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

Abstract

This invention belongs to the field of organic synthesis technology and relates to a method for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid, comprising the following steps: S1 Using 3,4-difluoro-2-methoxyaniline and a diazotizing reagent as raw materials, a diazotization reaction is carried out under the action of a copper catalyst and an inorganic acid to obtain the 3,4-difluoro-2-methoxyaniline diazonium salt; subsequently, a Sandmeyer reaction is performed with bromine to obtain 6-bromo-2,3-difluoroanisole; S2 The 6-bromo-2,3-difluoroanisole obtained in step S1 is reacted with diethyl malonate under the action of a ferricyanide to obtain 2-(3,4-difluoro-2-methoxyphenyl)malonic acid; S3 The 2-(3,4-difluoro-2-methoxyphenyl)malonic acid obtained in step S2 is reacted with concentrated sulfuric acid to obtain 3,4-difluoro-2-methoxyphenylacetic acid. This invention features mild reaction conditions, high yield, and high purity, making it suitable for industrial production.

Description

Technical Field

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

[0002] Suzetrigine, chemically known as 4-[[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)tetrahydro-4,5-dimethyl-5-(trifluoromethyl)-2-furanyl]carbonyl]amino]-2-pyridinecarboxamide, is a first-in-class selective NaV1.8 inhibitor developed by Vertex Pharmaceuticals. It was approved by the FDA in January 2025 under the brand name Journavx for the treatment of moderate to severe acute pain in adults. This product is the first novel analgesic approved in over 20 years and the world's first approved novel non-opioid oral analgesic.

[0003] 3,4-Difluoro-2-methoxyphenylacetic acid, as a key intermediate of thuzothridine, has attracted much attention. Its synthesis methods mainly include the following:

[0004] (1) The preparation method of 3,4-difluoro-2-methoxyphenylacetic acid disclosed in Chinese Patent CN117858875A has the following synthetic route:

[0005]

[0006] The raw materials used in this route are not readily available, the reaction operation is complex, and it uses expensive palladium catalysts, resulting in high costs and failing to meet the needs of economical and environmentally friendly industrial production.

[0007] (2) The preparation method of 3,4-difluoro-2-methoxyphenylacetic acid disclosed in Chinese patent CN120736958A has the following synthetic route:

[0008]

[0009] This route involves a long process, with the third step using high-pressure hydrogen reduction and an expensive palladium catalyst, resulting in high costs and significant safety hazards. Industrial production operations are therefore highly dangerous.

[0010] (3) The preparation method of 3,4-difluoro-2-methoxyphenylacetic acid disclosed in Chinese patent CN119285456A has the following synthetic route:

[0011]

[0012] This route uses alkyllithium reagents in the reaction. On the one hand, alkyllithium reagents are highly toxic and harmful to human health and the environment. On the other hand, alkyllithium reagents are extremely sensitive to water and oxygen, and are reagents with a high risk of ignition. They release a large amount of heat during the reaction, requiring strict control of the reaction temperature. The reaction conditions are very harsh and not suitable for industrial production. Summary of the Invention

[0013] To address the shortcomings of the existing technology, this invention provides a method for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid. This method uses 3,4-difluoro-2-methoxyaniline as the starting material. In a microchannel reactor, diazotization and Sandmeyer reactions yield 6-bromo-2,3-difluoroanisole, followed by substitution and decarboxylation reactions to obtain the target compound, 3,4-difluoro-2-methoxyphenylacetic acid. This route yields a highly stable diazonium salt, achieves a continuous reaction between the diazonium salt and bromine without separation, utilizes a closed reaction space, employs mild reaction conditions, has a high safety factor, avoids the use of expensive catalysts, and results in high yield and purity, making it suitable for industrial production.

[0014] The specific plan is as follows:

[0015] A method for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid includes the following steps:

[0016] S1 uses 3,4-difluoro-2-methoxyaniline and a diazotizing agent as raw materials, and carries out a diazotization reaction in the presence of a copper catalyst and an inorganic acid to obtain the 3,4-difluoro-2-methoxyaniline diazonium salt; then it undergoes a Sandmeyer reaction with bromine to obtain 6-bromo-2,3-difluoroanisole.

[0017] S2 The 6-bromo-2,3-difluoroanisole obtained in step S1 reacts with diethyl malonate in the presence of a fumed acid agent to give 2-(3,4-difluoro-2-methoxyphenyl)malonic acid;

[0018] The 2-(3,4-difluoro-2-methoxyphenyl)malonic acid obtained in step S2 is reacted with concentrated sulfuric acid to obtain 3,4-difluoro-2-methoxyphenylacetic acid.

[0019] The synthesis route (example) is as follows:

[0020] .

[0021] Preferably, in step S1, the diazotizing agent is at least one of sodium nitrite, nitrosylsulfuric acid, and isoamyl nitrite, more preferably sodium nitrite.

[0022] Preferably, in step S1, the copper catalyst is at least one of cuprous chloride, cuprous nitrate, and cuprous sulfate, more preferably cuprous chloride.

