A process for the preparation of 2-methoxy-3,4-difluorophenylacetic acid

Abstract

The application discloses a preparation method of 2-methoxy-3,4-difluorobenzenacetic acid, which comprises the following four steps. The method uses 2-methoxy-3,4-difluorobenzoic acid which is easy to synthesize and prepare as a starting material, and the product 2-methoxy-3,4-difluorobenzenacetic acid is prepared through four steps of reduction reaction, halogenation reaction or sulfonate esterification reaction, cyano substitution reaction and hydrolysis reaction. Compared with the prior art, the method avoids the problems of high price and difficulty in obtaining the starting material, and avoids the use of a noble metal palladium catalyst, and fundamentally provides a new scheme for reducing the cost. Although it is a multi-step reaction, the separation and purification operation of three intermediates is omitted, and a purification operation is performed at the stage of the final product compound shown in formula (I), so that the whole preparation process is simpler and more efficient, the cost is lower, the reaction is safer, and the reaction condition is more suitable for green industrialized production compared with the existing process.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, and specifically relates to a method for preparing 2-methoxy-3,4-difluorophenylacetic acid. Background Technology

[0002] Suzetrigine is an orally administered selective human sodium ion channel protein developed by Vertex Pharmaceuticals. V 1.8 Inhibitor, compared with other sodium ion channels, it has a lower inhibitory effect on Na+. V 1.8 exhibits high selectivity. Na V 1.8 is a voltage-gated sodium channel that plays a crucial role in pain signal transmission in the peripheral nervous system. It is a genetically validated target for pain treatment. Compared to opioids, they may provide better analgesia while avoiding side effects such as addiction. Suzetrigine received marketing approval from the U.S. Food and Drug Administration (FDA) in January 2025 for the treatment of moderate to severe acute pain in adults.

[0003] In the multiple routes for the preparation of suzetrigine reported in the existing literature, the key intermediate 2-methoxy-3,4-difluorophenylacetic acid is used:

[0004]

[0005] The existing patent application WO2022256842A1 reports two synthetic routes for 2-methoxy-3,4-difluorophenylacetic acid, as shown in the reaction formula below.

[0006]

[0007] However, the aforementioned existing technical routes use expensive and unavailable starting materials, and all employ cross-coupling reactions catalyzed by the precious metal palladium. Therefore, there is still a need to develop more economical, efficient, and suitable synthetic routes for large-scale industrial production. Summary of the Invention

[0008] To overcome the shortcomings of existing production methods and processes, the purpose of this invention is to provide a novel method for preparing 2-methoxy-3,4-difluorophenylacetic acid, a key intermediate of Suzetrigine. This method uses 2-methoxy-3,4-difluorobenzoic acid as a starting material and proceeds through a four-step process: reduction, halogenation or sulfonation, cyano substitution, and hydrolysis to produce 2-methoxy-3,4-difluorophenylacetic acid. Compared to existing processes, this method is lower in cost, safer, and the reaction conditions are more suitable for green industrial production.

[0009] To achieve the above objectives, the present invention adopts the following technical solution:

[0010] This invention provides a method for preparing 2-methoxy-3,4-difluorophenylacetic acid, comprising the following four steps:

[0011]

[0012] in,

[0013] Step 1: The starting compound 2-methoxy-3,4-difluorobenzoic acid shown in formula (V) is reacted in a solvent in the presence of a reducing agent and an additive to prepare the compound shown in formula (IV), wherein the carboxyl group in the starting compound shown in formula (V) is reduced to a hydroxyl group. The reaction is carried out under atmospheric pressure and stirring, and the reaction temperature range is -10 to 40°C, preferably 20 to 25°C. The specific reaction time needs to be sampled and monitored to determine whether the raw materials are completely converted.

[0014] Step 2: The compound shown in formula (IV) is reacted in a solvent in the presence of a halogenating agent or a sulfonating agent to prepare the compound shown in formula (III), wherein X is a halogen or sulfonate group. The reaction is carried out under atmospheric pressure and stirring, and the reaction temperature range is -10 to 40°C, preferably 0 to 25°C. The specific reaction time needs to be sampled and monitored to determine whether the raw materials are completely converted.

