Preparation method of bifendate intermediate

Abstract

The invention belongs to the technical field of medical intermediates, and particularly discloses a preparation method of a bifendate intermediate, the intermediate is methyl 3, 4-dihydroxy-5-methoxybenzoate, and the preparation method comprises the following steps: S1, mixing gallic acid with methanol, and heating for reaction to prepare methyl gallate; after the reaction, distilling to remove methanol; s2, adding borax and water into the material obtained in S1, uniformly mixing, and then adding liquid caustic soda to adjust the pH value to 8-9; the preparation method comprises the following steps of: adding dimethyl sulfate and caustic soda liquid into a reaction kettle, dropwise adding dimethyl sulfate and caustic soda liquid at the same time for mixing reaction, adding acid for acidification after the reaction is finished to adjust the pH value to 2-3, adding DMF for extraction, performing rotary evaporation on the obtained organic phase to remove DMF, and further refining to obtain methyl 3, 4-dihydroxy-5-methoxybenzoate. According to the invention, esterification and etherification are integrated into the same reactor, and the yield and purity of the product can be effectively ensured.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediates, and particularly relates to a method for preparing a biphenyl diester intermediate. Background Art

[0002] Bifendate (4,4'-dimethoxy-5,6,5',6'-dimethoxy-2,2'-dicarboxylic acid methyl biphenyl) is a drug that has significant effects in treating hepatitis and reducing serum transaminase levels. It has a therapeutic effect on liver diseases, especially viral hepatitis and drug-induced liver damage, can protect liver cells, enhance the liver's detoxification function, and significantly reduce serum transaminase levels. It has low toxicity and few side effects.

[0003] At present, the synthesis process of biphenyl diester mainly uses gallic acid as raw material, and biphenyl diester is obtained through esterification, etherification, bromination, cyclization, condensation and purification. The yield and purity of the biphenyl diester intermediate 3,4-dihydroxy-5-methoxybenzoic acid methyl ester after esterification and etherification have a great influence on the yield and purity of the finished biphenyl diester. Summary of the invention

[0004] The invention provides a method for preparing a biphenyl diester intermediate, wherein esterification and etherification are integrated into the same reactor for carrying out, and the yield and purity of the product can be effectively guaranteed.

[0005] In order to achieve the above objectives, the present invention adopts the following technical scheme: a method for preparing a biphenyl diester intermediate, wherein the biphenyl diester intermediate is methyl 3,4-dihydroxy-5-methoxybenzoate, and the preparation thereof comprises the following steps: S1, mixing gallic acid and methanol, heating and reacting to prepare methyl gallate; and distilling and removing methanol after the reaction; Borax and water are added to the materials obtained from S2 and S1, and then liquid alkali is added to adjust the pH to 8-9; dimethyl sulfate and liquid alkali are then added dropwise to react, and after the reaction is completed, acid is added to adjust the pH to 2-3, and DMF is added for extraction. The obtained organic phase is subjected to rotary evaporation to remove DMF, and further refined to obtain methyl 3,4-dihydroxy-5-methoxybenzoate.

[0006] Furthermore, the mass ratio of gallic acid to methanol is 1:3~4; the reaction temperature is 50-70°C, and the reaction time is 1-3h.

[0007] Furthermore, before the reaction, concentrated sulfuric acid as a catalyst is added in an amount of 15-30% of the mass of gallic acid.

[0008] Furthermore, after the reaction in S1 is completed, water and / or liquid alkali are added, and then the temperature is increased to distill and remove methanol, and the obtained distillation residue is directly used in S2 in an amount ratio of borax and dimethyl sulfate to raw material gallic acid of 0.4~0.5:0.7~1:1.

[0009] Furthermore, when the dimethyl sulfate and liquid alkali in S2 are mixed and added dropwise, the pH of the reaction system is controlled to be maintained at 8-9; and the reaction time is 1.5-3h.

[0010] Furthermore, the acid used for acidification may be hydrochloric acid, nitric acid and / or sulfuric acid.

[0011] Furthermore, during DMF extraction, the amount added is 2-4 times the mass of gallic acid; and the number of extractions is 2-3 times. Furthermore, when DMF was removed by rotary evaporation, the vacuum degree of the system was controlled to be -0.093 MPa.

