A method for preparing a pharmaceutical intermediate substituted with phenylacetic acid

Abstract

This invention discloses a method for preparing a substituted phenylacetic acid pharmaceutical intermediate, comprising the reaction steps represented by Reaction Formula 1 below. The method utilizes a specific organomagnesium-lithium composite reagent to replace the traditional magnesium / iodine initiation system for Grignardization, and combines this with special reaction conditions such as dry ice as a carbon dioxide source and low-temperature nucleophilic addition. This effectively suppresses side reactions such as Wurtz coupling and over-carboxylation, significantly improving the yield and purity of the target product, while simplifying the operation, reducing safety risks, and achieving green, efficient, and industrialized production of 3,4-difluoro-2-methoxyphenylacetic acid. Reaction Formula 1

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, and relates to a method for preparing a substituted phenylacetic acid pharmaceutical intermediate, specifically a method for preparing 3,4-difluoro-2-methoxyphenylacetic acid. Background Technology

[0002] The 3,4-difluoro-2-methoxyphenylacetic acid is a key intermediate in the synthesis of suzetrigine (VX-548) and has wide applications in the field of medicinal chemistry.

[0003] 3,4-Difluoro-2-methoxyphenylacetic acid, as an important intermediate of fluorinated aromatic carboxylic acids, has two strongly electron-withdrawing fluorine atoms, one electron-donating methoxy group, and one carboxymethyl side chain on its benzene ring. The complex electronic and steric effects pose a significant challenge to its synthesis. The key to its synthesis lies in how to efficiently introduce an acetate group (-CH₂COOH) side chain onto the 3,4-difluoro-2-methoxyphenyl ring.

[0004] The reported methods for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid can be mainly categorized as follows:

[0005] (1) The target product is obtained by condensation reaction of 3,4-difluoro-2-methoxybenzaldehyde with Darzens glycidyl ester, followed by hydrolysis and decarboxylation. Although the raw materials are readily available, the Darzens reaction requires strong bases (such as potassium tert-butoxide and sodium hydride) and α-halocarboxylic acid esters, which are subject to harsh reaction conditions and poor reaction selectivity. On fluorine-containing substrates, the side reaction of nucleophilic substitution of the F atom on the aromatic ring by alkoxy group (i.e., nucleophilic aromatic substitution side reaction on the aromatic ring, SNAr side reaction) is prone to occur, resulting in low yield and difficult purification, making it unsuitable for industrial scale-up.

[0006] (2) Using methyl 3,4-difluoro-2-methoxybenzoate as a raw material, the product is obtained by α-halogenation (such as NBS bromination or NCS chlorination), followed by nucleophilic substitution with sodium cyanide to obtain an α-cyano intermediate, and finally by acidic or alkaline hydrolysis. This method has a long route (at least 4 steps) and uses highly toxic sodium cyanide and strong acids / bases, resulting in large emissions of waste and high safety risks, which does not meet the requirements of green chemistry.

[0007] Chinese patent document CN119285456A uses alkyllithium, operates at low temperatures, and suffers from poor atom economy; CN117858875A reports a similar method, but also faces the same problems. The reported yields of 3,4-difluoro-2-methoxyphenylacetic acid are all between 65% and 78%, and the HPLC purity is between 95% and 98%. Moreover, both use an iodine initiation system, failing to fundamentally solve the side reaction problem in the Grignardization process of benzylic halogenated compounds.

[0008] Therefore, it is urgent to develop a preparation method of 3,4-difluoro-2-methoxyphenylacetic acid which can effectively inhibit the Wurtz coupling side reaction, avoid excessive carboxylation of Grignard reagent, has mild reaction conditions, high yield and purity, and is suitable for industrial production. The present application is proposed based on this demand. SUMMARY

[0009] In view of the above problems existing in the prior art, the present application aims to provide a preparation method of 3,4-difluoro-2-methoxyphenylacetic acid. The method uses a specific organic magnesium-lithium composite reagent to replace the traditional magnesium / iodine initiation system for Grignard reaction, and combines dry ice as a carbon dioxide source and low-temperature nucleophilic addition and other special reaction conditions to effectively inhibit side reactions such as Wurtz coupling and excessive carboxylation, significantly improve the yield and purity of the target product, simplify the operation, reduce the safety risk, and realize green, efficient and industrial production of 3,4-difluoro-2-methoxyphenylacetic acid.