[0015] Step 3: The compound shown in formula (III) is reacted in a solvent in the presence of a cyaniding agent to prepare the compound shown in formula (II). The reaction is carried out under atmospheric pressure solvent reflux and stirring. The reaction temperature range is 50-100℃, preferably 75-85℃. The specific reaction time needs to be sampled and monitored to determine whether the raw materials are completely converted.

[0016] Step 4: The compound shown in formula (II) is reacted in a solvent in the presence of an acid or base reagent to prepare the compound shown in formula (I) 2-methoxy-3,4-difluorophenylacetic acid. The reaction is carried out under normal pressure solvent reflux and stirring, and the reaction temperature range is 60-120℃. The specific reaction time needs to be sampled and monitored to determine whether the raw materials are completely converted.

[0017]

[0018] Preferably, the reducing agent in step one is selected from one or more of lithium borohydride, sodium borohydride, borane-tetrahydrofuran complex, sodium tri(acetoxy)borohydride, sodium cyanoborohydride, lithium triethylborohydride, lithium aluminum hydride, sodium dihydrobis(2-methoxyethoxy)aluminate, and diisobutylaluminum hydride, and more preferably sodium borohydride.

[0019] Preferably, the additive in step one is selected from one or more of concentrated sulfuric acid, trifluoroacetic acid, acetic acid, boron trifluoride-tetrahydrofuran complex, boron trifluoride-diethyl ether complex, boron trichloride, boron tribromide, aluminum chloride, magnesium chloride, calcium chloride, lithium chloride, nickel dichloride, and ferric chloride, more preferably boron trifluoride-tetrahydrofuran complex or boron trifluoride-diethyl ether complex.

[0020] Preferably, the solvent in step one is selected from one or more of 1,4-dioxane, toluene, xylene, dichloromethane, methyl tert-butyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, diisopropyl ether, and dibutyl ether, more preferably tetrahydrofuran.

[0021] The molar ratio of reactants, reducing agents and additives in step one is 1.0:1.5-3.0:1.5-3.0, more preferably 1.0:2.3-2.5:2.0-2.2; the concentration range of the reactants in the solution in step one is 20-30 mol / L.

[0022]

[0023] Preferably, step two is a halogenation reaction or a sulfonation reaction of the hydroxyl group, where X in the compound shown in formula (III) is a halogen or sulfonate group, and the halogen includes chlorine, bromine and iodine.

[0024] Preferably, the halogenated reagent in step two is selected from one or more of oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, di(trichloromethyl) carbonate, thionyl chloride, phosphorus tribromooxychloride, hydrobromic acid, elemental iodine, and N-bromosuccinimide, more preferably thionyl chloride or N-bromosuccinimide.

[0025] Preferably, in step two, the sulfonate group is selected from methanesulfonate, trifluoromethanesulfonate, perfluorobutyl sulfonate, benzenesulfonate, p-methylbenzenesulfonate, p-nitrobenzenesulfonate, p-trifluoromethylbenzenesulfonate, and naphthalenesulfonate. The sulfonating agent is selected from one or more of methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, perfluorobutyl sulfonyl fluoride, benzenesulfonyl chloride, p-methylbenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, p-trifluoromethylbenzenesulfonyl chloride, and naphthalenesulfonyl chloride, more preferably methanesulfonyl chloride or p-methylbenzenesulfonyl chloride.

[0026] Preferably, the solvent in step two is selected from one or more of toluene, xylene, chlorobenzene, dichloromethane, chloroform, acetonitrile, ethyl acetate, and 2-methyltetrahydrofuran; more preferably, it is dichloromethane.

[0027] In step two, the molar ratio of the reactant to the halogenated reagent or sulfonated esterification reagent is 1.0:1.0 to 3.0, more preferably 1.0:1.2 to 2.2; the concentration range of the reactant in the solution in step one is 20 to 30 mol / L.

[0028]

[0029] Step 3 is a cyanidation substitution reaction, wherein the cyaniding agent is selected from one or more of sodium cyanide, potassium cyanide, cuprous cyanide, and trimethylcyanosilane, more preferably sodium cyanide or trimethylcyanosilane.

