Method for synthesizing 3, 4-difluoro-2-methoxyphenylacetic acid without transition metal catalysis

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 3, 4-difluoro-2-methoxyphenylacetic acid without transition metal catalysis, which comprises the following steps: by taking 2, 3, 4-trifluoronitrobenzene as an initial raw material, carrying out substitution, methylation, reduction, Sandmeyer reaction, cross coupling, hydrolysis and other reactions, and synthesizing the 3, 4-difluoro-2-methoxyphenylacetic acid without transition metal catalysis. The total yield is 55.6%, and the content of the refined 3, 4-difluoro-2-methoxyphenylacetic acid reaches 99% or above. The method has the advantages of mild reaction conditions, simple operation, high reaction yield, easy purchase of used reagents and instruments, low cost, no need of any transition metal catalysis, and feasibility in specific practical application.

Description

Technical Field

[0001] This invention discloses a method for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid, belonging to the field of organic synthesis technology. The method uses 2,3,4-trifluoronitrobenzene as a starting material and synthesizes 3,4-difluoro-2-methoxyphenylacetic acid through substitution, methylation, reduction, Sandmeyer reaction, cross-coupling, and hydrolysis. This invention is simple to operate, has a high reaction yield, uses readily available reagents and instruments, and is low in cost, making it feasible in practical applications. This invention does not use any transition metals (such as copper, palladium, nickel, etc.) for catalysis, and no additional steps are required to remove such metal impurities. Background Technology

[0002] 3,4-Difluoro-2-methoxyphenylacetic acid is a key intermediate in suzetrigine. Suzetrigine is the world's first approved novel non-opioid oral drug, an oral voltage-gated sodium (NaV) channel inhibitor that selectively inhibits NaV1.8 pain signals; it is a novel analgesic.

[0003] Patent CN119371405 discloses a synthetic route for 3,4-difluoro-2-methoxyphenylacetic acid: using 3,4-difluoro-2-methoxybenzoic acid as a starting material, after reduction with borane, it is prepared into 3,4-difluoro-2-methoxybenzyl methanesulfonate, which is then reacted with highly toxic sodium cyanide to generate 2-(3,4-difluoro-2-methoxyphenyl)acetonitrile, and finally hydrolyzed to 3,4-difluoro-2-methoxyphenylacetic acid.

[0004]

[0005] This route is a common method for extending carbon chains, but its limitations are: 1. The starting material 3,4-difluoro-2-methoxybenzoic acid is expensive; 2. Borane is flammable and has a high risk factor; 3. It requires the use of highly toxic sodium cyanide.

[0006] Patent CN119285456 reports two synthetic routes for 3,4-difluoro-2-methoxyphenylacetic acid: 1) using 3,4-difluoro-2-methoxyphenylboronic acid and ethyl 2-bromoacetate, reacting under the action of a palladium catalyst, and finally hydrolyzing to the target product (yield 74%); 2) using tert-butyl 2-bromoacetate, first activating it with trimethylchlorosilane and zinc powder, then reacting it with 2-methoxy-3,4-difluorobromobenzene under the action of a palladium catalyst, and finally acid hydrolyzing to the target product (yield 85%).

[0007]

[0008]

[0009] Both routes utilize palladium, a precious metal, as a catalyst, significantly increasing their process costs. Furthermore, the raw materials 3,4-difluoro-2-methoxyphenylboronic acid and 2-methoxy-3,4-difluorobromobenzene are difficult to obtain, making it hard to find stable and high-quality supplies on the market, resulting in high prices. Additionally, the operations are cumbersome and require stringent reaction conditions.

[0010] Patent CN 119285456 A discloses a synthetic route for 3,4-difluoro-2-methoxyphenylacetic acid: after reacting 2,3-difluorophenol with 3,4-dihydropyran, an alkyl lithium reagent is added at low temperature, followed by the addition of tert-butyl 2-bromoacetate, and acid hydrolysis is performed to obtain 3,4-difluoro-2-hydroxyphenylacetic acid; finally, the reaction is carried out in the presence of a base and a methylating agent to obtain 3,4-difluoro-2-methoxyphenylacetic acid.