[0012] Furthermore, during the refining, a solvent is added to heat and dissolve the concentrated material of the rotary evaporation, and then cooled and crystallized. The solid obtained by filtration is methyl 3,4-dihydroxy-5-methoxybenzoate.

[0013] Furthermore, the solvent is one or more of tetrachloroethylene, chloroform and dichloromethane.

[0014] The present invention has the following beneficial effects: After the esterification reaction is completed and before the etherification reaction is carried out, a little water and / or liquid alkali is added to continue distillation, and the temperature is kept above 96°C to remove residual methanol as much as possible to avoid side reactions in subsequent reactions, which is helpful to improve the yield and purity of the intermediate. At the same time, during the etherification reaction, borax is first added for mixing, alkali is added to adjust the pH, and then dimethyl sulfate and liquid alkali are added dropwise simultaneously, which can stabilize the pH of the reaction system and reduce the appearance of by-products; after the reaction is completed, DMF is used for extraction, which has good extraction effect, low volatility, and is environmentally friendly. DETAILED DESCRIPTION

[0015] The present invention provides a method for preparing a biphenyl diester intermediate 3,4-dihydroxy-5-methoxybenzoic acid methyl ester, comprising the following steps: S1, mixing gallic acid and methanol, heating and reacting to prepare methyl gallate; and distilling and removing methanol after the reaction; Borax and water are added to the materials obtained from S2 and S1, and then liquid alkali is added to adjust the pH to 8-9; dimethyl sulfate and liquid alkali are then added dropwise to react, and after the reaction is completed, acid is added to adjust the pH to 2-3, and DMF is added for extraction. The obtained organic phase is subjected to rotary evaporation to remove DMF, and further refined to obtain methyl 3,4-dihydroxy-5-methoxybenzoate.

[0016] In the preferred embodiment, the mass ratio of gallic acid to methanol is 1:3-4; the reaction temperature is 50-70°C, and the reaction time is 1-3h.

[0017] In a more preferred embodiment, concentrated sulfuric acid as a catalyst is added before the reaction, and the amount added is 15-30% of the mass of gallic acid.

[0018] In some embodiments, water and / or liquid alkali are added after the reaction in S1 is completed, and then the temperature is increased to distill and remove methanol, and the obtained distillation residue is directly used in S2 in an amount ratio of borax and dimethyl sulfate to raw material gallic acid of 0.4~0.5:0.7~1:1.

[0019] In a preferred embodiment, when dimethyl sulfate and liquid alkali are mixed and added dropwise in S2, the pH of the reaction system is controlled to be maintained at 8-9; the reaction time is 1.5-3 hours. More preferably, the acid used for acidification can be hydrochloric acid, nitric acid and / or sulfuric acid.

[0020] In some embodiments, when DMF is extracted, the amount added is 2-4 times the mass of gallic acid; the number of extractions is 2-3 times. When DMF is removed by rotary evaporation, the vacuum degree of the system is controlled to be -0.093MPa. When refining, a solvent is added to heat and dissolve the concentrated material by rotary evaporation, and then cooled and crystallized. The solid obtained by filtration is methyl 3,4-dihydroxy-5-methoxybenzoate.

[0021] In a preferred embodiment, the solvent is one or more of tetrachloroethylene, chloroform, and dichloromethane.

[0022] The present invention is described in detail below in conjunction with specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and a specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0023] Example 1 Preparation method of biphenyl diester intermediate 3,4-dihydroxy-5-methoxybenzoic acid methyl ester (1) Add 20 g of gallic acid and 60 g of methanol into a 500 ml four-necked flask, stir, heat to 30 °C, add 4 g of concentrated sulfuric acid dropwise, keep the temperature at 50 °C, react for 1 h, and evaporate the methanol at above 65 °C.