[0030] Preferably, an alkaline reagent may be added in step three and used in conjunction with the cyanidation reagent. The alkaline reagent is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, potassium fluoride, cesium fluoride, tetrabutylammonium fluoride, and tetramethylammonium fluoride, more preferably potassium carbonate or tetrabutylammonium fluoride.

[0031] Preferably, the solvent in step three is selected from one or more of dichloromethane, chloroform, acetonitrile, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetone, N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; more preferably, it is acetonitrile.

[0032] In step three, the molar ratio of the reactant, cyaniding reagent, and basic reagent is 1.0:1.5-3.0:0-3.0, more preferably 1.0:1.8-2.2:1.8-2.2; the concentration range of the reactant in the solution in step three is 20-30 mol / L.

[0033]

[0034] Step four is a reaction in which the cyano group is hydrolyzed to the carboxyl group under acidic or alkaline conditions. The acid reagent used is selected from one or more of sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, and trifluoroacetic acid, more preferably sulfuric acid. The alkaline reagent used is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide, more preferably potassium hydroxide or sodium hydroxide.

[0035] Preferably, the solvent in step four is selected from one or more of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methanol, ethanol, isopropanol, tert-butanol, ethylene glycol, acetone, N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and water; more preferably, it is a mixture of ethanol and water.

[0036] The molar ratio of the reactant to the acid or base reagent in step four is 1.0:4.0 to 6.0, more preferably 1.0:4.5 to 5.0; the concentration of the reactant in the solution in step four is 15 to 30 mol / L.

[0037] Preferably, according to the preparation method of the present invention, the reaction products from step one to step three can be used in the next step after conventional purification and separation operations, or a four-step continuous process can be adopted, that is, the reaction products from step one to step three are used directly in the next reaction without purification and separation operations to prepare the final compound shown in formula (I).

[0038] Preferably, the starting compound 2-methoxy-3,4-difluorobenzoic acid, represented by formula (V) according to the preparation method of the present invention, can be simply prepared according to conventional techniques, for example, using inexpensive and readily available 1,2,3-trifluorobenzene as the starting material, according to existing techniques (e.g.)<European Journal of Organic Chemistry,2003,3,447-451> ,<Journal of Physical Chemistry A,2000,104,352-361.> or<Bioorganicand Medicinal Chemistry Letters,2016,26,2455-2458.> The method reported in [the paper] yields the product efficiently and at low cost via a hydrogen dehydrogenation and carbonyl insertion reaction of n-butyllithium and a selective methoxy substitution reaction for fluorine.

[0039]

[0040] Beneficial effects

[0041] This invention uses easily synthesized 2-methoxy-3,4-difluorobenzoic acid as the starting material, and prepares the product 2-methoxy-3,4-difluorophenylacetic acid through a four-step continuous addition method involving reduction, halogenation or sulfonation, cyanation substitution, and hydrolysis. Compared with existing technologies, this invention avoids the problems of high and difficult-to-obtain starting materials and the use of precious palladium catalysts, fundamentally providing a new solution to reduce costs. Although it is a multi-step reaction, it eliminates the separation and purification operations of three intermediates, performing a purification operation only at the stage of the final product compound shown in formula (I). The entire preparation process is simpler and more efficient, with lower costs, safer reaction, and reaction conditions more suitable for green industrial production compared to existing processes. Detailed Implementation

[0042] The present invention will now be described in detail. Before proceeding with the description, it should be understood that the terminology used in this specification and the appended claims should not be construed as limited to its general or dictionary meaning, but rather should be interpreted according to the meaning and concept corresponding to the technical aspects of the invention, based on the principle that the inventors are allowed to appropriately define the terms for the best interpretation. Therefore, the description presented herein is merely a preferred example for illustrative purposes and is not intended to limit the scope of the invention. It should be understood that other equivalents or modifications can be obtained from it without departing from the spirit and scope of the invention.