[0011]

[0012] The second step of this preparation method generates positional isomers, which makes subsequent purification difficult. Summary of the Invention

[0013] To overcome the above-mentioned technical defects, this invention provides a method for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid. 2,3,4-trifluoronitrobenzene is reacted with potassium hydroxide to generate the intermediate 2-hydroxy-3,4-difluoronitrobenzene; this intermediate is then alkylated with dimethyl sulfate to obtain 2-methoxy-3,4-difluoronitrobenzene; the nitro group is then reduced, followed by diazotization under the action of sodium nitrite, and then reacted with tetrahydroxydiboron to generate 2-methoxy-3,4-difluorophenylboronic acid; phenylboronic acid and ethyl diazonium chloride can be reacted with ammonium chloride to obtain ethyl phenylacetate in high yield; finally, alkaline hydrolysis yields 3,4-difluoro-2-methoxyphenylacetic acid.

[0014] This invention utilizes inexpensive and readily available 2,3,4-trifluoronitrobenzene as the starting material. The intermediate reactions are mild, simple to operate, and yield the intermediates in high yield, providing a low-cost and efficient route for the preparation of 3,4-difluoro-2-methoxyphenylacetic acid. Furthermore, this route does not use any transition metals (such as copper, palladium, nickel, etc.) for catalysis, and no additional steps are required to remove such metal impurities.

[0015] A method for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid without transition metal catalysis includes the following steps:

[0016] The reaction equation is as follows:

[0017]

[0018] A method for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid without transition metal catalysis includes the following steps:

[0019] Step 1: Add a first base and 2,3,4-trifluoronitrobenzene to the first solvent to react and generate 2-hydroxy-3,4-difluoronitrobenzene;

[0020] Step 2: Add 2-hydroxy-3,4-difluoronitrobenzene, the methylating agent, and the second base to the second solvent, and heat to react, generating 2-methoxy-3,4-difluoronitrobenzene;

[0021] Step 3: Add 2-methoxy-3,4-difluoronitrobenzene and nitro reducing agent to the third solvent, then add ammonium chloride solution dropwise to react and generate 2-methoxy-3,4-difluoroaniline;

[0022] Step 4: Dissolve 2-methoxy-3,4-difluoroaniline in a fourth solvent, add an aqueous solution of nitrite dropwise, and then add tetrahydroxydiboron to generate 2-methoxy-3,4-difluorophenylboronic acid;

[0023] Step 5: Dissolve 2-methoxy-3,4-difluorophenylboronic acid, glycine ethyl ester, nitrite and ammonium chloride in the fifth solvent, and heat to react to generate ethyl 2-methoxy-3,4-difluorophenylacetate;

[0024] Step 6: React ethyl 2-methoxy-3,4-difluorophenylacetic acid, hydrolysis reagent, and sixth solvent to obtain 3,4-difluoro-2-methoxyphenylacetic acid.

[0025] Furthermore, in step 1, the reaction temperature is 20-50℃;

[0026] The first alkali is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, and magnesium hydroxide;

[0027] The molar ratio of 2,3,4-trifluoronitrobenzene to the first base is 1:(2.2-4);

[0028] The first solvent is one or more of water, dimethyl sulfoxide, acetonitrile, methanol, and ethanol.

[0029] Furthermore, in step 2, the reaction temperature is 60-120℃;

[0030] The second alkali is one or more of potassium carbonate and sodium carbonate;

[0031] The molar ratio of the 2-hydroxy-3,4-difluoronitro group, the methylating agent, and the second base is 1:(1.2-2):(1.2-3).

[0032] The methylating agent is one of dimethyl sulfate and iodomethane solution;

[0033] The second solvent is one or more of acetone, toluene, and acetonitrile.

[0034] Furthermore, in step 3, the reaction temperature is 25-80℃;

[0035] The molar ratio of 2-methoxy-3,4-difluoronitrobenzene, nitro reducing agent, and ammonium chloride is 1:(3-10):(3-10);

[0036] The nitro reducing agent is one of iron powder and zinc powder;

[0037] The third solvent is selected from one or more of methanol, ethanol, isopropanol, and tetrahydrofuran.

[0038] Furthermore, in step 4, the reaction temperature is -30~30℃;

[0039] The molar ratio of 2-methoxy-3,4-difluoroaniline, nitrite, and tetrahydroxydiboron is 1:(2.5-6):(2.5-5).

[0040] The nitrite is one or more of sodium nitrite, potassium nitrite, and magnesium nitrite;

[0041] The fourth solvent is selected from one or more of methanol, ethanol, and isopropanol.

[0042] Furthermore, in step 5, the reaction temperature is 60-120℃;

[0043] The molar ratio of 2-methoxy-3,4-difluorophenylboronic acid, glycine ethyl ester, nitrite and ammonium chloride is 1:(1.2-3):(1.5-4):(1.5-4);

[0044] The nitrite is one or more of sodium nitrite, potassium nitrite, and magnesium nitrite;

[0045] The fifth solvent is selected from one or more of water, toluene, and 1,4-dioxane.