[0024] (2) Add 10 g of borax and 180 g of pure water, stir, adjust the pH to 8 with liquid alkali, add liquid alkali and 16 g of dimethyl sulfate dropwise, keep the reaction pH in the range of 8-9, stir for 1.5 h, add concentrated sulfuric acid to adjust the pH, control the pH in the flask at 2-3, add DMF as an extractant and extract twice, 40 g each time, the extraction time is within 15 min, let stand and separate the oil phase, evaporate the DMF and chloroform at -0.093 MPa, add 50 g of dichloroethane after the kettle becomes a paste, raise the temperature to 50 ° C, beat for 20 min, cool to below 10 ° C, filter and dry the obtained solid phase, and obtain 17.88 g of methyl 3,4-dihydroxy-5-methoxybenzoate; the yield is 89.4%; the purity is 78.4% when tested by high performance liquid chromatography.

[0025] Example 2 Preparation method of biphenyl diester intermediate 3,4-dihydroxy-5-methoxybenzoic acid methyl ester (1) Add 20 g of gallic acid and 60 g of methanol to a 500 ml four-necked flask, stir, raise the temperature to 30 °C, add 4 g of concentrated sulfuric acid dropwise, keep the temperature at 60 °C, react for 1.5 h, evaporate the methanol, add 2 g of pure water, heat to above 96 °C and distill for 10 min.

[0026] (2) Add 10g of borax and 180g of pure water, stir, adjust the pH to 8.5 with liquid alkali, add liquid alkali and 16g of dimethyl sulfate dropwise, keep the reaction pH in the range of 8-9, stir for 1.5h, add concentrated sulfuric acid to adjust the pH, control the pH in the flask in the range of 2-3, add DMF as an extractant to extract twice, 40g each time, the extraction time is within 20min, stand and separate the oil phase, evaporate DMF at -0.093MPa, add 50g of dichloroethane after the kettle becomes a paste, heat to 55℃, beat for 30min, cool to below 10℃, filter and dry the obtained solid phase, and obtain 18.46g of methyl 3,4-dihydroxy-5-methoxybenzoate. The yield is 92.3% and the purity is 82.4%.

[0027] Example 3 Preparation method of biphenyl diester intermediate 3,4-dihydroxy-5-methoxybenzoic acid methyl ester (1) Add 20 g of gallic acid and 60 g of methanol to a 500 ml four-necked flask, stir, heat to 40 °C, add 4 g of concentrated sulfuric acid dropwise, keep the temperature at 60 °C, react for 2 h, evaporate the methanol, add 1 g of water and 1 g of liquid alkali, heat to above 96 °C and distill for 10 min.

[0028] (2) Add 10g of borax and 180g of pure water, stir, adjust pH to 9 with liquid alkali, add liquid alkali and 16g of dimethyl sulfate dropwise, keep the reaction pH in the range of 8-9, stir for 2h, add concentrated sulfuric acid to adjust pH, control the pH in the flask in the range of 2-3, add DMF as an extractant to extract twice, 40g each time, the extraction time is within 20min, stand and separate the oil phase, evaporate DMF at -0.093MPa, add 50g of dichloroethane after the kettle becomes a paste, heat to 55℃, beat for 30min, cool to below 10℃, filter and dry the obtained solid phase, and obtain 18.78g of methyl 3,4-dihydroxy-5-methoxybenzoate. The yield is 93.9% and the purity is 85.6%.

[0029] Example 4 Preparation method of biphenyl diester intermediate 3,4-dihydroxy-5-methoxybenzoic acid methyl ester (1) Add 20 g of gallic acid and 70 g of methanol to a 500 ml four-necked flask, stir, heat to 35 °C, add 4 g of concentrated sulfuric acid dropwise, keep the temperature at 50 °C, react for 1 h, evaporate the methanol, add 1 g of water and 1 g of liquid alkali, heat to above 96 °C and distill for 10 min.

[0030] (2) Add 9g of borax and 200g of pure water, stir, adjust pH to 9 with liquid alkali, add liquid alkali and 16g of dimethyl sulfate dropwise, keep the reaction pH in the range of 8-9, stir for 2h, add concentrated hydrochloric acid to adjust pH, control the pH in the flask in the range of 2-3, add DMF as an extractant to extract twice, 40g each time, the extraction time is within 20min, stand and separate the oil phase, evaporate DMF at -0.093MPa, add 50g of trichloroethane after the kettle becomes a paste, heat to 55℃, beat for 30min, cool to below 10℃, filter and dry the obtained solid phase, and obtain 18.24g of methyl 3,4-dihydroxy-5-methoxybenzoate. The yield is 91.2% and the purity is 80.5%.