[0043] In this document, the terms “comprising,” “including,” “having,” “containing,” or any other similar terms are open-ended conjunctions intended to cover non-exclusive inclusions. For example, a composition or article containing a plurality of elements is not limited to those listed herein, but may also include other elements not explicitly listed but typically inherent to the composition or article. Furthermore, unless explicitly stated to the contrary, the term “or” is inclusive, not exclusive. For example, the condition “A or B” is satisfied in any of the following cases: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); A and B are both true (or exist). Moreover, in this document, the terms “comprising,” “including,” “having,” and “containing” should be interpreted as specifically disclosed and simultaneously cover closed or semi-closed conjunctions such as “composed of” and “substantially composed of.”

[0044] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible secondary ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "1 to 8" should be considered as specifically disclosing all secondary ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly secondary ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its scope.

[0045] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, regardless of whether such ranges are separately disclosed. Furthermore, when a range of numerical values ​​is mentioned herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

[0046] In this document, numerical values ​​should be understood as having a precision with significant digits, provided that the purpose of the invention can be achieved.

[0047] In this article, room temperature refers to any temperature between 20 and 30°C, such as 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30°C, and any temperature in between.

[0048] The following embodiments are merely examples illustrating implementations of the present invention and do not constitute any limitation on the present invention. Those skilled in the art will understand that modifications made without departing from the spirit and concept of the present invention fall within the protection scope of the present invention. Unless otherwise specified, the reagents and instruments used in the following embodiments are commercially available products.

[0049] Example 1: Preparation process in step one

[0050]

[0051] Sodium borohydride (50.28 g, 1.33 mol, 2.5 eq) and tetrahydrofuran (500 mL) were added to a three-necked flask. Stirring was started, and under nitrogen protection, a boron trifluoride-tetrahydrofuran complex (150.9 g, 1.08 mol, 2 eq) was slowly added dropwise under an ice-water bath. Then, a tetrahydrofuran (500 mL) solution of the starting compound 2-methoxy-3,4-difluorobenzoic acid (100.0 g, 0.53 mol, 1 eq) as shown in formula (V) was added dropwise. The mixture was heated to room temperature (20–25 °C) and stirred for 2 hours. TLC monitoring showed complete conversion of the starting material. Under an ice bath, the reaction mixture was slowly added dropwise to a 4M hydrochloric acid aqueous solution to adjust the pH to 1–2. The aqueous phase was extracted three times with methyl tert-butyl ether. The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding 80 g of the crude product shown in formula (IV). No further purification was performed, and the product was directly added to the next step.

[0052] The product was analyzed by GC-MS, and its molecular weight was 174.05.

[0053] Product testing 1 H NMR (400MHz, DMSO-d6) δ7.23-7.09(m,2H),5.22-5.19(m,1H),4.49(s,2H),3.90(s,3H).

[0054] Example 2: Preparation process in step two

[0055]

[0056] The crude compound (197.0 g, 1.13 mol, 1 eq) of formula (IV) obtained in Example 1 and dichloromethane (800 mL) were added to a three-necked flask. Stirring was started, and under nitrogen protection, thionyl chloride (269.2 g, 2.26 mol, 2 eq) was slowly added dropwise under an ice-water bath. The mixture was heated to room temperature (20–25 °C) and stirred for 4 hours. TLC monitoring showed complete conversion of the starting material. The reaction mixture was quenched with saturated sodium carbonate aqueous solution under an ice bath. The mixture was separated, extracted twice with dichloromethane, and the organic phases were combined. The organic phase was washed with saturated sodium carbonate aqueous solution, separated, and the aqueous phase was discarded. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure to obtain 164.8 g of the crude compound (III-1). No further purification was performed, and the mixture was directly added to the next step.

[0057] The product was analyzed by GC-MS, and its molecular weight was 192.02.

[0058] Product testing 1 H NMR (400MHz, DMSO-d6) δ7.07-6.99(m,1H),6.89-6.83(m,1H),4.65(s,2H),3.98(s,3H).

