A method for synthesizing 3,4-difluoro-2-methoxybenzoic acid

Abstract

This invention relates to the field of pharmaceutical intermediate synthesis, specifically to a method for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid. The method includes the following steps: Compound III reacts with diethyl malonate in the presence of a copper catalyst, a nitrogen-containing ligand, and base I; then, an inorganic strong base II is directly added for hydrolysis, followed by acidification to obtain compound IV; compound IV undergoes decarboxylation in an acidic solution to yield 3,4-difluoro-2-methoxyphenylacetic acid (compound I) with a purity of up to 99.3% and an overall yield of up to 74.04%. This invention features a simple route, mild reaction conditions, low cost, environmental friendliness, stable yields at each step, and simple post-processing, making it suitable for industrial production.

Description

Technical Field

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

[0002] 3,4-Difluoro-2-methoxyphenylacetic acid is an important fluorophenylacetic acid compound and a key intermediate in drug development. It is not only a core building block for synthesizing drugs that inhibit highly active or overexpressed signal transduction pathways in cancer tissues for the treatment of highly proliferative and tumor diseases, but also an important intermediate for the synthesis of furan ring-containing drugs.

[0003] These furan-ring-containing drugs are primarily used to treat or alleviate pain caused by many diseases, including chronic pain, acute pain, intestinal pain, musculoskeletal pain, and neuropathic pain. Among them, suzetrigine (trade name Journavx), developed by Vertex Pharmaceuticals, is an oral selective NaV1.8 inhibitor and was the world's first approved novel non-opioid oral analgesic. It was approved by the FDA in January 2025 for the clinical treatment of moderate to severe acute pain in adults. With the widespread use of these furan-ring-containing drugs in pain management, the market demand for 3,4-difluoro-2-methoxyphenylacetic acid continues to grow, placing higher demands on the economy, safety, and scalability of its synthesis process.

[0004] Currently, there are publicly reported methods for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid, mainly including the following two technical routes: Method 1: Chinese patent CN117858875A uses tert-butyl 2-bromoacetate to react first with trimethylchlorosilane and zinc powder, then with 1-bromo-3,4-difluoro-2-methoxybenzene in a coupling reaction under a palladium catalyst, and finally acid hydrolysis to obtain 3,4-difluoro-2-methoxyphenylacetic acid. This route can achieve a yield of 85%. However, this route has obvious drawbacks: the palladium catalyst is expensive, and the coupling reaction needs to be carried out at high temperatures, which is difficult to meet the economic requirements of industrial production.

[0005]

[0006] Method 2: Chinese patent CN119285456A uses 2,3-difluorophenol and 3,4-dihydropyran as raw materials in the presence of sulfonic acid resin to generate the intermediate 2-(2,3-difluorophenoxy)pyran. This intermediate is then reacted with alkyllithium and tert-butyl 2-bromoacetate followed by acid hydrolysis to obtain the intermediate 3,4-difluoro-2-hydroxyphenylacetic acid. Finally, it reacts with a methylating agent in the presence of a base to generate the target compound 3,4-difluoro-2-methoxyphenylacetic acid. The alkyllithium reagent used in this route is highly toxic and extremely sensitive to air and moisture. The reaction releases a large amount of heat, requiring strict control of reaction conditions and posing a high safety risk, making it unsuitable for industrial production. Furthermore, the nucleophilic substitution selectivity of alkyllithium reagents is poor, easily generating byproducts, increasing the difficulty of separating and purifying the target product. The post-processing also requires a large amount of acidic reagent, further exacerbating the safety hazards.

[0007]

[0008] In summary, existing synthetic routes generally suffer from problems such as expensive catalysts, harsh reaction conditions, numerous byproducts, complex post-processing, and significant safety risks, making them unsuitable for large-scale industrial production. Therefore, there is an urgent need to develop a novel synthetic route that uses readily available raw materials, is simple in process, is safe and stable, and is economical and environmentally friendly, to ensure the efficient synthesis of 3,4-difluoro-2-methoxyphenylacetic acid. Summary of the Invention

[0009] The purpose of this invention is to provide a method for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid, which solves the problems of expensive catalysts, harsh reaction conditions, numerous byproducts, and high safety risks in the prior art. This method uses 2,3-difluorophenol as the starting material and proceeds through four steps: bromination, oxymethylation, Ullmann coupling, and acid decarboxylation to efficiently prepare the target product. It features mild reaction conditions, safety and environmental friendliness, and suitability for industrial production.