[0046] Furthermore, in step 6, the reaction temperature is 0-100℃;

[0047] The molar ratio of ethyl 2-methoxy-3,4-difluorophenylacetate to hydrolysis reagent is 1:(1.2-5);

[0048] The hydrolysis reagent is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, and magnesium hydroxide;

[0049] The sixth solvent is selected from one or more of water, methanol, ethanol, isopropanol, and tetrahydrofuran.

[0050] Furthermore, after the reaction in step 1 is complete, hydrochloric acid is added dropwise at room temperature.

[0051] Furthermore, in step 4, the reaction temperature is -5 to 5°C.

[0052] Furthermore, in step 6, the reaction temperature is 40~45℃.

[0053] In some embodiments, in step 1 above, the reaction temperature of 2,3,4-trifluoronitrobenzene and potassium hydroxide is 20-50°C, preferably 25-35°C. While increasing the temperature can increase the reaction rate, it will also increase the amount of impurities 2,3-difluoro-4-nitrophenol and 2-fluoro-4-nitro-1,3-benzenediol.

[0054] In some embodiments, in step 2 above, the reaction temperature of 2-hydroxy-3,4-difluoronitro, dimethyl sulfate and potassium carbonate is 60-120°C, preferably 100-110°C.

[0055] In some embodiments, in step 3 above, the reaction temperature of 2-methoxy-3,4-difluoronitro, iron powder and ammonium chloride is 25-80 °C, preferably 40-70 °C.

[0056] In some embodiments, in step 4 above, the reaction temperature of 2-methoxy-3,4-difluoroaniline, sodium nitrite and tetrahydroxydiboron is -30~30 ℃, preferably -5~5 ℃.

[0057] In some embodiments, in step 5 above, the reaction temperature of 2-methoxy-3,4-difluorophenylboronic acid, glycine ethyl ester hydrochloride, sodium nitrite and ammonium chloride is 60-120°C, preferably 100-110°C.

[0058] In some embodiments, in step 6 above, the reaction temperature of ethyl 2-methoxy-3,4-difluorophenylacetate and sodium hydroxide is 0-100°C, preferably 40-45°C.

[0059] In some embodiments, in step 5 above, ammonium chloride can greatly improve the yield by acting as an activator, and the yield of crude product without the addition of ammonium chloride is less than 50%.

[0060] Compared with the prior art, the present invention has the following beneficial effects:

[0061] 1) The raw materials used in this invention are all common, easy to purchase, and inexpensive;

[0062] 2) The process is simple to operate, safe and stable, and the reaction conditions are mild;

[0063] 3) No transition metals (such as copper, palladium, nickel, etc.) are used for catalysis, and no additional operations are required to remove such metal impurities in the later stage. Attached Figure Description

[0064] Figure 1 This is the 1H NMR spectrum of 2-methoxy-3,4-aniline oxalate obtained in Example 3.

[0065] Figure 2 This is the 1H NMR spectrum of 3,4-difluoro-2-methoxyphenylacetic acid obtained in Example 6. Detailed Implementation

[0066] The present invention will now be described in further detail with reference to specific embodiments and accompanying drawings.

[0067] Example 1: Synthesis of Intermediate 2:

[0068] At room temperature, 200 mL of water and potassium hydroxide (21.1 g, 376.0 mmol, 3.3 eq) were added sequentially to a three-necked flask, followed by the slow addition of 2,3,4-trifluoronitrobenzene (20.0 g, 112.9 mmol). After the addition was complete, the mixture was stirred at room temperature for 6 hours, and TLC showed no significant residue of the starting material. 24 mL of concentrated hydrochloric acid was added to adjust the pH to 3, and the mixture was stirred at 0 °C for half an hour. After filtration and drying, a pale yellow solid (18.3 g, yield: 92.5%) was obtained, which is intermediate 2, namely 2-hydroxy-3,4-difluoronitrobenzene.

[0069] Example 2: Synthesis of intermediate 3:

[0070] At room temperature, 160 mL of toluene, intermediate 2 (18.2 g, 103.9 mmol), dimethyl sulfate (17.1 g, 135.6 mmol, 1.3 eq), and powdered potassium carbonate (20.2 g, 146.1 mmol, 1.4 eq) were added sequentially to a three-necked flask. The mixture was heated to 100 °C and stirred for 2.5 hours. TLC showed no significant residue of the starting material. After cooling to room temperature, 150 mL of distilled water was added, and the mixture was separated. The aqueous phase was extracted twice with ethyl acetate, and the organic phase was collected. After washing with saturated brine and drying with anhydrous sodium sulfate, the organic phase was filtered and dissolved in a rotary evaporator to finally obtain a white solid intermediate 3 (18.4 g, yield: 93.6%), which is 2-methoxy-3,4-difluoronitrobenzene.