[0059] Example 3: Preparation process in step three

[0060]

[0061] The crude compound (164.8 g, 0.86 mol, 1 eq) of formula (III-1) obtained in Example 2, acetonitrile (1.0 L), and potassium carbonate (236.5 g, 1.71 mol, 2 eq) were added to a three-necked flask. Stirring was started, and under nitrogen protection, trimethylcyanosilane (169.8 g, 1.71 mol, 2 eq) was slowly added dropwise under an ice-water bath. The mixture was refluxed at 85 °C with stirring for 16 hours, and TLC monitoring showed complete conversion of the starting material. The mixture was cooled to room temperature, quenched with saturated sodium carbonate aqueous solution, and separated, retaining the organic phase. The aqueous phase was extracted twice with methyl tert-butyl ether, and the organic phases were combined, washed with saturated sodium chloride aqueous solution, separated, and the aqueous phase was discarded. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, yielding 152.0 g of the crude compound of formula (II). No further purification was performed, and the mixture was directly added to the next step.

[0062] The product was analyzed by GC-MS, and its molecular weight was 183.05. 1 H NMR (400MHz, DMSO-d6) δ7.24-7.18(m,2H),3.94(s,2H),3.99(s,3H).

[0063] Example 4: Preparation process in step four

[0064]

[0065] Sodium hydroxide (152.0 g, 3.8 mol, 4.58 eq) was added to water (760 mL) and stirred until dissolved. After the system temperature cooled to room temperature, the crude compound of formula (II) obtained in Example 3 (152.0 g, 0.83 mol, 1 eq) was dissolved in ethanol (760 mL) and added to the sodium hydroxide solution. The mixture was purged with nitrogen and refluxed at 100 °C with stirring for 2 hours. TLC monitoring showed complete conversion of the starting material. The mixture was then cooled to room temperature. Vacuum concentration was used to remove most of the ethanol solvent. The aqueous phase was extracted twice with methyl tert-butyl ether, the organic phase was discarded, and the aqueous phase was retained. Under ice bath conditions, 8M hydrochloric acid aqueous solution was added to the aqueous phase to adjust the pH to 1-2. The aqueous phase was extracted three times with methyl tert-butyl ether, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to remove the organic phase. A large amount of yellow solid precipitated out. Heptane was added to the solid residue and stirred. The mixture was filtered, the solid was collected, and the filter cake was dried to give 117.0 g of the pale yellow solid product, 2-methoxy-3,4-difluorophenylacetic acid, as shown in formula (I). The overall molar yield of the four-step combined extraction was 52%.

[0066] Product testing 1¹H NMR (400MHz, DMSO-d⁶) δ 12.38 (s, ¹H), 7.11–7.07 (m, ²H), 3.87 (s, ³H), 3.56 (s, ²H). Product was analyzed by LC-MS and ESI. - :m / z=201.04.

[0067] Example 5: Preparation process in step two

[0068]

[0069] The crude compound (174.0 g, 1 mol, 1 eq) and dichloromethane (1.8 L) were added to a three-necked flask. Stirring was started, and under nitrogen protection, triphenylphosphine (524 g, 2 mol, 2.0 eq) and N-bromosuccinimide (356 g, 2 mol, 2.0 eq) were slowly added in portions under an ice-water bath. The reaction was maintained at 0–5 °C with stirring for 3–4 hours, and TLC was used to monitor complete conversion of the starting material. The mixture was quenched with water, and the organic phase was separated. The aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, and the aqueous phase was discarded. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove most of the solvent, and then n-heptane was added and stirred at room temperature. The suspension was filtered under reduced pressure on a silica gel layer to remove the solid. The filtrate was concentrated under reduced pressure to remove the solvent, yielding 201.5 g of the crude compound (III-2). No further purification was performed, and the mixture was directly added to the next step.

[0070] The product was analyzed by GC-MS, and its molecular weight was 237.04.

[0071] Product testing 1 H NMR (400MHz, DMSO-d6) δ7.09-7.02(m,1H),6.86-6.82(m,1H),4.48(s,2H),4.09(s,3H).