[0010] To achieve the above objectives, this invention provides a method for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid, comprising the following steps: Compound III reacts with diethyl malonate in the presence of a copper catalyst, a nitrogen-containing ligand, and base I; then, an inorganic strong base II is directly added for hydrolysis, followed by acidification to obtain compound IV; compound IV undergoes a decarboxylation reaction in an acidic solution upon heating to obtain compound I. The synthetic route is as follows: , Wherein, the base I is sodium tert-butoxide, potassium tert-butoxide, sodium hydride, or potassium carbonate, and the nitrogen-containing ligand is one or more of L1, L2, L3, and L4: .

[0011] Furthermore, this invention provides a method for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid, comprising the following steps: 2,3-difluorophenol reacts with a brominating reagent and an organic base to obtain compound II; compound II reacts with a methylating reagent with an inorganic base to obtain compound III; compound III reacts with diethyl malonate in the presence of a copper catalyst, a nitrogen-containing ligand, and base I, followed by direct hydrolysis with a strong inorganic base II and acidification to obtain compound IV; compound IV undergoes a decarboxylation reaction in an acidic solution to obtain compound I. The synthetic route is as follows: , The brominating agent is N-bromosuccinimide, and the methylating agent is dimethyl sulfate or iodomethane.

[0012] Furthermore, in the step of synthesizing compound IV from compound III, the copper catalyst is cuprous bromide, cuprous chloride, or cuprous iodide, preferably cuprous iodide, which has stable catalytic activity and good ligand compatibility in the coupling reaction; the organic solvent is dimethyl sulfoxide, isopropanol, tetrahydrofuran, or dioxane.

[0013] Furthermore, in the step of synthesizing compound IV from compound III, the molar ratio of compound III: diethyl malonate: copper catalyst: nitrogen-containing ligand: base I is 1:1.1~2:0.01~0.02:0.015~0.04:2, the reaction temperature is 40~60℃, and the reaction time is 24~28 h.

[0014] Furthermore, in the step of synthesizing compound IV from compound III, the inorganic strong base II is sodium hydroxide, potassium hydroxide, or lithium hydroxide, the hydrolysis temperature is 45~50℃, and the acidification includes: adding 6 mol / L dilute hydrochloric acid solution to adjust the pH of the solution to 1~2, so that compound IV precipitates out.

[0015] Furthermore, in the step of synthesizing compound I from compound IV, the acidic solution is a 6 mol / L dilute hydrochloric acid solution, and the heating decarboxylation reaction is carried out under reflux.

[0016] Furthermore, the step of synthesizing compound I from compound IV also includes a purification step: the reaction solution is concentrated under reduced pressure, organic solvent I is added and distilled under reduced pressure to obtain crude compound I; organic solvent II is added and heated to dissolve, organic solvent III is added dropwise, the system temperature is cooled, stirred to precipitate crystals, filtered, and dried to obtain compound I. The organic solvent I is toluene, the organic solvent II is isopropanol, the organic solvent III is n-heptane, the heating temperature for dissolving is 50~55℃, and the cooling temperature is 5~10℃.

[0017] Furthermore, in the step of synthesizing compound II from 2,3-difluorophenol, the organic base is isopropylamine, triethylamine, or pyridine, preferably isopropylamine; the molar ratio of 2,3-difluorophenol:brominator:organic base is 1:1~1.5:1~1.5; the reaction solvent is dichloromethane, chloroform, or acetonitrile, preferably dichloromethane, which has good solubility for 2,3-difluorophenol, brominator, and organic base, and has a low boiling point, making post-processing concentration simple.

[0018] Furthermore, in the step of synthesizing compound III from compound II, the inorganic base is potassium carbonate or cesium carbonate, the molar ratio of compound II: methylating agent: inorganic base is 1:1~1.5:1.5~2.5, and the reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidone.