[0031] Example 5 Preparation method of biphenyl diester intermediate 3,4-dihydroxy-5-methoxybenzoic acid methyl ester (1) Add 20 g of gallic acid and 80 g of methanol to a 500 ml four-necked flask, stir, heat to 35 °C, add 6 g of concentrated sulfuric acid dropwise, keep the temperature at 50 °C, react for 3 h, evaporate the methanol, add 1 g of water and 1 g of liquid alkali, heat to above 96 °C and distill for 10 min.

[0032] (2) Add 8g of borax and 240g of pure water, stir, adjust pH to 9 with liquid alkali, drop liquid alkali and 16g of dimethyl sulfate, keep the reaction pH in the range of 8-9, stir for 2h, add concentrated nitric acid to adjust pH, control the pH in the flask in the range of 2-3, add DMF as an extractant to extract twice, 40g each time, the extraction time is within 20min, stand and separate the oil phase, evaporate DMF at -0.093MPa, add 50g of tetrachloroethylene after the kettle becomes a paste, heat to 65℃, beat for 30min, cool to below 10℃, filter and dry the obtained solid phase, and obtain 18.06g of methyl 3,4-dihydroxy-5-methoxybenzoate. The yield is 90.3% and the purity is 82.1%.

[0033] Example 6 Based on Example 3, the only difference is that chloroform is used as the solvent during extraction. The final yield of 3,4-dihydroxy-5-methoxybenzoic acid methyl ester is 90.8% and the purity is 82.6%.

[0034] The above embodiments describe the preferred implementation of the present invention, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing a biphenyl diester intermediate, characterized in that: The biphenyl diester intermediate is 3,4-dihydroxy-5-methoxybenzoic acid methyl ester, and its preparation comprises the following steps: S1, mixing gallic acid and methanol, heating and reacting to prepare methyl gallate; and distilling and removing methanol after the reaction; Borax and water are added to the materials obtained from S2 and S1, and then liquid alkali is added to adjust the pH to 8-9; dimethyl sulfate and liquid alkali are then added dropwise to react, and after the reaction is completed, acid is added to adjust the pH to 2-3, and DMF is added for extraction. The obtained organic phase is subjected to rotary evaporation to remove DMF, and further refined to obtain methyl 3,4-dihydroxy-5-methoxybenzoate.

2. The preparation method according to claim 1, characterized in that: The mass ratio of gallic acid to methanol is 1:3~4; the reaction temperature is 50-70°C, and the reaction time is 1-3h.

3. The preparation method according to claim 2, characterized in that: Before the reaction, concentrated sulfuric acid is added as a catalyst in an amount of 15-30% of the mass of gallic acid.

4. The preparation method according to claim 1, characterized in that: After the reaction in S1 is completed, water and / or liquid alkali are added, and then the temperature is increased to distill and remove methanol. The obtained distillation residue is directly used in S2. The dosage ratio of borax and dimethyl sulfate to raw material gallic acid is 0.4~0.5:0.7~1:

1.

5. The preparation method according to claim 1, characterized in that: When dimethyl sulfate and liquid alkali are mixed and added dropwise in S2, the pH of the reaction system is controlled to be maintained at 8-9; the reaction time is 1.5-3h.

6. The preparation method according to claim 1, characterized in that: The acid used for acidification may be hydrochloric acid, nitric acid and / or sulfuric acid.

7. The preparation method according to claim 1, characterized in that: When DMF is extracted, the amount added is 2-4 times the mass of gallic acid; the number of extractions is 2-3 times.

8. The preparation method according to claim 1, characterized in that: When DMF was removed by rotary evaporation, the vacuum degree of the system was controlled to be -0.093 MPa.

9. The preparation method according to claim 1, characterized in that: During the refining process, a solvent is added to heat and dissolve the concentrated material from the rotary evaporation, and then cooled and crystallized. The solid obtained by filtration is methyl 3,4-dihydroxy-5-methoxybenzoate.

10. The preparation method according to claim 1, characterized in that: The solvent is one or more of tetrachloroethylene, chloroform and dichloromethane.