[0072] Example 6: Preparation process in step three

[0073]

[0074] The crude compound (201.5 g, 0.85 mol, 1 eq) of formula (III-2) obtained in Example 5 and acetonitrile (1.0 L) were added to a three-necked flask. Stirring was started, and under nitrogen protection, sodium cyanide (55.0 g, 1.12 mol, 1.32 eq) was slowly added in portions under an ice-water bath. The mixture was refluxed at 85 °C with stirring for 16 hours, and TLC monitoring showed complete conversion of the starting material. After cooling to room temperature, the mixture was quenched with an aqueous sodium hypochlorite solution, and methyl tert-butyl ether was added with thorough stirring. The organic phase was separated and retained. The aqueous phase was extracted twice with methyl tert-butyl ether, and the organic phases were combined, washed with saturated sodium chloride solution, and the aqueous phase was discarded. The organic phase was concentrated under reduced pressure to remove the solvent, yielding 123.0 g of the crude compound (II) as a brown liquid product. No further purification was performed, and the mixture was directly added to the next step.

[0075] The product was analyzed by GC-MS, and its molecular weight was 183.05.

[0076] Product testing 1 H NMR (400MHz, DMSO-d6) δ7.24-7.18(m,2H),3.94(s,2H),3.99(s,3H).

[0077] Example 7: Preparation process in step two

[0078]

[0079] The crude product of the compound shown in formula (IV) (174.0 g, 1 mol, 1 eq) and dichloromethane (1.8 L) were added to a three-necked flask. The mixture was stirred and kept under nitrogen protection. Pyridine (158.0 g, 2 mol, 2.0 eq) was added under an ice-water bath, followed by the slow addition of methanesulfonyl chloride (138.0 g, 1.2 mol, 1.2 eq). The mixture was stirred at 0–5 °C for 3–4 hours. The reaction mixture was monitored by TLC to ensure complete conversion of the starting material. The mixture was then quenched with water at 0–5 °C. The organic phase was separated and retained. The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with water, and the aqueous phase was discarded. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, yielding 176.5 g of the crude product of the compound shown in formula (III-3). No further purification was performed, and the mixture was directly added to the next step.

[0080] The product was analyzed by GC-MS, and its molecular weight was 252.02.

[0081] Product testing 1 H NMR (400MHz, DMSO-d6) δ7.06-7.01(m,1H),6.90-6.86(m,1H),4.79(s,2H),3.90(s,3H),3.14(s,3H).

[0082] 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 2-methoxy-3,4-difluorophenylacetic acid, comprising the following four steps: in, X is a halogen or sulfonate group. Step 1: The starting compound 2-methoxy-3,4-difluorobenzoic acid, as shown in formula (V), was reacted in a solvent in the presence of a reducing agent and an additive to prepare the compound shown in formula (IV); Step 2: The compound shown in formula (IV) is reacted in a solvent in the presence of a halogenating agent or a sulfonating agent to prepare the compound shown in formula (III); Step 3: The compound shown in formula (III) is reacted in a solvent in the presence of a cyaniding agent to prepare the compound shown in formula (II); Step 4: The compound shown in formula (II) is reacted in a solvent in the presence of an acid or base reagent to prepare the compound shown in formula (I) 2-methoxy-3,4-difluorophenylacetic acid.

2. The preparation method according to claim 1, characterized in that, Preferably, the reducing agent in step one is selected from one or more of lithium borohydride, sodium borohydride, borane-tetrahydrofuran complex, sodium tri(acetoxy)borohydride, sodium cyanoborohydride, lithium triethylborohydride, lithium aluminum hydride, sodium dihydrobis(2-methoxyethoxy)aluminate, and diisobutylaluminum hydride, more preferably sodium borohydride. Preferably, the additive in step one is selected from one or more of concentrated sulfuric acid, trifluoroacetic acid, acetic acid, boron trifluoride-tetrahydrofuran complex, boron trifluoride-diethyl ether complex, boron trichloride, boron tribromide, aluminum chloride, magnesium chloride, calcium chloride, lithium chloride, nickel dichloride, and ferric chloride, more preferably boron trifluoride-tetrahydrofuran complex or boron trifluoride-diethyl ether complex; Preferably, the solvent in step one is selected from one or more of 1,4-dioxane, toluene, xylene, dichloromethane, methyl tert-butyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, diisopropyl ether, and dibutyl ether, more preferably tetrahydrofuran; Preferably, the molar ratio of reactant, reducing agent and additive in step one is 1.0:1.5-3.0:1.5-3.0, more preferably 1.0:2.3-2.5:2.0-2.2; the concentration range of reactant in solution in step one is 20-30 mol / L. Preferably, the reaction temperature range is -10 to 40°C.