[0019] Beneficial effects: This invention provides a method for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid. The method involves reacting compound III with diethyl malonate in the presence of a copper catalyst, a nitrogen-containing ligand, and base I. Following this reaction, an inorganic strong base II is added for hydrolysis, followed by acidification to obtain 2-(2,3-difluoro-6-methoxyphenyl)malonic acid (compound IV). Compound IV is then decarboxylated by heating in an acidic solution. After the reaction is complete, the mixture is concentrated under reduced pressure, subjected to azeotropic dehydration by adding an organic solvent and distilling under reduced pressure, followed by low-temperature stirring and crystallization, and filtration to prepare 3,4-difluoro-2-methoxyphenylacetic acid (compound I). The purity can reach 99.3%, and the overall reaction yield can reach 74.04%. Furthermore, using 2,3-difluorophenol as the starting material, the reaction proceeds under the action of a brominating reagent and an organic base to obtain 6-bromo-2,3-difluorophenol (compound II); compound II reacts with a methylating reagent under the action of an inorganic base to obtain 6-bromo-2,3-difluoroanisole (compound III); compound III is then synthesized into compound I via the same route, resulting in a total of 4 steps and an overall yield of 61.3%. The synthetic method of this invention utilizes inexpensive and readily available raw materials, has a short route, and high atom utilization at each step; each reaction is carried out at a relatively mild temperature, avoiding harsh conditions such as high temperature and high pressure, ensuring safe operation and easy scale-up production; it avoids expensive palladium catalysts, uses readily available raw materials, and simplifies post-reaction processing, making it suitable for industrial-scale production. Attached Figure Description

[0020] Figure 1 It is 3,4-difluoro-2-methoxyphenylacetic acid 1 HNMR spectrum. Detailed Implementation

[0021] The present invention will be further described below with reference to specific embodiments, but these embodiments are merely exemplary and do not constitute any limitation on the scope of the present invention. Those skilled in the art should understand that modifications or substitutions can be made to the details and form of the technical solutions of the present invention without departing from the spirit and scope of the invention, but all such modifications and substitutions fall within the protection scope of the present invention.

[0022] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; the reagents and materials described are commercially available unless otherwise specified.

[0023] The abbreviations for the reaction reagents mentioned in the instructions are as follows: NBS: N-bromosuccinimide; DMSO: Dimethyl sulfoxide.

[0024] Example 1: Synthesized compound I:

[0025] Synthesis of Compound IV

[0026] Compound III (11.15 g, 0.05 mol) and DMSO (50 mL) were added to the reaction flask and stirred until completely dissolved. Under nitrogen protection, cuprous iodide (0.19 g, 0.001 mol), ligand L1 (0.41 g, 0.002 mol), diethyl malonate (8.81 g, 0.055 mol) and potassium carbonate (13.82 g, 0.1 mol) were added in sequence. The reaction system was heated to 40-50 °C and stirred for 24 h. The reaction was monitored by TLC. After the raw materials were completely converted, the reaction mixture was cooled to 5-10°C, and water (112 mL) and methyl tert-butyl ether (112 mL) were added. The mixture was stirred for 10 min, allowed to stand and separated. The aqueous phase was extracted once again with methyl tert-butyl ether (100 mL). The organic phases were combined and washed with saturated sodium chloride solution (100 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain an oily liquid.

[0027] The above oily liquid was dissolved in ethanol (100 mL), and sodium hydroxide (5 g, 0.125 mol) was added. The reaction system was heated to 45-50 °C and stirred for 5 h. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure at 30-45 °C until no liquid flowed out. Water (50 mL) and methyl tert-butyl ether (50 mL) were added to the concentrate, and the mixture was stirred for 10 min. The mixture was allowed to stand and separated. The aqueous phase was separated, and 6 mol / L hydrochloric acid solution was slowly added dropwise to the aqueous phase with stirring to adjust the pH to 1-2. A large amount of solid precipitated. The solid was filtered, and the filter cake was dried under vacuum at 40-50 °C to obtain compound IV (7.63 g, purity 96.4%, yield 62%).