[0010] To achieve the above-mentioned purpose, the present application provides a preparation method of 3,4-difluoro-2-methoxyphenylacetic acid represented by the following reaction formula 1, which comprises the following steps:

[0011]

[0012] Reaction formula 1

[0013] (1) Halogenation step: taking 3,4-difluoro-2-methoxybenzyl alcohol (compound A) as the starting material, under the action of a halogenating agent, 1-(halomethyl)-3,4-difluoro-2-methoxybenzene (compound B) is obtained;

[0014] (2) Grignard reaction step: compound B is reacted with an organic magnesium-lithium composite reagent in an organic solvent under the protection of an inert gas to obtain a Grignard reagent solution containing benzyl magnesium chloride lithium chloride complex (compound C);

[0015] (3) Carboxylation step: solid dry ice is added to the Grignard reagent solution obtained in step (2) to control the reaction temperature for nucleophilic addition reaction, and a lithium carboxylate salt solution of 3,4-difluoro-2-methoxyphenylacetic acid is obtained, and after post-treatment, pure 3,4-difluoro-2-methoxyphenylacetic acid compound D is obtained.

[0016] Preferably, X in compound B in step (1) is Cl or Br.

[0017] Preferably, the halogenating reagent in step (1) is selected from thionyl chloride (SOCl2), oxalyl chloride ((COCl)2), N-bromosuccinimide (NBS) / triphenylphosphine (PPh3) system, phosphorus tribromide (PBr3), hydrogen bromide / acetic acid system or hydrobromic acid / sulfuric acid system; preferably thionyl chloride or N-bromosuccinimide / triphenylphosphine; most preferably thionyl chloride.

[0018] Preferably, the molar ratio of the halogenating reagent to compound A in step (1) is 1:1.0 to 1:3.0, more preferably 1:1.5 to 1:2.5.

[0019] Preferably, the reaction temperature in step (1) is 0 to 50°C, preferably 10 to 40°C; and the reaction time is 1 to 10 hours, preferably 2 to 6 hours.

[0020] Preferably, the reaction in step (1) is carried out in an organic solvent selected from one or more of dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile or toluene; preferably dichloromethane.

[0021] Preferably, the organic solvent in step (2) is one or more of anhydrous tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), anhydrous diethyl ether or anhydrous methyl tert-butyl ether; preferably anhydrous tetrahydrofuran.

[0022] Preferably, the molar ratio of the organic magnesium-lithium complex reagent (i-PrMgCl·LiCl) to compound B in step (2) is 1:1.0 to 1:2, more preferably 1:1.05 to 1:1.5.

[0023] Preferably, the reaction temperature in step (2) is -20 to 30°C, preferably -10 to 10°C; and the reaction time is 0.5 to 6 hours, preferably 1 to 3 hours.

[0024] Preferably, in step (3), the molar ratio of compound B to dry ice (solid CO2) is 1:1.5 to 1:15, more preferably 1:3 to 1:11.

[0025] Preferably, in step (3), the reaction temperature is -25 to -5°C, preferably -20 to -10°C; and the reaction time is 0.5 to 4 hours, preferably 1 to 2 hours.

[0026] Preferably, in step (3), the post-treatment is: adding a dilute aqueous acid solution to the magnesium-lithium carboxylate salt solution obtained in step (3) to adjust the pH to 1 to 4, so that the target product 3,4-difluoro-2-methoxyphenylacetic acid is free and separated, and after filtration, washing and drying, the pure 3,4-difluoro-2-methoxyphenylacetic acid (compound D) is obtained.