[0071] Example 3: Synthesis of intermediate 4:

[0072] At room temperature, 80 mL of ethanol, intermediate 3 (17.5 g, 92.6 mmol), and iron powder (26 g, 46.5 mmol, 5 eq) were added sequentially to a 500 mL three-necked flask. The mixture was heated to 40 °C with stirring, and an aqueous solution of ammonium chloride (24.9 g ammonium chloride, 46.5 mmol, 5 eq, dissolved in 170 mL of water) was slowly added dropwise. The temperature was maintained at 40-50 °C during the addition. After the addition was complete, the temperature was raised to 70 °C and stirred for 2 hours. TLC showed no significant residue of the raw material. After cooling to room temperature, the mixture was filtered. Ethyl acetate (100 mL) and water (200 mL) were added to the filtrate, and the mixture was separated. The organic phase was washed once with water and once with saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a reddish-brown liquid. This crude product was dissolved in methyl tert-butyl ether (50 mL), and oxalic acid (8.7 g, 96.7 mmol) was added in portions with stirring. After stirring at room temperature for 1 hour, stirring was continued in an ice-water bath for 1 hour, resulting in the precipitation of a solid. The solid was filtered and dried to obtain a white powder (21.1 g, yield: 91.8%), which is intermediate 4, namely 2-methoxy-3,4-difluoroaniline.

[0073] 1 HNMR(300MHz,DMSO-d6)δ6.83(q,J=9.0Hz,1H),6.46-6.38(m, 1H), 3.79 (s,3H).

[0074] Example 4: Synthesis of intermediate 5:

[0075] Intermediate 4 (21.1 g, 84.8 mmol) and 85 mL of methanol were added to a three-necked flask. After 2-methoxy-3,4-difluoroaniline (intermediate 4) was completely dissolved, 85 mL of 3 mol / L hydrochloric acid was added and the mixture was stirred for 10 minutes. The temperature was lowered to -5 to 0 °C, and an aqueous solution of sodium nitrite (17.6 g sodium nitrite, 254.4 mmol, 3 eq, dissolved in 80 mL of water) was slowly added dropwise. After the addition was complete, the mixture was reacted for 30 minutes at 0–5 °C with stirring. Then, tetrahydroxydiboron (22.81 g, 254.4 mmol, 3 eq) was added to the three-necked flask, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, 300 mL of distilled water was added to the mixture, and the mixture was extracted three times with dichloromethane. The organic phase was collected, dried with anhydrous sodium sulfate, filtered, and the dichloromethane was removed by rotary evaporation to finally obtain white solid intermediate 5 (13.2 g, yield: 93.0%), which is 2-methoxy-3,4-difluorophenylboronic acid.

[0076] Example 5: Synthesis of Intermediate 6:

[0077] Toluene (140 mL) and water (70 mL) were added separately to three-necked flasks, followed by intermediate 5 (13.2 g, 70.4 mmol), glycine ethyl ester hydrochloride (14.7 g, 105.6 mmol, 1.5 eq), sodium nitrite (9.2 g, 133.8 mmol, 1.9 eq), and ammonium chloride (7.5 g, 140.8 mmol, 2 eq). The mixture was heated to 100–110 °C and stirred for 12 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was separated. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The solvent was removed by rotary evaporation to obtain intermediate 6 (16.7 g, crude product, no further purification required, directly used in the next step), which is ethyl 2-methoxy-3,4-difluorophenylacetate.

[0078] Example 6: Synthesis of 3,4-difluoro-2-methoxyphenylacetic acid:

[0079] At room temperature, 80 mL of methanol, 20 mL of water, 16.7 g of intermediate 5 (crude product), and 140 mL (140 mmol) of 1 mol / L sodium hydroxide solution were added sequentially to a three-necked flask. The mixture was heated to 40-45 °C and stirred for 2 hours. TLC showed no obvious residue of raw material. After the methanol was concentrated to dryness, 100 mL of water was added. The mixture was extracted twice with ethyl acetate and n-hexane (V:V=1:2). 1 mol / L hydrochloric acid was added dropwise to the aqueous phase to adjust the pH to 4-5, and a solid precipitated. The solid was filtered and dried to obtain a white solid 3,4-difluoro-2-methoxyphenylacetic acid (10.7 g, two-step yield: 75.3%).