[0028] Synthesis of Compound I (3,4-difluoro-2-methoxyphenylacetic acid)

[0029] 100 mL of 6 mol / L hydrochloric acid solution and compound IV (20 g, 0.081 mol) were added to a reaction flask, stirred, and heated to reflux for 4 h. The reaction was monitored by LC until the starting material was completely converted. The mixture was then concentrated under reduced pressure using a water pump until no distillate was obtained. Toluene (40 mL) was added to the residue, and the mixture was heated to 50–70 °C and concentrated under reduced pressure until no distillate was obtained. Isopropanol (20 mL) was then added, and the mixture was heated to 50–55 °C and stirred until dissolved. Heptane (80 mL) was added dropwise while maintaining the temperature and stirring. After the addition was complete, the system was cooled to 5–10 °C, stirred, and allowed to crystallize for 2 h. The mixture was filtered, and the filter cake was dried under vacuum at 40–50 °C to obtain 3,4-difluoro-2-methoxyphenylacetic acid (compound I, a white powdery solid, 14.61 g, purity 99.3%, yield 89.2%). 1 The HNMR spectrum is as follows Figure 1 As shown, 1 H NMR (400MHz, DMSO-d6) δ: 12.43(s, 1H), 7.14-7.06(m, 2H), 3.87(s, 3H), 3.57(s, 2H).

[0030] Example 2: Synthesized compound I:

[0031] Synthesis of Compound II

[0032] At room temperature, isopropylamine (52.2 mL, 0.6 mol) was slowly added dropwise to a solution of 2,3-difluorophenol (65.05 g, 0.5 mol) in dichloromethane (500 mL). After the addition was complete, the reaction system was cooled to -78 °C, and N-bromosuccinimide (97.89 g, 0.55 mol) was added in portions over 2 h. After the addition was complete, the mixture was stirred at -78 °C for 30 min. The reaction was monitored by TLC. After the starting material was completely converted, the reaction mixture was heated to 25°C and 500 mL of 2 mol / L hydrochloric acid solution was added. The mixture was stirred for 15 min. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (250 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by rotary evaporation under reduced pressure to remove the solvent. Hexane (500 mL) was added to the residue and stirred for 10 min for slurry purification. The residue was filtered and concentrated under reduced pressure to obtain 6-bromo-2,3-difluorophenol (compound II, yellow solid, 95.09 g, yield 91%).

[0033] Synthesis of Compound III

[0034] Compound II (50 g, 0.24 mol) and N,N-dimethylformamide (200 mL) were added to the reaction flask and stirred until dissolved. Then potassium carbonate (66.34 g, 0.48 mol) was added, and the reaction system was heated to 45-50 °C. Dimethyl sulfate (37.84 g, 0.3 mol) was added dropwise at this temperature. After the addition was complete, the reaction was stirred at 45-50 °C for 10 h. The reaction was monitored by TLC. After the starting material was completely converted, the reaction mixture was cooled to 5-10°C, water (500 mL) was added, and the mixture was stirred for 1 h. Then ethyl acetate (250 mL) was added and stirred for 10 min. The mixture was allowed to stand and separated. The aqueous phase was extracted once again with ethyl acetate (250 mL). The organic phases were combined and washed with water (150 mL × 3) and then washed once with saturated sodium chloride solution (100 mL). The mixture was dried over anhydrous sodium sulfate. The filtrate was filtered through a sintered funnel lined with silica gel (100 g, 200-300 mesh). The filter cake was washed with ethyl acetate. The filtrate and the eluent were combined and concentrated under reduced pressure to obtain compound III (yellow oily solid, 48.71 g, purity 95%, yield 91%).

[0035] Synthesis of Compound IV

[0036] Compound III (11.15 g, 0.05 mol) and DMSO (50 mL) were added to the reaction flask and stirred until completely dissolved. Under nitrogen protection, cuprous iodide (0.19 g, 0.001 mol), ligand L1 (0.41 g, 0.002 mol), diethyl malonate (8.81 g, 0.055 mol) and potassium carbonate (13.82 g, 0.1 mol) were added in sequence. The reaction system was heated to 40-50 °C and stirred for 24 h. The reaction was monitored by TLC. After the raw materials were completely converted, the reaction mixture was cooled to 5-10°C, and water (112 mL) and methyl tert-butyl ether (112 mL) were added. The mixture was stirred for 10 min, allowed to stand and separated. The aqueous phase was extracted once again with methyl tert-butyl ether (100 mL). The organic phases were combined and washed with saturated sodium chloride solution (100 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain an oily liquid.