[0027] Preferably, the post-treatment in step (3) is specifically as follows: after the reaction is completed, 1 to 3 times volume of water is added to dilute the reaction solution, 1 to 3 mol / L dilute hydrochloric acid or dilute sulfuric acid is slowly added dropwise to adjust the pH to 1 to 4 (preferably pH=2 to 3), and stirring is performed for 30 minutes to make the target product 3,4-difluoro-2-methoxyphenylacetic acid completely precipitate; the precipitated solid is collected by filtration, washed with a small amount of cold water and cold ethanol in sequence, and vacuum dried at 40 to 60°C for 4 to 8 hours to obtain white to white-like solid 3,4-difluoro-2-methoxyphenylacetic acid pure product.

[0028] Advantages

[0029] Compared with the prior art, the preparation method of 3,4-difluoro-2-methoxyphenylacetic acid has the following advantages:

[0030] By using Knochel type mild Grignard reagent i-PrMgCl·LiCl to replace the traditional metal magnesium / iodine initiation system, and combining with low-temperature carboxylation reaction of dry ice as CO2 source, the separation yield of 3,4-difluoro-2-methoxyphenylacetic acid can reach more than 90%, which is significantly higher than the level of 60 to 78% of the traditional metal Mg / iodine method. The product has high purity, the reaction condition is mild, the energy consumption is low, the three wastes are less, and it is green and environmentally friendly. DETAILED DESCRIPTION

[0031] Hereinafter, the present application will be described in detail. Before proceeding with the description, it should be understood that the terms used in the specification and the appended claims should not be construed as being limited to the general and dictionary meanings and should be construed as having meanings and concepts corresponding to the technical aspects of the present application based on the principle that the inventor is allowed to define appropriate terms in order to best explain the application. Therefore, the description presented herein is merely a preferred example for the purpose of illustration and is not intended to limit the scope of the application, and it should be understood that other equivalent ways or modifications can be derived from the application without departing from the spirit and scope of the application.

[0032] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," or any other similar term are intended to be open-ended. For example, a composition or article that comprises elements A, B, and C should be construed to mean that elements A, B, and C are present, but not excluding elements D and E. Further, unless otherwise specified, the use of "or" is to be interpreted as inclusive "or," meaning A or B or both. For example, the phrase "A or B" means "A or B or both." Also, unless otherwise specified, the use of "and" is to be interpreted as descriptive "and" rather than conjunctive "and." For example, the phrase "A and B" means "A and B, but not necessarily both." Moreover, the use of the term "including" as well as other forms such as "include," "includes," "comprise," "comprises," "comprising," "contain," "contains," "containing," "characterized by," "comprised of," and "comprises essentially of," are not to be construed as limiting. Rather, these terms are to be construed as meaning "comprising." Further, unless otherwise specified, the use of the term "about" is to be construed as meaning "approximately," "substantially," or "essentially."

[0033] As used herein, all features or conditions of a range or a parameter are to be understood as being preferred unless otherwise specified. Thus, a description of a range or a parameter should be considered as having specifically disclosed the entire range and every possible subrange as well as individual numerical values within the range, even though the subranges or numerical values can not have been explicitly stated. For example, a range of "1 to 8" should be considered as having specifically disclosed, inter alia, all subranges between and

[0034] If a numerical range or other range or parameter is expressed in a range format, it will be understood that regardless of the breadth of the range, the minimum and maximum values of the range are each disclosed. The upper and lower limits of these disclosed ranges can be independently combined with one another to disclose further ranges. In addition, unless otherwise specified, a range "comprising" a value should be interpreted as including the value or endpoint. For example, a range of "1 to 8" should be interpreted to include the values of 1, 2, 3, 4, 5, 6, 7, 8, and 1-8.

[0035] As used herein, numerical values should be understood to be approximate, unless otherwise specified. For example, the numerical value 40.0 should be understood to encompass the range from 39.50 to 40.49.

