", "compound represented by formula A" and "formula A" refer to the same compound.

[0071] In the present invention, "optionally" or "optionally" means that it may or may not be present; or it may or may not be performed; for example, "optionally adding a reaction solvent to the crude product obtained in step (C)" means that a reaction solvent may or may not be added to the crude product obtained in step (C). DETAILED DESCRIPTION

[0072] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0073] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0074] In the present invention, h represents hour; g represents gram; and mL represents milliliter.

[0075] In the present invention, HPLC means high performance liquid chromatography.

[0076] In the present invention, the reaction is considered complete when the remaining amount of the raw materials does not exceed 5%, 3%, 2%, 1% or 0.5% of the amount of the raw materials charged.

[0077] Example 1 Preparation of Compound B

[0078]

[0079] Add p-toluenesulfonic acid (17.2 g) to the reaction flask, then add dichloromethane (100 mL), cool to 0°C, add the catalyst anhydrous aluminum chloride (18.7 g) in batches, then add acetyl chloride (7.9 g) dropwise, react at 0°C for 1 hour, heat to 20-25°C for 1 hour, then heat to reflux for 2-8 hours. HPLC detection shows that the raw material content is less than 1%. Slowly pour the reaction solution into ice water, stir for half an hour, let stand, separate the liquids, add dichloromethane (150 mL) to extract the liquids, combine the organic phases, dry, concentrate, and add ethanol (20 mL) for crystallization to obtain compound B, 20.3 g, with a yield of 95%.

[0080] 1 H-NMR(400MHz, CDCl3)δ:8.24(s,1H),7.85(d,1H),7.36(d,1H),2.66(s,3H),2.37(s,3H),2.08(br,1H). 13 C-NMR (100MHz, CDCl3) δ200.1,151.3,146.2,139.7,135.4,133.3,125.8,32.7,20.5.m / z[M+1] + =215.35.

[0081] Example 2 Preparation of Compound C

[0082]

[0083] Compound B (18.2 g) was added to a reaction flask, followed by tetrahydrofuran (100 mL). Potassium fluoride (5.4 g) was added with stirring, and the mixture was heated to 80°C and refluxed for 8 hours. The mixture was concentrated under reduced pressure to remove most of the solvent, cooled to room temperature, and water (100 mL) was added. Ethyl acetate (150 mL) was then added for extraction. The aqueous phase was extracted once more with a small amount of ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Crystallization was performed using a mixed solvent of ethyl acetate and isopropanol (30 mL, volume ratio 1:1) to obtain 5-fluoro-4-methylacetophenone (11.7 g, 90% yield).

[0084] Example 3 Preparation of Compound C

[0085] Compound B (18.2 g) was added to a reaction flask, followed by tetrahydrofuran (100 mL). With stirring, lithium chloride (4.0 g) was added, and the mixture was heated to 80°C and refluxed for 8 hours. The mixture was concentrated under reduced pressure to remove most of the solvent, cooled to room temperature, and water (100 mL) was added. Ethyl acetate (150 mL) was then added for extraction. The aqueous phase was extracted once more with a small amount of ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Crystallization was performed using a mixed solvent of ethyl acetate and isopropanol (30 mL, volume ratio 1:1) to obtain 5-chloro-4-methylacetophenone (12.7 g, yield 88%).

[0086] Example 4 Preparation of Compound C

[0087] Compound B (18.2 g) was added to a reaction flask, followed by tetrahydrofuran (100 mL). Potassium bromide (11.3 g) was added with stirring, and the mixture was heated to 80°C and refluxed for 8 hours. The mixture was concentrated under reduced pressure to remove most of the solvent, cooled to room temperature, and water (100 mL) was added. Ethyl acetate (150 mL) was then added for extraction. The aqueous phase was extracted once more with a small amount of ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Crystallization was performed using a mixed solvent of ethyl acetate and isopropanol (30 mL, volume ratio 1:1) to obtain 5-bromo-4-methylacetophenone (15.2 g, yield 92%).

[0088] Example 5 Preparation of Compound C

[0089] Compound B (18.2 g) was added to a reaction flask, followed by tetrahydrofuran (100 mL). Potassium iodide (15.8 g) was added with stirring, and the mixture was heated to 80°C and refluxed for 8 hours. The mixture was concentrated under reduced pressure to remove most of the solvent, cooled to room temperature, and water (100 mL) was added. Ethyl acetate (150 mL) was then added for extraction. The aqueous phase was extracted once more with a small amount of ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Crystallization was performed using a mixed solvent of ethyl acetate and isopropanol (30 mL, volume ratio 1:1) to obtain 5-iodo-4-methylacetophenone (17.4 g, yield 85%).

