Preparation method of 3, 4-difluoro-2-methoxyphenylacetic acid

Abstract

The invention discloses a preparation method of 3, 4-difluoro-2-methoxyphenylacetic acid, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: reacting 2, 3-difluorophenol with 3, 4-dihydropyran under the action of sulfonic acid resin to generate an intermediate 2-(2, 3-difluorophenoxy) pyran; then lithiating, reacting with tert-butyl 2-bromoacetate, and performing acidolysis to obtain a 3, 4-difluoro-2-hydroxyphenylacetic acid intermediate; and finally reacting with a methylation reagent in the presence of alkali to generate the target compound 3, 4-difluoro-2-methoxyphenylacetic acid. The preparation method has the advantages that the route is overall reasonable, the preparation method comprises three steps, and a simple and effective new route is provided for the preparation of the 3, 4-difluoro-2-methoxyphenylacetic acid.

Description

Technical Field

[0001] The invention relates to a preparation method of 3,4-difluoro-2-methoxyphenylacetic acid, and belongs to the technical field of organic synthesis. Background Art

[0002] 3,4-Difluoro-2-methoxyphenylacetic acid (CAS No: 1558274-26-2) is an important fluorophenylacetic acid compound. It can be used as a key intermediate to participate in the synthesis of drug compounds that can inhibit overactive or overexpressed signal transduction pathways in cancer tissues and treat hyperproliferation and tumor diseases. It is a drug molecule building block with great utilization value. At the same time, 3,4-difluoro-2-methoxyphenylacetic acid is also an important intermediate for the synthesis of furan ring-containing drugs. Several representative structures of furan ring-containing drugs are as follows:

[0003]

[0004] Such furan ring-containing drugs are mainly used to treat or relieve pain caused by many diseases, including chronic pain, acute pain, intestinal pain, musculoskeletal pain, neuropathic pain, etc. The mechanism of action of such furan ring-containing drugs is that they can well regulate voltage-gated sodium channels (Navs). Sodium channels are widely present in nerves, skeletal muscles and myocardium, enabling excitable cells to generate and conduct action potentials (APs), playing an important role in the transmission of nerve signals and the regulation of cardiac rhythm. As the use of such furan ring-containing drugs continues to increase, the use of 3,4-difluoro-2-methoxyphenylacetic acid has also continued to expand.

[0005] There are few reports on the synthesis of 3,4-difluoro-2-methoxyphenylacetic acid. There are mainly two routes: using tert-butyl 2-bromoacetate to react with trimethylsilyl chloride and zinc powder, and then reacting with 1-bromo-3,4-difluoro-2-methoxybenzene under the action of palladium catalyst, and finally acidolysis to synthesize the target product (yield 85%); using 3,4-difluoro-2-methoxyphenylboronic acid and ethyl 2-bromoacetate to react under the action of palladium catalyst, and finally acidolysis to synthesize the target product (yield 74%) (WO2022256842).

[0006] In view of the defects of the above technical route, it is necessary to conduct in-depth research on the synthesis route of 3,4-difluoro-2-methoxyphenylacetic acid to provide a better, easy-to-obtain raw material, simple, safe, stable and economical process route to meet the growing market demand. Summary of the invention

[0007] In order to overcome the above technical defects, the present invention provides a method for preparing 3,4-difluoro-2-methoxyphenylacetic acid. 2,3-Difluorophenol and 3,4-dihydropyran are reacted with sulfonic acid resin to generate an intermediate 2-(2,3-difluorophenoxy)pyran; then, it is reacted with tert-butyl 2-bromoacetate by lithiation and then acidolyzed to obtain a 3,4-difluoro-2-hydroxyphenylacetic acid intermediate; finally, it is reacted with a methylating agent in the presence of a base to generate a target compound 3,4-difluoro-2-methoxyphenylacetic acid. The route of the present invention is reasonable as a whole, and is carried out in three steps, providing a concise and effective new path for the preparation of 3,4-difluoro-2-methoxyphenylacetic acid.