[0036] The preparation method of the present application uses solid dry ice as a CO2 source, which has the following advantages over the introduction of CO2 gas: the sublimation rate of dry ice is moderate (about 1 to 2 L / min (standard state)), which facilitates accurate control of the CO2 concentration of the reaction system; the sublimation process of dry ice absorbs a large amount of heat (about 25 kJ per mole of CO2 sublimation), which can be used as a cooling source for the reaction system, and the reaction liquid temperature can be stably controlled in the low temperature range of-20 to-10℃ without the need for additional low-temperature constant temperature equipment; dry ice sublimation does not have gas-entrained water vapor (avoiding the quenching of trace water vapor in conventional CO2 gas to the Grignard reagent); dry ice slowly dissolves in the reaction, continuously providing CO2, so that the Grignard reagent is always in an environment of excess CO2, further inhibiting the over-carboxylation side reaction of the Grignard reagent with the generated lithium carboxylate to form ketones or tertiary alcohols.

[0037] The carboxylation temperature of step (3) of the preparation method of the present application needs to be strictly controlled in the range of-25 to-5℃ (preferably-20 to-10℃). If the temperature is too high, for example greater than 0℃, over-addition occurs, generating ketone byproducts (dibenzyl ketone), and the yield and purity are significantly reduced; if the temperature is too low, for example less than-25℃, the reaction rate is too slow, special low-temperature equipment is required, and the production efficiency is low. In the temperature range of-25 to-5℃ according to the present application, the reaction rate is moderate, the side reaction is effectively inhibited, and the yield and purity are optimal.

[0038] The following examples are only listed as examples of embodiments of the present application and do not constitute any limitation on the present application, and those skilled in the art can understand that modifications within the scope of the essence and concept of the present application fall within the protection scope of the present application. Unless otherwise specified, the reagents and instruments used in the following examples are commercially available products.

[0039] Example 1: Thionyl chloride chlorination + i-PrMgCl·LiCl + dry ice carboxylation

[0040] Step one (halogenation reaction):

[0041] Into a 500 mL jacketed glass reactor, 3,4-difluoro-2-methoxybenzyl alcohol (20 g, 114.84 mmol) and dichloromethane (200 mL) were added successively, and the substrate was stirred to completely dissolve. N,N-dimethylformamide (41.96 mg, 0.5742 mmol, 0.5 mol%) was added, and thionyl chloride (27.32 g, 229.68 mmol, 2.0 eq) was slowly added dropwise at 25-35°C for about 30 minutes. After the dropwise addition was completed, the reaction was continued to stir at 25-35°C for 3 hours. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure (30-40°C water bath), to obtain 1-(chloromethyl)-3,4-difluoro-2-methoxybenzene crude product (light yellow oil), which was directly used in the next step reaction.

[0042] Step two (Grignard reaction):

[0043] Into the above crude product, anhydrous tetrahydrofuran (150 mL) was added to form a solution. Another 500 mL four-necked reaction flask was replaced with nitrogen for 3 times, and then the reaction flask was placed in a low-temperature constant-temperature water bath at -10 to 0°C. i-PrMgCl·LiCl THF solution (1.3 mol / L, 96.95 mL, 126.0 mmol, 1.10 eq) was added under nitrogen flow, and stirred uniformly. The above 1-(chloromethyl)-3,4-difluoro-2-methoxybenzene THF solution was slowly added dropwise, and the reaction liquid temperature was controlled at -5 to 5°C during the dropwise addition process for about 1 hour. After the dropwise addition was completed, the reaction was continued to stir at -5 to 5°C for 2 hours, to obtain a THF solution of benzyl magnesium chloride lithium chloride complex (Knochel type mild Grignard reagent) (light yellow to light brown). HPLC monitoring showed that there was no obvious 1-(chloromethyl)-3,4-difluoro-2-methoxybenzene raw material residue, and the content of Wurtz coupling dimer by-product in the reaction solution was less than 0.2%.

[0044] Step three (carboxylation reaction):

[0045] The above Grignard reagent solution was cooled to -20 to -15°C (precise temperature control by dry ice-acetone bath), and pre-pulverized solid dry ice (about 60 g, 1.36 mol, about 12 eq, completely immersed in the reaction solution) was gradually added. The reaction liquid immediately started to bubble vigorously (CO2 was absorbed by the Grignard reagent and accompanied by heat release), and by controlling the addition rate of dry ice and the reaction bath temperature, the reaction liquid temperature was strictly controlled in the range of -20 to -10°C (about 1 hour for adding dry ice). After the addition of dry ice was completed, the reaction was continued to stir at -20 to -10°C for 1.5 hours. TLC monitoring showed that the Grignard reagent point completely disappeared, and the reaction was complete, to obtain a lithium carboxylate solution of 3,4-difluoro-2-methoxyphenylacetic acid.