[0090] Example 6 Preparation of Compound D

[0091]

[0092] Add 5-chloro-4-methylacetophenone (12 g) to the reaction flask, then add dichloromethane (100 mL), cool to 0°C, then introduce chlorine gas, then raise the temperature to 25°C~40°C, stir and react for 6 hours to obtain a solution of compound D, which is directly used in the next step without separation.

[0093] Example 7 Preparation of Compound D

[0094] 5-Fluoro-4-methylacetophenone (11 g) was added to a reaction flask, followed by dichloromethane (100 mL). The temperature was lowered to 0°C, and bromine was added dropwise. The temperature was then raised to 25°C to 40°C, and the reaction was stirred for 8 hours to obtain a solution of Compound D, which was used directly in the next step without isolation. A small amount of the reaction solution was separated and purified to obtain Compound D, 2,2,2-tribromo-1-(5-fluoro-2-methylphenyl)ethanone, for structural analysis.

[0095] 1 H-NMR(400MHz, CDCl3)δ:7.75(s,1H),7.33(d,1H),7.20(d,1H),2.45(s,3H). 13 C-NMR (100MHz, CDCl3) δ194.3,161.4,139.8,136.2,134.7,131.5,128.3,39.4,21.3.m / z[M+2] + =390.91.

[0096] Example 8 Preparation of Compound D

[0097] 5-Fluoro-4-methylacetophenone (11 g) was added to a reaction flask, followed by dichloromethane (100 mL). The temperature was lowered to 0°C, and iodine was added. The temperature was then raised to 25°C to 40°C, and the reaction was stirred for 7 hours to obtain a solution of Compound D, which was used directly in the next step without isolation. A small amount of the reaction solution was separated and purified to obtain Compound D, 2,2,2-triiodo-1-(5-fluoro-2-methylphenyl)ethanone, for structural analysis.

[0098] 1 H-NMR(400MHz, CDCl3)δ:7.76(s,1H),7.35(d,1H),7.21(d,1H),2.48(s,3H). 13 C-NMR (100MHz, CDCl3) δ193.9,161.7,138.7,135.8,134.6,131.2,127.8,39.1,21.2.

[0099] m / z[M+1] + =530.7.

[0100] Example 9 Preparation of Compound D

[0101] 5-Chloro-4-methylacetophenone (12 g) was added to a reaction flask, followed by dichloromethane (100 mL). The temperature was lowered to 0°C, bromine was added, and the temperature was raised to 25°C-40°C. The reaction was stirred for 8 hours to obtain a solution of Compound D, which was used directly in the next step without isolation. A small amount of the reaction solution was separated and purified to obtain Compound D, 2,2,2-tribromo-1-(5-chloro-2-methylphenyl)ethanone, for structural analysis.

[0102] 1 H-NMR(400MHz, CDCl3)δ:7.73(s,1H),7.36(d,1H),7.19(d,1H),2.41(s,3H). 13 C-NMR (100MHz, CDCl3) δ197.1,162.5,139.5,136.2,135.1,132.4,128.3,38.9,21.7.

[0103] m / z[M+2] + =407.52.

[0104] Example 10 Preparation of Compound D

[0105] 5-Chloro-4-methylacetophenone (12 g) was added to a reaction flask, followed by dichloromethane (100 mL). The temperature was lowered to 0°C, and iodine was added. The temperature was then raised to 25°C to 40°C, and the reaction was stirred for 7 hours to obtain a solution of Compound D, which was used directly in the next step without isolation. A small amount of the reaction solution was separated and purified to obtain Compound D, 2,2,2-triiodo-1-(5-chloro-2-methylphenyl)ethanone, for structural analysis.

[0106] 1 H-NMR(400MHz, CDCl3)δ:7.78(s,1H),7.37(d,1H),7.22(d,1H),2.46(s,3H). 13 C-NMR (100MHz, CDCl3) δ197.3,162.6,139.8,136.1,135.8,132.5,128.1,38.2,21.9.

[0107] m / z[M+2] + =547.69.

[0108] Example 11 Preparation of Compound D

[0109] 5-Bromo-4-methylacetophenone (15 g) was added to a reaction flask, followed by dichloromethane (100 mL). The temperature was lowered to 0°C, chlorine gas was introduced, and the temperature was raised to 25°C-40°C. The reaction was stirred for 8 hours to obtain a solution of Compound D, which was used directly in the next step without isolation. A small amount of the reaction solution was separated and purified to obtain Compound D, 2,2,2-trichloro-1-(5-bromo-2-methylphenyl)ethanone, for structural analysis.

[0110] 1 H-NMR(400MHz, CDCl3)δ:7.81(s,1H),7.39(d,1H),7.25(d,1H),2.49(s,3H). 13 C-NMR (100MHz, CDCl3) δ198.1,164.2,138.5,137.2,136.3,134.7,129.6,39.5,22.6.

[0111] m / z[M+2] + =317.28.