[0008] The method for preparing 3,4-difluoro-2-methoxyphenylacetic acid of the present invention comprises the following steps:

[0009] A. 3,4-dihydropyran (DHP) and 2,3-difluorophenol are reacted in the presence of a sulfonic acid resin to generate 2-(2,3-difluorophenoxy)pyran;

[0010] B. Mix 2-(2,3-difluorophenoxy)pyran and an organic solvent, add an alkyl lithium reagent at low temperature, then add tert-butyl 2-bromoacetate to react, and obtain 3,4-difluoro-2-hydroxyphenylacetic acid after acid hydrolysis;

[0011] C. Mix 3,4-difluoro-2-hydroxyphenylacetic acid and an organic solvent, and react in the presence of a base and a methylating agent to obtain 3,4-difluoro-2-methoxyphenylacetic acid.

[0012] The reaction equation is shown as follows:

[0013]

[0014] Furthermore, in the above step A, the molar ratio of 2,3-difluorophenol to 3,4-dihydropyran is 1:1-4.5.

[0015] Furthermore, in the above step A, the weight ratio of the sulfonic acid resin to 2,3-difluorophenol is 1:0.05-0.1.

[0016] Furthermore, in the above step B, the molar ratio of the alkyl lithium, 2-(2,3-difluorophenoxy)pyran and tert-butyl 2-bromoacetate is 1-1.1:1:1.1-1.4.

[0017] Furthermore, in the above step B, the organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran or cyclopentyl methyl ether, preferably tetrahydrofuran.

[0018] Furthermore, in the above step B, the lithium reagent is n-butyllithium or n-hexyllithium.

[0019] Furthermore, in the above step B, the acid is hydrochloric acid, sulfuric acid or trifluoroacetic acid, preferably trifluoroacetic acid.

[0020] Furthermore, in the above step C, the molar ratio of the base to 3,4-difluoro-2-hydroxyphenylacetic acid is 1.2-2.3:1, and preferably the molar ratio of the base to 3,4-difluoro-2-hydroxyphenylacetic acid is 2.2:1.

[0021] Furthermore, in the above step C, the base is sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.

[0022] Furthermore, in the above step C, the methylating agent is dimethyl sulfate or methyl iodide, preferably dimethyl sulfate.

[0023] Furthermore, in the above step C, the molar ratio of the methylating agent to 3,4-difluoro-2-hydroxyphenylacetic acid is 1.2-1.5:1.

[0024] Compared with the synthesis method reported in the literature, the present invention has the following beneficial effects:

[0025] 1. Sulfonic acid resin is used to catalyze 2,3-difluorophenol and 3,4-dihydropyran to generate the first intermediate. After the reaction is completed, the sulfonic acid resin can be completely recovered and reused. Excess 3,4-dihydropyran is recovered by vacuum distillation with an almost quantitative yield. The hydroxyl group is directly methylated with dimethyl sulfate in the presence of a base, which has good economic benefits.

[0026] 2. Using THP as the hydroxyl protecting group of 2,3-difluorophenol greatly improves the yield compared with direct methylation of 2,3-difluorophenol and then similar steps. The inferred mechanism is that the electrons on the phenyl ether oxygen atom and the pyran oxygen atom in 2-(2,3-difluorophenoxy)pyran jointly complex with metallic lithium, thereby positioning it preferentially in the ortho position of the hydroxyl group rather than the ortho position of fluorine, and the single-step yield reaches 83%.

[0027] 3. This process avoids expensive palladium catalysts, the raw materials are easily available in the market, the process is simple, safe and stable, and is suitable for industrial scale expansion. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The HNMR spectrum of 3,4-difluoro-2-methoxyphenylacetic acid was obtained for Example 4. Specific embodiments

[0029] The present invention is further described below by specific examples. These embodiments should be understood to be only used to illustrate the present invention and not to limit the scope of protection of the present invention. After reading the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0030] Example 1

[0031]

[0032] Under nitrogen protection, 16.0 g (0.19 mol) of 3,4-dihydropyran, 13.0 g (0.1 mol) of 2,3-difluorophenol and 1.1 g of Amberlyst-15 sulfonic acid resin were mixed and reacted at room temperature for 4 hours. The sulfonic acid resin catalyst was filtered and recovered. The filtrate was distilled under reduced pressure to recover the excess 3,4-dihydropyran. The residue was a yellow oily liquid product 2-(2,3-difluorophenoxy)pyran 21.4 g, with a yield of 100%, HPLC 99.3%. LC-MS [M+H] + =215.3.