[0046] Step four (post-treatment):

[0047] After the reaction was completed, 1 mol / L dilute hydrochloric acid (300 mL) was added to the reaction solution to adjust the pH to 2 to 3, and stirred for 30 minutes to completely precipitate the target product; the precipitated white solid was collected by filtration, washed with a small amount of cold water (50 mL x 2), cold ethanol (30 mL) in turn, and dried under vacuum at 50°C for 6 hours to obtain white solid 3,4-difluoro-2-methoxybenzeneacetic acid 21.2 g, HPLC purity 99.7%, molar yield 93.0% (based on 3,4-difluoro-2-methoxybenzyl alcohol), 1 H NMR data: 12.42, br, 1H; 7.07-7.15, m, 2H; 3.89, d, 3H; 3.58, s, 2H.

[0048] Example 2: NBS / PPh3 bromination method + i-PrMgCl.LiCl + dry ice carboxylation

[0049] Step one (halogenation reaction): similar to step one of example 1, 1-(bromomethyl)-3,4-difluoro-2-methoxybenzene 24.5 g was obtained.

[0050] Step two (Grignard reaction): dissolve the above 1-(bromomethyl)-3,4-difluoro-2-methoxybenzene in anhydrous THF (200 mL); take another 500 mL four-necked reaction flask, replace with nitrogen for 3 times, then place it in a -10 to 0°C constant temperature water bath, add i-PrMgCl.LiCl THF solution (1.3 mol / L, 95.5 mL, 124.1 mmol, 1.10 eq) under nitrogen flow, stir uniformly; slowly add the above 1-(bromomethyl)-3,4-difluoro-2-methoxybenzene THF solution, about 1 hour to drop, control the reaction liquid temperature at -5 to 5°C during the drop process; continue to stir for 1.5 hours at -5 to 5°C after dropping, to obtain benzyl magnesium bromide lithium chloride complex THF solution.

[0051] Step three (carboxylation reaction): similar to step three of example 1, use dry ice (60 g, 1.36 mol) at -20 to -10°C for 1.5 hours.

[0052] Step four (post-treatment): similar to step four of example 1, white solid 3,4-difluoro-2-methoxybenzeneacetic acid 21.0 g was obtained, HPLC purity 99.8%, molar yield 92.1% (based on 3,4-difluoro-2-methoxybenzene alcohol).

[0053] Example 3: add CuCl as Grignard promoter

[0054] Step one (halogenation): Similar to step one of Example 1, to obtain 1-(chloromethyl)-3,4-difluoro-2-methoxybenzene crude.

[0055] Step two (Grignard reaction): Dissolve the above crude in anhydrous THF (150 mL); take another 500 mL four-necked flask, replace with nitrogen for 3 times, then place in -10 to 0 °C constant temperature water bath, under the nitrogen flow, add i-PrMgCl.LiCl THF solution (1.3 mol / L, 96.95 mL, 126.0 mmol, 1.10 eq) and anhydrous cuprous chloride (CuCl, 124 mg, 1.25 mmol, 1.1 mol%) successively, stir uniformly; slowly drop the above 1-(chloromethyl)-3,4-difluoro-2-methoxybenzene THF solution, about 1 hour drop, control the reaction liquid temperature at -5 to 5 °C during the drop process; continue to stir for 1.5 hours at -5 to 5 °C after drop, to obtain the benzyl magnesium chloride lithium chloride complex (containing a small amount of CuCl) THF solution.

[0056] Step three (carboxylation): Similar to step three of Example 1, use dry ice (60 g) at -20 to -10 °C for 1.5 hours.