[0112] Example 12 Preparation of Compound D

[0113] 5-Bromo-4-methylacetophenone (15 g) was added to a reaction flask, followed by dichloromethane (100 mL). The temperature was lowered to 0°C, bromine was added, and the temperature was raised to 25°C-40°C. The reaction was stirred for 8 hours to obtain a solution of Compound D, which was used directly in the next step without isolation. A small amount of the reaction solution was separated and purified to obtain Compound D, 2,2,2-tribromo-1-(5-bromo-2-methylphenyl)ethanone, for structural analysis.

[0114] 1 H-NMR(400MHz, CDCl3)δ:7.69(s,1H),7.29(d,1H),7.18(d,1H),2.37(s,3H). 13 C-NMR (100MHz, CDCl3) δ193.6,161.8,135.7,134.6,133.8,131.4,125.2,36.1,20.3.

[0115] m / z[M+2] + =451.92.

[0116] Example 13 Preparation of Compound D

[0117] 5-Bromo-4-methylacetophenone (15 g) was added to a reaction flask, followed by dichloromethane (100 mL). The temperature was lowered to 0°C, and iodine was added. The temperature was then raised to 25°C to 40°C, and the reaction was stirred for 7 hours to obtain a solution of Compound D, which was used directly in the next step without isolation. A small amount of the reaction solution was separated and purified to obtain Compound D, 2,2,2-triiodo-1-(5-bromo-2-methylphenyl)ethanone, for structural analysis.

[0118] 1 H-NMR(400MHz, CDCl3)δ:7.70(s,1H),7.32(d,1H),7.24(d,1H),2.42(s,3H). 13 C-NMR (100MHz, CDCl3) δ195.9,163.2,137.4,134.9,133.2,131.1,126.7,35.8,21.5.

[0119] m / z[M+1] + =591.84.

[0120] Example 14 Preparation of Compound D

[0121] 5-Iodo-4-methylacetophenone (17 g) was added to a reaction flask, followed by dichloromethane (100 mL). The temperature was lowered to 0°C, chlorine gas was introduced, and the temperature was raised to 25°C to 40°C. The reaction was stirred for 7 hours to obtain a solution of Compound D, which was used directly in the next step without isolation. A small amount of the reaction solution was separated and purified to obtain Compound D, 2,2,2-trichloro-1-(5-iodo-2-methylphenyl)ethanone, for structural analysis.

[0122] 1 H-NMR(400MHz, CDCl3)δ:7.48(s,1H),7.16(d,1H),6.95(d,1H),2.31(s,3H). 13 C-NMR (100MHz, CDCl3) δ199.4,163.1,137.3,134.7,133.4,131.5,126.6,35.4,21.2.

[0123] m / z[M+1] + =364.2.

[0124] Example 15 Preparation of Compound D

[0125] 5-Iodo-4-methylacetophenone (17 g) was added to a reaction flask, followed by dichloromethane (100 mL). The temperature was lowered to 0°C, bromine was added, and the temperature was raised to 25°C-40°C. The reaction was stirred for 7 hours to obtain a solution of Compound D, which was used directly in the next step without isolation. A small amount of the reaction solution was separated and purified to obtain Compound D, 2,2,2-tribromo-1-(5-iodo-2-methylphenyl)ethanone, for structural analysis.

[0126] 1 H-NMR(400MHz, CDCl3)δ:7.47(s,1H),7.15(d,1H),6.93(d,1H),2.29(s,3H). 13 C-NMR (100MHz, CDCl3) δ198.5,162.9,136.8,134.1,132.9,130.1,125.4,34.8,20.6.

[0127] m / z[M+2] + =498.91.

[0128] Example 16 Preparation of Compound D

[0129] 5-Iodo-4-methylacetophenone (17 g) was added to a reaction flask, followed by dichloromethane (100 mL). The temperature was lowered to 0°C, and iodine was added. The temperature was then raised to 25°C to 40°C, and the reaction was stirred for 7 hours to obtain a solution of Compound D, which was used directly in the next step without isolation. A small amount of the reaction solution was separated and purified to obtain Compound D, 2,2,2-triiodo-1-(5-iodo-2-methylphenyl)ethanone, for structural analysis.

[0130] 1 H-NMR(400MHz, CDCl3)δ:7.44(s,1H),7.13(d,1H),6.92(d,1H),2.28(s,3H). 13 C-NMR (100MHz, CDCl3) δ198.2,162.7,136.4,133.8,132.6,129.5,125.1,33.5,20.3.

[0131] m / z[M+1] + =638.95.