[0033] Example 2

[0034]

[0035] Under nitrogen protection, 21.4 g (0.1 mol) of 2-(2,3-difluorophenoxy)pyran and 75 mL of tetrahydrofuran were mixed, the temperature was controlled below -20°C, 65.6 mL of 1.6 M n-butyl lithium solution was slowly added dropwise, and after the addition was complete, 25.4 g (0.13 mol) of tert-butyl 2-bromoacetate was added, and the reaction was continued for 4 hours. The reaction system was controlled to be below 10°C, and 50% trifluoroacetic acid aqueous solution was added for hydrolysis, and the pH was controlled to be less than 1. Then, the reaction system was heated to 60°C for 2 hours, cooled to room temperature, and the organic layer was distilled under reduced pressure to obtain a crude product, and then MTBE / ethyl acetate / cyclohexane (v / v / v=5 / 2 / 12) was used for pulping to obtain 15.6 g of 3,4-difluoro-2-hydroxyphenylacetic acid, with a yield of 83% (5% isomer impurities calculated by NMR external standard conversion of mother liquor), and HPLC 99.1%. LC-MS [M+H] + =189.2

[0036] Comparative Examples

[0037]

[0038] Under nitrogen protection, 14.4 g (0.1 mol) of 2,3-difluoroanisole and 75 mL of tetrahydrofuran were mixed, the temperature was controlled below -20 ° C, 65.6 mL of 1.6 M n-butyl lithium solution was slowly added dropwise, and after the addition was completed, 25.4 g (0.13 mol) of tert-butyl 2-bromoacetate was added, and the reaction was carried out for 4 hours. The reaction system was controlled to be below 10 ° C, and 50% trifluoroacetic acid aqueous solution was added for hydrolysis, and the pH was controlled to be <1. Then the temperature of the reaction system was raised to 60 ° C for 2 hours, and the reaction was cooled to room temperature for stratification. The organic layer contained 11.7 g of 3,4-difluoro-2-methoxyphenylacetic acid according to the external standard, and the yield was 58%.

[0039] Example 3

[0040]

[0041] Under nitrogen protection, 21.4 g (0.1 mol) of 2-(2,3-difluorophenoxy)pyran and 75 mL of 2-methyltetrahydrofuran were mixed, the temperature was controlled below -20°C, 50 mL of 2.2 M n-hexyllithium solution was slowly added dropwise, and after the addition was complete, 27.3 g (0.14 mol) of tert-butyl 2-bromoacetate was added, and the reaction was carried out for 5 hours. The reaction system was controlled to be below 10°C, 6N hydrochloric acid was added for hydrolysis, and the pH was controlled to be <1. The reaction system was then heated to 65°C for reaction for 3 hours, cooled to room temperature, and the organic layer was distilled under reduced pressure to obtain a crude product, which was then slurried with MTBE / ethyl acetate / cyclohexane (v / v / v=5 / 2 / 12) to obtain 14.3 g of 3,4-difluoro-2-hydroxyphenylacetic acid with a yield of 76% (7% isomeric impurities calculated by NMR external standard of mother liquor), and HPLC 99.1%.

[0042] Example 4

[0043]

[0044] Under nitrogen protection, 18.8 g (0.1 mol) of 3,4-difluoro-2-hydroxyphenylacetic acid, 50 mL of acetone and 22.0 g of sodium hydroxide aqueous solution (40%) were mixed and stirred at room temperature for 1 hour, and then 17.7 g (0.14 mol) of dimethyl sulfate was added, the temperature was raised to reflux, the reaction was carried out for 6 hours, the temperature was lowered to room temperature, 50 mL of water was added, and then 100 mL of dichloromethane was added, the aqueous layer was separated, 2N hydrochloric acid was added to adjust the pH to 1-2, and then 100 mL of dichloromethane was added to extract twice, and the organic layer was distilled under reduced pressure to obtain an off-white solid crude product, and MTBE / n-heptane (v / v=2 / 5) was used to beat the pulp to obtain 17.2 g of 3,4-difluoro-2-methoxyphenylacetic acid, a white solid, with a yield of 85%, and HPLC 99.3%. 1HNMR (400MHz, DMSO-d6): 12.41 (s, 1H), 7.16-7.02 (m, 2H), 3.87 (d, J = 1.8Hz, 3H), 3.57 (m, 2H).