[0057] Step four (post-treatment): Similar to step four of Example 1, to obtain 3,4-difluoro-2-methoxybenzeneacetic acid 21.6 g, HPLC purity 99.8%, molar yield 94.7% (calculated from 3,4-difluoro-2-methoxybenzyl alcohol).

[0058] Comparative Example 1: Do not use Knochel type mild Grignard reagent, use traditional Mg / I2 scheme + CO2 gas

[0059] According to step one (thionyl chloride chlorination) of Example 1, 1-(chloromethyl)-3,4-difluoro-2-methoxybenzene crude was obtained; according to step two (Mg / I2 induced Grignard) of Example 1, the THF solution of Grignard reagent was obtained; according to step three (-15 to -10 °C, dry CO2 gas) of Example 1, the carboxylation reaction was carried out; according to step four of Example 1, the post-treatment was carried out. Finally, 3,4-difluoro-2-methoxybenzeneacetic acid 20.8 g was obtained, HPLC purity 88.9%, molar yield 84.6. This comparative example reproduces the traditional metal Mg / I2 + CO2 gas scheme, the yield and purity are significantly lower than Example 1 of the application.

[0060] Comparative Example 2: Do not add LiCl, only use i-PrMgCl

[0061] Prepared using a method similar to Example 1, except that i-PrMgCl·LiCl was replaced with an equimolar amount of i-PrMgCl (2.0 mol / L THF solution, 63 mL, 126.0 mmol, 1.10 eq), and anhydrous LiCl was not added. The final yield was 19.5 g of 3,4-difluoro-2-methoxyphenylacetic acid, with an HPLC purity of 97.5% and a molar yield of 72.5%. This comparative example demonstrates that LiCl plays an irreplaceable and crucial role in stabilizing the active center of i-PrMgCl, improving the solubility of Grignard reagents, and inhibiting Wurtz coupling side reactions. This is the core reason why the i-PrMgCl·LiCl composite reagent can achieve high yield and high purity.

[0062] Comparative Example 3: Instead of using dry ice, CO2 gas was introduced.

[0063] Except for replacing the solid dry ice in step three of Example 1 with CO2 gas (flow rate approximately 200 mL / min), the preparation was carried out in a similar manner to Example 1. During the reaction, it was found that the CO2 gas introduction rate was difficult to control precisely, and significant exothermic reactions occurred when the local CO2 concentration was too high, causing the reaction solution temperature to fluctuate between -15 and -5°C. The trace amounts of water vapor entrained in the CO2 gas (which are difficult to completely remove even after drying with concentrated sulfuric acid) quenched some of the Grignard reagent, slightly increasing the equivalent consumption of the Grignard reagent. Finally, 20.4 g of 3,4-difluoro-2-methoxyphenylacetic acid was obtained, with an HPLC purity of 99.2% and a molar yield of 80.5%. This comparative example demonstrates the advantages of using dry ice as the CO2 source compared to introducing CO2 gas: dry ice has a moderate sublimation rate, can simultaneously serve as a cold source, has no water vapor entrainment, and the CO2 concentration is easier to control, resulting in a certain improvement in both reaction yield and purity.

[0064] Comparative Example 4: The temperature of the carboxylation step was too high.

[0065] Except for controlling the carboxylation step in step three at a temperature of 0 to 10 °C, the preparation was carried out in a similar manner to Example 1. The final yield was 19.8 g of 3,4-difluoro-2-methoxyphenylacetic acid with an HPLC purity of 86.2% and a molar yield of 73.8%. This comparative example demonstrates the necessity of carrying out the carboxylation reaction at a low temperature of -20 to -10 °C. Low temperatures significantly suppress the β-hydrogen elimination of the Grignard reagent and excessive carboxylation side reactions, which is crucial for obtaining a high-purity product.

[0066] Comparative Example 5: Grignification was carried out at 40 to 50°C without using a low-temperature reaction.