[0037] The above oily liquid was dissolved in ethanol (100 mL), and sodium hydroxide (5 g, 0.125 mol) was added. The reaction system was heated to 45-50 °C and stirred for 5 h. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure at 30-45 °C until no liquid flowed out. Water (50 mL) and methyl tert-butyl ether (50 mL) were added to the concentrate, and the mixture was stirred for 10 min. The mixture was allowed to stand and separated. The aqueous phase was separated, and 6 mol / L hydrochloric acid solution was slowly added dropwise to the aqueous phase with stirring to adjust the pH to 1-2. A large amount of solid precipitated. The solid was filtered, and the filter cake was dried under vacuum at 40-50 °C to obtain compound IV (7.63 g, purity 96.4%, yield 62%).

[0038] Synthesis of Compound I (3,4-difluoro-2-methoxyphenylacetic acid)

[0039] Add 100 mL of 6 mol / L hydrochloric acid solution and compound IV (20 g, 0.081 mol) to the reaction flask, stir and heat to reflux, and react for 4 h. Monitor the reaction by LC. After the raw material is completely converted, concentrate under reduced pressure with a water pump to a fractionless liquid. Add toluene (40 mL) to the residue, heat to 50-70 °C and concentrate under reduced pressure to a fractionless liquid. Add isopropanol (20 mL), heat to 50-55 °C and stir to dissolve. Add n-heptane (80 mL) dropwise while maintaining the temperature and stirring. After the addition is complete, cool the system to 5-10 °C, stir to crystallize for 2 h, filter, and dry the filter cake under vacuum at 40-50 °C to obtain 3,4-difluoro-2-methoxyphenylacetic acid (compound I, off-white powder solid, 14.61 g, purity 99.3%, yield 89.2%).

[0040] Example 3: Synthetic compound IV

[0041] Diethyl malonate (32.03 g, 0.2 mol) and isopropanol (150 mL) were added to the reaction flask and stirred until dissolved. The reaction system was cooled to 0-5℃, and sodium tert-butoxide (19.22 g, 0.2 mol) was added in portions. After the addition was complete, the mixture was stirred at 0-5℃ for 30 min. Under nitrogen protection, cuprous bromide (0.143 g, 0.001 mol), ligand L2 (0.405 g, 0.0015 mol), and compound III (22.3 g, 0.1 mol) were added in sequence. The reaction system was heated to 55-60℃ and stirred for 28 h.

[0042] The reaction was monitored by TLC. After the raw materials were completely converted, sodium hydroxide (20 g, 0.5 mol) was added, and the mixture was stirred at 45-50 °C for 8 h. The reaction was cooled to room temperature and concentrated under reduced pressure at 30-45 °C until no liquid flowed out. Water (200 mL) and methyl tert-butyl ether (200 mL) were added to the concentrate, and the mixture was stirred for 10 min. The mixture was allowed to stand and separated. The aqueous phase was separated, and 6 mol / L hydrochloric acid solution was slowly added dropwise to the aqueous phase with stirring to adjust the pH to 1-2. A large amount of solid precipitated out. The solid was filtered, and the filter cake was dried under vacuum at 40-50 °C to obtain compound IV (20.42 g, purity 95.8%, yield 83%).

[0043] Example 4: Synthetic compound IV

[0044] Diethyl malonate (32.03 g, 0.2 mol) and isopropanol (150 mL) were added to the reaction flask and stirred until dissolved. The reaction system was cooled to 0-5℃, and sodium tert-butoxide (19.22 g, 0.2 mol) was added in portions. After the addition was complete, the mixture was stirred at 0-5℃ for 30 min. Under nitrogen protection, cuprous bromide (0.143 g, 0.001 mol), ligand L3 (0.583 g, 0.0015 mol), and compound III (22.3 g, 0.1 mol) were added in sequence. The reaction system was heated to 55-60℃ and stirred for 28 h.