[0045] Example 5

[0046]

[0047] 18.8 g (0.1 mol) of 3,4-difluoro-2-hydroxyphenylacetic acid, 60 mL of tetrahydrofuran solvent and 16.9 g of sodium carbonate were mixed and stirred at room temperature for 1 hour, then 19.9 g (0.14 mol) of methyl iodide was added, the temperature was raised to reflux, the reaction was carried out for 10 hours, the temperature was lowered to room temperature, 50 mL of water was added, and then 100 mL of dichloromethane was added. 2N hydrochloric acid was added to the separated aqueous layer to adjust the pH to 1-2, and then 100 mL of dichloromethane was added to extract twice, the layers were separated, and the organic layer was distilled under reduced pressure to obtain an off-white solid crude product. After slurrying with MTBE / n-heptane (v / v=2 / 5), 15.8 g of 3,4-difluoro-2-methoxyphenylacetic acid was obtained as a white solid with a yield of 78% and an HPLC of 99.2%.

[0048] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing 3,4-difluoro-2-methoxyphenylacetic acid, the reaction equation is expressed as follows: The steps include: A. 3,4-dihydropyran and 2,3-difluorophenol are reacted in the presence of a sulfonic acid resin to generate 2-(2,3-difluorophenoxy)pyran; B. Mix 2-(2,3-difluorophenoxy)pyran and an organic solvent, add an alkyl lithium reagent at low temperature, then add tert-butyl 2-bromoacetate to react, and obtain 3,4-difluoro-2-hydroxyphenylacetic acid after acid hydrolysis; C. Mix 3,4-difluoro-2-hydroxyphenylacetic acid and an organic solvent, and react in the presence of a base and a methylating agent to obtain 3,4-difluoro-2-methoxyphenylacetic acid.

2. The method for preparing 3,4-difluoro-2-methoxyphenylacetic acid according to claim 1, characterized in that: In step A, the molar ratio of 2,3-difluorophenol to 3,4-dihydropyran is 1:1-4.

5.

3. The method for preparing 3,4-difluoro-2-methoxyphenylacetic acid according to claim 1, characterized in that: In step A, the weight ratio of 2,3-difluorophenol to sulfonic acid resin is 1:0.05-0.

1.

4. The method for preparing 3,4-difluoro-2-methoxyphenylacetic acid according to claim 1, characterized in that: In step B, the molar ratio of the alkyl lithium, 2-(2,3-difluorophenoxy)pyran and tert-butyl 2-bromoacetate is 1-1.1:1:1.1-1.

4.

5. The method for preparing 3,4-difluoro-2-methoxyphenylacetic acid according to claim 1, characterized in that: In step B, the organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran or cyclopentyl methyl ether, preferably tetrahydrofuran.

6. The method for preparing 3,4-difluoro-2-methoxyphenylacetic acid according to claim 1, characterized in that: In step B, the lithium reagent is n-butyllithium or n-hexyllithium.

7. The method for preparing 3,4-difluoro-2-methoxyphenylacetic acid according to claim 1, characterized in that: In step B, the acid is hydrochloric acid, sulfuric acid or trifluoroacetic acid, preferably trifluoroacetic acid.

8. The method for preparing 3,4-difluoro-2-methoxyphenylacetic acid according to claim 1, characterized in that: In step C, the molar ratio of the base to 3,4-difluoro-2-hydroxyphenylacetic acid is 1.2-2.3:1, and preferably the molar ratio of the base to 3,4-difluoro-2-hydroxyphenylacetic acid is 2.2:

1.

9. The method for preparing 3,4-difluoro-2-methoxyphenylacetic acid according to claim 1, characterized in that: In step C, the base is sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide, preferably sodium hydroxide; the methylating agent is dimethyl sulfate or methyl iodide, preferably dimethyl sulfate.

10. The method for preparing 3,4-difluoro-2-methoxyphenylacetic acid according to claim 1, characterized in that: In step C, the molar ratio of the methylating agent to 3,4-difluoro-2-hydroxyphenylacetic acid is 1.2-1.5:1.

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