[0067] Except for controlling the Grignification reaction temperature in step two to 40-50°C, the preparation was carried out in a similar manner to Example 1. HPLC monitoring showed that the content of Wurtz coupling dimerization byproduct reached 3.2%, and due to the increased temperature, the 1,2-elimination side reaction also increased significantly, generating approximately 1.2% of 3,4-difluoro-2-methoxystyrene byproduct. Finally, 18.2 g of 3,4-difluoro-2-methoxyphenylacetic acid was obtained, with an HPLC purity of 82.3% and a molar yield of 73.8%. This comparative example demonstrates the necessity of carrying out the Grignification reaction at a low temperature (-5 to 5°C) in the present invention: low temperature can significantly inhibit Wurtz coupling and 1,2-elimination side reactions, which is key to obtaining high-yield, high-purity products.

[0068] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for preparing 3,4-difluoro-2-methoxyphenylacetic acid represented by the following reaction formula 1, the method comprising the following steps: Reaction 1 (1) Halogenation reaction steps: Starting with 3,4-difluoro-2-methoxybenzyl alcohol compound A, under the action of halogenation reagent, 1-(halomethyl)-3,4-difluoro-2-methoxybenzene compound B was obtained; (2) Grignard reaction step: Compound B is reacted with an organomagnesium lithium complex reagent in an organic solvent under the protection of an inert gas to obtain a Grignard reagent solution compound C containing a benzyl magnesium chloride lithium chloride complex, wherein the organomagnesium lithium complex reagent is i-PrMgCl·LiCl or i-PrMgCl·CuCl. (3) Carboxylation reaction step: Add solid dry ice to the Grignard reagent solution obtained in step (2), control the reaction temperature to carry out nucleophilic addition reaction, and obtain lithium carboxylate solution of 3,4-difluoro-2-methoxyphenylacetic acid. After post-treatment, pure compound D of 3,4-difluoro-2-methoxyphenylacetic acid is obtained.

2. The preparation method according to claim 1, characterized in that, In step (1), X in compound B is Cl or Br; The halogenated reagent mentioned in step (1) is thionyl or N-bromosuccinimide / triphenylphosphine; In step (1), the molar ratio of the halogenated reagent to compound A is 1:1.5 to 1:2.5; In step (1), the reaction temperature is 0 to 50°C; the reaction time is 1 to 10 hours. The halogenated reagent mentioned in step (1) is selected from thionyl chloride, oxalyl chloride, N-bromosuccinimide / triphenylphosphine system, phosphorus tribromide, hydrogen bromide / acetic acid system or hydrobromic acid / sulfuric acid system, and the molar ratio of the halogenated reagent to compound A is 1:1.0 to 1:3.0; The reaction in step (1) is carried out in an organic solvent selected from one or more of dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, or toluene.

3. The preparation method according to claim 2, characterized in that, The organic solvent in step (1) is dichloromethane.

4. The preparation method according to claim 1, characterized in that, The reaction temperature in step (1) is 10 to 40°C; the reaction time is 2 to 6 hours.

5. The preparation method according to claim 1, characterized in that, The halogenated reagent mentioned in step (1) is thionyl chloride.

6. The preparation method according to claim 1, characterized in that, The organic solvent in step (2) is anhydrous tetrahydrofuran; In step (2), the molar ratio of the organomagnesium-lithium composite reagent to compound B is 1:1.05 to 1:1.

5. In step (2), the reaction temperature is -20 to 30°C; the reaction time is 0.5 to 6 hours. The reaction in step (2) is carried out in an organic solvent, which is one or more of anhydrous tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), anhydrous diethyl ether or anhydrous methyl tert-butyl ether; In step (2), the molar ratio of the organomagnesium lithium composite reagent to compound B is 1:1.0 to 1:

2.

7. The preparation method according to claim 1, characterized in that, In step (2), the reaction temperature is -10 to 10°C and the reaction time is 1 to 3 hours.

8. The preparation method according to claim 1, characterized in that, In step (3), the molar ratio of compound B to dry ice is 1:1.5 to 1:15; In step (3), the reaction temperature is -25 to -5℃; the reaction time is 0.5 to 4 hours.

9. The preparation method according to claim 1, characterized in that, In step (3), the reaction temperature is -20 to -10℃; the reaction time is 1 to 2 hours.

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