3. The preparation method according to claim 1, characterized in that, Preferably, in step two, X in the compound represented by formula (III) is a halogen or sulfonate group; Preferably, the halogen includes chlorine, bromine, and iodine; Preferably, the halogenated reagent in step two is selected from one or more of oxaloyl chloride, phosphorus oxychloride, phosphorus pentachloride, di(trichloromethyl) carbonate, thionyl chloride, phosphorus tribromooxychloride, hydrobromic acid, elemental iodine, and N-bromosuccinimide, more preferably thionyl chloride or N-bromosuccinimide. Preferably, in step two, the sulfonate group is selected from methanesulfonate, trifluoromethanesulfonate, perfluorobutyl sulfonate, benzenesulfonate, p-methylbenzenesulfonate, p-nitrobenzenesulfonate, p-trifluoromethylbenzenesulfonate, and naphthalenesulfonate, and the sulfonating agent is selected from one or more of methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, perfluorobutyl sulfonyl fluoride, benzenesulfonyl chloride, p-methylbenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, p-trifluoromethylbenzenesulfonyl chloride, and naphthalenesulfonyl chloride, more preferably methanesulfonyl chloride or p-methylbenzenesulfonyl chloride; Preferably, the solvent in step two is selected from one or more of toluene, xylene, chlorobenzene, dichloromethane, chloroform, acetonitrile, ethyl acetate, and 2-methyltetrahydrofuran; more preferably, it is dichloromethane. In step two, the molar ratio of the reactant to the halogenated reagent or sulfonated esterification reagent is 1.0:1.0 to 3.0, more preferably 1.0:1.2 to 2.2; the concentration range of the reactant in the solution in step one is 20 to 30 mol / L. Preferably, the reaction temperature range is -10 to 40°C.

4. The preparation method according to claim 1, characterized in that, Preferably, the cyaniding reagent in step three is selected from one or more of sodium cyanide, potassium cyanide, cuprous cyanide, and trimethylcyanosilane, more preferably sodium cyanide or trimethylcyanosilane; Preferably, an alkaline reagent may be added in step three and used in conjunction with the cyanidation reagent. The alkaline reagent is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, potassium fluoride, cesium fluoride, tetrabutylammonium fluoride, and tetramethylammonium fluoride, more preferably potassium carbonate or tetrabutylammonium fluoride. Preferably, the solvent in step three is selected from one or more of dichloromethane, chloroform, acetonitrile, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetone, N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; more preferably, it is acetonitrile. In step three, the molar ratio of the reactant, cyaniding reagent, and basic reagent is 1.0:1.5–3.0:0–3.0, more preferably 1.0:1.8–2.2:1.8–2.2; the concentration range of the reactant in the solution in step three is 20–30 mol / L. Preferably, the reaction temperature range is 50–100°C.

5. The preparation method according to claim 1, characterized in that, Preferably, the acid reagent used in step four is selected from one or more of sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, and trifluoroacetic acid, more preferably sulfuric acid; the alkaline reagent used is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide, more preferably potassium hydroxide or sodium hydroxide. Preferably, the solvent in step four is selected from one or more of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methanol, ethanol, isopropanol, tert-butanol, ethylene glycol, acetone, N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and water; more preferably, it is a mixture of ethanol and water. The molar ratio of the reactant to the acid or base reagent in step four is 1.0:4.0 to 6.0, more preferably 1.0:4.5 to 5.0; the concentration range of the reactant in the solution in step four is 15 to 30 mol / L. Preferably, the reaction temperature range is 60–120°C.

6. The preparation method according to claim 1, characterized in that, Preferably, the reaction products from step one to step three can be used in the next step after conventional purification and separation operations, or a four-step continuous process can be adopted, that is, the reaction products from step one to step three are used directly in the next reaction without purification and separation operations to prepare the final compound shown in formula (I).

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