[0132] Example 17 Preparation of Compound I

[0133]

[0134] To the solution of Compound D in Example 7, a 20% aqueous sodium hydroxide solution (20 mL) was added. The mixture was stirred at 25°C to 50°C for 4-20 hours. The mixture was allowed to stand for separation. The organic phase was washed once with a small amount of water. The aqueous phases were combined, and hydrochloric acid was added to adjust the pH to 1-2. The mixture was filtered. The resulting filter cake was recrystallized from ethanol or an ethanol-water mixture to obtain Compound I: 5-fluoro-2-methylbenzoic acid, 9.9 g, in an 89% yield. m / z [M+1] + =155.09.

[0135] Example 18 Preparation of Compound I

[0136]

[0137] To the solution of Compound D in Example 6, a 20% aqueous sodium hydroxide solution (20 mL) was added. The mixture was stirred at 25°C to 50°C for 4-20 hours. The mixture was allowed to stand for separation. The organic phase was washed once with a small amount of water. The aqueous phases were combined, and hydrochloric acid was added to adjust the pH to 1-2. The mixture was filtered. The resulting filter cake was recrystallized from ethanol or an ethanol-water mixture to obtain Compound I: 5-chloro-2-methylbenzoic acid, 10.4 g, in an 86% yield. m / z [M+1] + =171.63.

[0138] Example 19 Preparation of Compound I

[0139]

[0140] To the solution of Compound D in Example 11, add 20% aqueous sodium hydroxide solution (20 mL), stir and react at 25°C to 50°C for 4-20 hours, let stand, separate the layers, wash the organic phase once with a small amount of water, combine the aqueous phases, add hydrochloric acid, adjust the pH to 1-2, filter, and recrystallize the resulting filter cake from ethanol or an ethanol-water mixture to obtain Compound I: 5-bromo-2-methylbenzoic acid, 12.1 g, 80% yield. m / z [M+2] + =217.36.

[0141] Example 20 Preparation of Compound I

[0142]

[0143] To the solution of Compound D in Example 14, a 20% aqueous sodium hydroxide solution (20 mL) was added. The mixture was stirred at 25°C to 50°C for 4-20 hours. The mixture was allowed to stand for separation. The organic phase was washed once with a small amount of water. The aqueous phases were combined, and hydrochloric acid was added to adjust the pH to 1-2. The mixture was filtered. The resulting filter cake was recrystallized from ethanol or an ethanol-water mixture to obtain Compound I: 5-iodo-2-methylbenzoic acid, 12.5 g, in a yield of 73%. m / z [M+1] + =263.36.

[0144] The methods of the present invention have been described through preferred embodiments. It is apparent that those skilled in the art will be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and spirit of the present invention to implement and apply the technology of the present invention. Those skilled in the art may refer to the disclosure herein and appropriately modify the process parameters to achieve the desired effect. It is particularly important to note that all similar substitutions and modifications apparent to those skilled in the art are considered encompassed by the present invention.

Claims

1. A method for preparing Compound I, comprising the following steps: Step a: Compound A undergoes Friedel-Crafts acylation reaction with acetyl chloride in a reaction solvent at reaction temperature in the presence of a catalyst. After the reaction is complete, compound B is obtained. Step b: Compound B undergoes a substitution reaction with a metal halide in a reaction solvent at a reaction temperature. After the reaction is complete, compound C is obtained. Step c: Compound C reacts with halogen in a reaction solvent at the reaction temperature. After the reaction is complete, compound D is obtained. Step d: Compound D is hydrolyzed and eliminated in the presence of an aqueous base solution at the reaction temperature to obtain compound I. in, X1 is selected from at least one of F, Cl, Br or I; X2 is selected from at least one of Cl, Br or I.

2. The method according to claim 1, wherein in step a, the reaction solvent is selected from at least one of dichloromethane, dichloroethane, nitromethane, nitrobenzene and carbon disulfide.

3. The method according to claim 1, wherein in step a, the reaction temperature is -10°C to 25°C; or the molar ratio of acetyl chloride to compound A is 1.2:1 to 3:

1.

4. The method according to claim 1, wherein in step a, the catalyst is selected from at least one of anhydrous aluminum chloride, anhydrous zinc chloride, ferric chloride and titanium tetrachloride.

5. The method according to claim 1, wherein in step b, the metal halide is at least one of potassium fluoride, lithium chloride, cuprous chloride, potassium bromide, cuprous bromide, potassium iodide and cuprous iodide.

6. The method according to claim 1, wherein in step b, the reaction temperature is 40°C-120°C.

7. The method according to claim 1, wherein in step c, the reaction temperature is -10°C to 40°C; or the molar ratio of the halogen to compound C is 5:1 to 20:

1.

8. method according to claim 1, in step c, described halogen is selected from at least one of Br2 concentrated sodium hydroxide solution, bromine, chlorine and iodine.

9. The method of claim 1, wherein in step d, the aqueous alkali solution is selected from a sodium hydroxide aqueous solution or a potassium hydroxide aqueous solution.

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