[0080] 1 HNMR (300MHz, Chloroform-d) δ6.92-6.80 (m, 2H), 3.99-3.98 (d, J=1.77Hz, 3H), 3.64 (s, 2H).

Claims

1. A method for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid without transition metal catalysis, characterized in that, Includes the following steps: Step 1: Add a first base and 2,3,4-trifluoronitrobenzene to the first solvent to react and generate 2-hydroxy-3,4-difluoronitrobenzene; Step 2: Add 2-hydroxy-3,4-difluoronitrobenzene, the methylating agent, and the second base to the second solvent, and heat to react, generating 2-methoxy-3,4-difluoronitrobenzene; Step 3: Add 2-methoxy-3,4-difluoronitrobenzene and nitro reducing agent to the third solvent, then add ammonium chloride solution dropwise to react and generate 2-methoxy-3,4-difluoroaniline; Step 4: Dissolve 2-methoxy-3,4-difluoroaniline in a fourth solvent, add an aqueous solution of nitrite dropwise, and then add tetrahydroxydiboron to generate 2-methoxy-3,4-difluorophenylboronic acid; Step 5: Dissolve 2-methoxy-3,4-difluorophenylboronic acid, glycine ethyl ester, nitrite and ammonium chloride in the fifth solvent, and heat to react to generate ethyl 2-methoxy-3,4-difluorophenylacetate; Step 6: React ethyl 2-methoxy-3,4-difluorophenylacetic acid, hydrolysis reagent, and sixth solvent to obtain 3,4-difluoro-2-methoxyphenylacetic acid.

2. The method according to claim 1, characterized in that: In step 1, the reaction temperature is 20-50℃; And / or, The first alkali is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, and magnesium hydroxide; And / or, The molar ratio of 2,3,4-trifluoronitrobenzene to the first base is 1:(2.2-4); And / or, The first solvent is one or more of water, dimethyl sulfoxide, acetonitrile, methanol, and ethanol.

3. The method according to claim 1, characterized in that: In step 2, the reaction temperature is 60-120℃; And / or, The second alkali is one or more of potassium carbonate and sodium carbonate; And / or, The molar ratio of the 2-hydroxy-3,4-difluoronitro group, the methylating agent, and the second base is 1:(1.2-2):(1.2-3). And / or, The methylating agent is one of dimethyl sulfate and iodomethane solution; And / or, The second solvent is one or more of acetone, toluene, and acetonitrile.

4. The method according to claim 1, characterized in that: In step 3, the reaction temperature is 25-80℃; And / or, The molar ratio of 2-methoxy-3,4-difluoronitrobenzene, nitro reducing agent, and ammonium chloride is 1:(3-10):(3-10); And / or, The nitro reducing agent is one of iron powder and zinc powder; And / or, The third solvent is selected from one or more of methanol, ethanol, isopropanol, and tetrahydrofuran.

5. The method according to claim 1, characterized in that: In step 4, the reaction temperature is -30~30℃; And / or, The molar ratio of 2-methoxy-3,4-difluoroaniline, nitrite, and tetrahydroxydiboron is 1:(2.5-6):(2.5-5). And / or, The nitrite is one or more of sodium nitrite, potassium nitrite, and magnesium nitrite; And / or, The fourth solvent is selected from one or more of methanol, ethanol, and isopropanol.

6. The method according to claim 1, characterized in that: In step 5, the reaction temperature is 60-120℃; And / or, The molar ratio of 2-methoxy-3,4-difluorophenylboronic acid, glycine ethyl ester, nitrite and ammonium chloride is 1:(1.2-3):(1.5-4):(1.5-4); And / or, The nitrite is one or more of sodium nitrite, potassium nitrite, and magnesium nitrite; And / or, The fifth solvent is selected from one or more of water, toluene, and 1,4-dioxane.

7. The method according to claim 1, characterized in that: In step 6, the reaction temperature is 0-100℃; And / or, The molar ratio of ethyl 2-methoxy-3,4-difluorophenylacetate to hydrolysis reagent is 1:(1.2-5); And / or, The hydrolysis reagent is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, and magnesium hydroxide; And / or, The sixth solvent is selected from one or more of water, methanol, ethanol, isopropanol, and tetrahydrofuran.

8. The method according to claim 1, characterized in that: After the reaction in step 1 is complete, add hydrochloric acid dropwise at room temperature.

9. The method according to claim 5, characterized in that: In step 4, the reaction temperature is -5~5℃.

10. The method according to claim 7, characterized in that: In step 6, the reaction temperature is 40~45℃.

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