[0045] The reaction was monitored by TLC. After the raw materials were completely converted, sodium hydroxide (20 g, 0.5 mol) was added, and the mixture was stirred at 45-50 °C for 8 h. The reaction was cooled to room temperature and concentrated under reduced pressure at 30-45 °C until no liquid flowed out. Water (200 mL) and methyl tert-butyl ether (200 mL) were added to the concentrate, and the mixture was stirred for 10 min. The mixture was allowed to stand and separated. The aqueous phase was separated, and 6 mol / L hydrochloric acid solution was slowly added dropwise to the aqueous phase with stirring to adjust the pH to 1-2. A large amount of solid precipitated out. The solid was filtered, and the filter cake was dried under vacuum at 40-50 °C to obtain compound IV (19.45 g, purity 95.6%, yield 79%).

[0046] Example 5: Synthetic compound IV

[0047] Diethyl malonate (32.03 g, 0.2 mol) and isopropanol (150 mL) were added to the reaction flask and stirred until dissolved. The reaction system was cooled to 0-5℃, and sodium tert-butoxide (19.22 g, 0.2 mol) was added in portions. After the addition was complete, the mixture was stirred at 0-5℃ for 30 min. Under nitrogen protection, cuprous bromide (0.143 g, 0.001 mol), ligand L4 (0.493 g, 0.0015 mol), and compound III (22.3 g, 0.1 mol) were added in sequence. The reaction system was heated to 55-60℃ and stirred for 28 h.

[0048] The reaction was monitored by TLC. After the raw materials were completely converted, sodium hydroxide (20 g, 0.5 mol) was added, and the mixture was stirred at 45-50 °C for 8 h. The reaction was cooled to room temperature and concentrated under reduced pressure at 30-45 °C until no liquid flowed out. Water (200 mL) and methyl tert-butyl ether (200 mL) were added to the concentrate, and the mixture was stirred for 10 min. The mixture was allowed to stand and separated. The aqueous phase was separated, and 6 mol / L hydrochloric acid solution was slowly added dropwise to the aqueous phase with stirring to adjust the pH to 1-2. A large amount of solid precipitated out. The solid was filtered, and the filter cake was dried under vacuum at 40-50 °C to obtain compound IV (16.49 g, purity 95.8%, yield 67%).

[0049] Example 6: Synthetic compound III Synthesis of Compound II

[0050] At room temperature, triethylamine (104.2 mL, 0.75 mol) was slowly added dropwise to a chloroform (500 mL) solution of 2,3-difluorophenol (65.05 g, 0.5 mol). After the addition was complete, the reaction system was cooled to -78 °C, and N-bromosuccinimide (133.49 g, 0.75 mol) was added in portions over 2 h. After the addition was complete, the mixture was stirred at -78 °C for 30 min. The reaction was monitored by TLC. After the starting material was completely converted, the reaction mixture was heated to 25°C and 500 mL of 2 mol / L hydrochloric acid solution was added. The mixture was stirred for 15 min. The organic phase was separated, and the aqueous phase was extracted with chloroform (250 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by rotary evaporation under reduced pressure to remove the solvent. Hexane (500 mL) was added to the residue and stirred for 10 min for slurry purification. The residue was filtered and concentrated under reduced pressure to obtain 6-bromo-2,3-difluorophenol (compound II, yellow solid, 93.2 g, yield 89%).

[0051] Synthesis of Compound III

[0052] Compound II (50 g, 0.24 mol) and N-methylpyrrolidone (200 mL) were added to the reaction flask and stirred until dissolved. Then, cesium carbonate (195.49 g, 0.6 mol) was added, and the reaction system was heated to 45-50 °C. Iodomethane (51.1 g, 0.36 mol) was added dropwise at this temperature. After the addition was complete, the reaction was stirred at 45-50 °C for 10 h. The reaction was monitored by TLC. After the starting material was completely converted, the reaction mixture was cooled to 5-10°C, water (500 mL) was added, and the mixture was stirred for 1 h. Then ethyl acetate (250 mL) was added and stirred for 10 min. The mixture was allowed to stand and separated. The aqueous phase was extracted once again with ethyl acetate (250 mL). The organic phases were combined and washed with water (150 mL × 3) and then washed once with saturated sodium chloride solution (100 mL). The mixture was dried over anhydrous sodium sulfate. The filtrate was filtered through a sintered funnel lined with silica gel (100 g, 200-300 mesh). The filter cake was washed with ethyl acetate. The filtrate and the eluent were combined and concentrated under reduced pressure to obtain compound III (yellow oily solid, 46.2 g, purity 95%, yield 86%).