[0023] Preferably, in step S1, the inorganic acid is at least one of hydrobromic acid, hydrochloric acid, and sulfuric acid, and more preferably hydrobromic acid.

[0024] Specifically, step S1 is carried out in a microchannel reactor, and includes: preparing an aqueous solution of the diazotizing reagent; preparing a mixed aqueous solution using 3,4-difluoro-2-methoxyaniline, a copper catalyst, and an inorganic acid; passing the aqueous solution of the diazotizing reagent and the mixed aqueous solution into microchannel reactor I to carry out the diazotization reaction and obtain a 3,4-difluoro-2-methoxyaniline diazonium salt solution; preparing a bromine solution using bromine and an organic solvent; and passing the 3,4-difluoro-2-methoxyaniline diazonium salt solution and the bromine solution into microchannel reactor II to carry out the Sandmeyer reaction and obtain 6-bromo-2,3-difluoroanisole.

[0025] Preferably, in step S1, the molar ratio of 3,4-difluoro-2-methoxyaniline to copper catalyst is 1:(0.005~0.01); the molar ratio of 3,4-difluoro-2-methoxyaniline to inorganic acid is 1:(3.0~5.0); the molar ratio of 3,4-difluoro-2-methoxyaniline to diazotizing agent is 1:(1.0~1.2); and the molar ratio of 3,4-difluoro-2-methoxyaniline to bromine is 1:(1.1~2.0).

[0026] Preferably, in step S1, the concentration of the diazotizing reagent aqueous solution is 15wt%~20wt%; the concentration of 3,4-difluoro-2-methoxyaniline in the mixed aqueous solution is 15wt%~25wt%; and the concentration of the bromine solution is 15wt%~25wt%.

[0027] Preferably, in step S1, the diazotization reaction time is 1-5 min and the Sandmeyer reaction time is 1-3 min.

[0028] Preferably, in step S1, the flow rate of the diazotizing reagent aqueous solution is 2~7 mL / min; the flow rate of the mixed aqueous solution is 5~15 mL / min; the flow rate of the 3,4-difluoro-2-methoxyaniline diazonium salt solution is 10~15 mL / min; and the flow rate of the bromine solution is 8~12 mL / min.

[0029] Preferably, in step S1, the diazotization reaction temperature is 0~10℃.

[0030] Preferably, in step S1, the Sandmeyer reaction temperature is 0~10℃.

[0031] Preferably, in step S2, the acid-absorbing agent is at least one of potassium carbonate, sodium hydroxide, and sodium carbonate, more preferably potassium carbonate.

[0032] Preferably, in step S2, the molar ratio of 6-bromo-2,3-difluoroanisole to diethyl malonate is 1:(1.5~2.5); the molar ratio of 6-bromo-2,3-difluoroanisole to fumonisin is 1:(3.0~4.0).

[0033] Preferably, in step S2, the reaction temperature is 90~100℃ and the reaction time is 5~6h.

[0034] Preferably, in step S3, the molar ratio of 2-(3,4-difluoro-2-methoxyphenyl)malonic acid to concentrated sulfuric acid is 1:(1.0~2.0), and the concentration of concentrated sulfuric acid is more preferably 98wt%.

[0035] Preferably, in step S3, the reaction temperature is 60~70℃ and the reaction time is 2~3h.

[0036] Compared with existing technologies, the beneficial effects are as follows: This invention obtains 3,4-difluoro-2-methoxyphenylacetic acid through a three-step reaction. The diazonium salt obtained by this route has high stability, and the continuous reaction of diazonium salt and bromine is achieved without separation. The reaction space is closed, the reaction conditions are mild, the safety factor is high, and the use of expensive catalysts is avoided. The yield is high, the purity is high, and it is suitable for industrial production. Attached Figure Description

[0037] Figure 1 The HPLC chromatogram of 3,4-difluoro-2-methoxyphenylacetic acid prepared in Example 1 is shown. Detailed Implementation

[0038] The embodiments of the present invention will be described in further detail below. The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention. Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0039] Example 1

[0040] A method for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid includes the following steps:

[0041] S1. Weigh 47.7g of sodium nitrite and dissolve it in 200mL of deionized water to prepare a sodium nitrite aqueous solution; weigh 150.6g of bromine and dissolve it in 300mL of dichloromethane, then bring the volume to 500mL with dichloromethane to prepare a bromine solution; under stirring, dissolve 100g of 3,4-difluoro-2-methoxyaniline and 0.62g of cuprous chloride in 284mL of hydrobromic acid (48wt%), then bring the volume to 400mL with deionized water to prepare a mixed aqueous solution; use a constant flow pump to pass the sodium nitrite aqueous solution and the mixed aqueous solution into microchannel reactor I for reaction, wherein the flow rate of the mixed aqueous solution is 10mL / min and the flow rate of the sodium nitrite aqueous solution is 5mL / min, and the residence time is... A 3,4-difluoro-2-methoxyaniline diazonium salt solution was obtained at 6°C for 1.5 min. The 3,4-difluoro-2-methoxyaniline diazonium salt solution and bromine solution were then introduced into microchannel reactor II via a constant flow pump for a Sandmeyer reaction. The flow rate of the 3,4-difluoro-2-methoxyaniline diazonium salt solution was 12 mL / min, the flow rate of the bromine solution was 10 mL / min, the residence time was 1.2 min, and the temperature was 4°C, yielding a 6-bromo-2,3-difluoroanisole solution. After standing for 10 min and separation, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 129.5 g of 6-bromo-2,3-difluoroanisole, with a yield of 92.4%.