[0053] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for the synthesis of 3,4-difluoro-2-methoxyphenylacetic acid, characterized in that, The synthetic route includes the following steps: Compound III reacts with diethyl malonate in the presence of a copper catalyst, a nitrogen-containing ligand, and base I; then, it is directly hydrolyzed by the addition of a strong inorganic base II, followed by acidification to obtain compound IV; compound IV undergoes decarboxylation in an acidic solution upon heating to yield compound I. The synthetic route is as follows: ， Wherein, the base I is sodium tert-butoxide, potassium tert-butoxide, sodium hydride, or potassium carbonate, and the nitrogen-containing ligand is one or more of L1, L2, L3, and L4: 。 2. The method of synthesis of 3,4-difluoro-2-methoxybenzoic acid according to claim 1, characterized by, The synthetic route includes the following steps: 2,3-difluorophenol reacts with a brominating reagent and an organic base to give compound II; compound II reacts with a methylating reagent in the presence of an inorganic base to give compound III; compound III reacts with diethyl malonate in the presence of a copper catalyst, a nitrogen-containing ligand, and base I, followed by direct hydrolysis with a strong inorganic base II and acidification to give compound IV; compound IV undergoes decarboxylation in an acidic solution upon heating to give compound I. The synthetic route is as follows: ， The brominating agent is N-bromosuccinimide, and the methylating agent is dimethyl sulfate or iodomethane.

3. The method of synthesis of 3,4-difluoro-2-methoxybenzoic acid according to claim 1 or 2, characterized in that, In the step of synthesizing compound IV from compound III, the copper catalyst is cuprous bromide, cuprous chloride, or cuprous iodide, and the organic solvent is dimethyl sulfoxide, isopropanol, tetrahydrofuran, or dioxane.

4. The method of synthesis of 3,4-difluoro-2-methoxybenzoic acid according to claim 1 or 2, characterized by, In the step of synthesizing compound IV from compound III, the molar ratio of compound III: diethyl malonate: copper catalyst: nitrogen-containing ligand: base I is 1:1.1~2:0.01~0.02:0.015~0.04:2, the reaction temperature is 40~60℃, and the reaction time is 24~28 h.

5. The method of synthesis of 3,4-difluoro-2-methoxybenzoic acid according to claim 1 or 2, characterized by, In the step of synthesizing compound IV from compound III, the inorganic strong base II is sodium hydroxide, potassium hydroxide, or lithium hydroxide, the hydrolysis temperature is 45~50℃, and the acidification includes adding 6 mol / L dilute hydrochloric acid solution to adjust the pH of the solution to 1~2, so that compound IV precipitates out.

6. The method of synthesis of 3,4-difluoro-2-methoxybenzoic acid according to claim 1 or 2, characterized by, In the step of synthesizing compound I from compound IV, the acidic solution is a 6 mol / L dilute hydrochloric acid solution, and the heating decarboxylation reaction is carried out under reflux.

7. The method of synthesis of 3,4-difluoro-2-methoxybenzoic acid according to claim 1 or 2, characterized by, The steps for synthesizing compound I from compound IV also include a purification step: the reaction solution is concentrated under reduced pressure, organic solvent I is added and distilled under reduced pressure to obtain crude compound I; organic solvent II is added and heated to dissolve, organic solvent III is added dropwise, the system temperature is cooled, stirred to precipitate crystals, filtered, and dried to obtain compound I.

8. The method for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid according to claim 7, characterized in that, Organic solvent I is toluene, organic solvent II is isopropanol, and organic solvent III is n-heptane. The heating and dissolution temperature is 50-55°C, and the cooling temperature is 5-10°C.

9. The method for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid according to claim 2, characterized in that, In the step of synthesizing compound II from 2,3-difluorophenol, the organic base is isopropylamine, triethylamine, or pyridine, the molar ratio of 2,3-difluorophenol:brominated reagent:organic base is 1:1~1.5:1~1.5, and the reaction solvent is dichloromethane, chloroform, or acetonitrile.

10. The method for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid according to claim 2, characterized in that, In the step of synthesizing compound III from compound II, the inorganic base is potassium carbonate or cesium carbonate, the molar ratio of compound II: methylating agent: inorganic base is 1:1~1.5:1.5~2.5, and the reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone.

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