[0042] S2. Add 100g of 6-bromo-2,3-difluoroanisole, 216.9g of potassium carbonate, 143.6g of diethyl malonate, 100mL of water, and 500mL of DMF to a 2L reaction flask. Start stirring, heat to 90℃, and stir for 6 hours. After the reaction is complete, add 1000mL of water dropwise to the reaction solution. After the addition is complete, maintain the temperature at 0℃ and stir for 2 hours. Filter and dry to obtain 96.0g of yellow solid 2-(3,4-difluoro-2-methoxyphenyl)malonic acid, with a yield of 87.0%.

[0043] S3. Add 90g of 2-(3,4-difluoro-2-methoxyphenyl)malonic acid, 54.8g of concentrated sulfuric acid (98wt%), and 270mL of methanol to a 500mL reaction flask. Start stirring, heat to 60℃, and stir for 3h. After the reaction is complete, cool to 0℃ and stir to crystallize for 2h. Filter, dry, and obtain 60.7g of off-white solid 3,4-difluoro-2-methoxyphenylacetic acid, yield 82.1%, purity 99.632%.

[0044] like Figure 1 The HPLC chromatogram of 3,4-difluoro-2-methoxyphenylacetic acid is shown in Table 1, with the corresponding peak results.

[0045] Table 1 Peak Results

[0046]

[0047] Example 2

[0048] Referring to Example 1, the difference is that in step S3, 90g of 2-(3,4-difluoro-2-methoxyphenyl)malonic acid, 64.8g of concentrated sulfuric acid (98wt%), and 300mL of methanol were added to a 500mL reaction flask. The mixture was stirred, heated to 60°C, and stirred for 3 hours. After the reaction was completed, the mixture was cooled to 0°C and stirred to crystallize for 2 hours. The mixture was then filtered and dried to obtain 53.5g of a white solid, 3,4-difluoro-2-methoxyphenylacetic acid, with a yield of 72.4% and a purity of 98.134%.

[0049] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for synthesizing 3,4-difluoro-2-methoxyphenylacetic acid, characterized in that, Includes the following steps: S1 uses 3,4-difluoro-2-methoxyaniline and a diazotizing agent as raw materials, and carries out a diazotization reaction in the presence of a copper catalyst and an inorganic acid to obtain the 3,4-difluoro-2-methoxyaniline diazonium salt; then it undergoes a Sandmeyer reaction with bromine to obtain 6-bromo-2,3-difluoroanisole. S2 The 6-bromo-2,3-difluoroanisole obtained in step S1 reacts with diethyl malonate in the presence of a fumed acid agent to give 2-(3,4-difluoro-2-methoxyphenyl)malonic acid; The 2-(3,4-difluoro-2-methoxyphenyl)malonic acid obtained in step S2 is reacted with concentrated sulfuric acid to obtain 3,4-difluoro-2-methoxyphenylacetic acid.

2. The synthesis method according to claim 1, characterized in that, Step S1 is carried out in a microchannel reactor, specifically as follows: an aqueous solution of the diazotizing reagent is prepared; a mixed aqueous solution is prepared using 3,4-difluoro-2-methoxyaniline, a copper catalyst, and an inorganic acid; the aqueous solution of the diazotizing reagent and the mixed aqueous solution are passed into microchannel reactor I to carry out the diazotization reaction to obtain a 3,4-difluoro-2-methoxyaniline diazonium salt solution; a bromine solution is prepared using bromine and an organic solvent; the 3,4-difluoro-2-methoxyaniline diazonium salt solution and the bromine solution are passed into microchannel reactor II to carry out the Sandmeyer reaction to obtain 6-bromo-2,3-difluoroanisole.

3. The synthesis method according to claim 1, characterized in that, In step S1, the diazotizing agent is at least one of sodium nitrite, nitrosylsulfuric acid, and isoamyl nitrite.

4. The synthesis method according to claim 1, characterized in that, In step S1, the copper catalyst is at least one of cuprous chloride, cuprous nitrate, and cuprous sulfate.

5. The synthesis method according to claim 1, characterized in that, In step S1, the inorganic acid is at least one of hydrobromic acid, hydrochloric acid, and sulfuric acid.

6. The synthesis method according to claim 1, characterized in that, In step S1, the diazotization reaction temperature is 0~10℃, and the Sandmeyer reaction temperature is 0~10℃.

7. The synthesis method according to claim 1, characterized in that, In step S2, the acid-absorbing agent is at least one of potassium carbonate, sodium hydroxide, and sodium carbonate.

8. The synthesis method according to claim 1, characterized in that, In step S2, the reaction temperature is 90~100℃.

9. The synthesis method according to claim 1, characterized in that, In step S3, the reaction temperature is 60~70℃.

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