CN108239054B

CN108239054B - Preparation method of benzofuran-3-carboxylic acid

Info

Publication number: CN108239054B
Application number: CN201611223263.4A
Authority: CN
Inventors: 许刘华; 王育盛; 邓招; 黄鲁宁; 陈茜; 陶安平; 顾虹
Original assignee: Shanghai Aobo Biomedical Co ltd
Current assignee: Shanghai Aobo Biomedical Co ltd
Priority date: 2016-12-27
Filing date: 2016-12-27
Publication date: 2022-01-21
Anticipated expiration: 2036-12-27
Also published as: CN108239054A

Abstract

The invention relates to a preparation method of benzofuran-3-carboxylic acid, which takes an intermediate 1 as a raw material, and prepares the benzofuran-3-carboxylic acid through ring opening and ring closing under an alkaline condition. The method has the characteristics of mild reaction conditions, simple operation and high yieldAnd is suitable for industrial production.

Description

Preparation method of benzofuran-3-carboxylic acid

Technical Field

The invention relates to a preparation method of benzofuran-3-carboxylic acid

Technical Field

Benzofuran-3-carboxylic acid is an important chemical intermediate, and the structural formula of the intermediate is as follows:

the literature reports a number of synthetic methods for benzofuran 3-carboxylic acids, but the transformation is generally carried out using 3-substituted benzofurans. Lu Pengfei et al report that dibenzofuran-2, 3-dicarboxylic acid is selectively decarboxylated to give 3-carboxylic acid (method 1), in which 2, 3-dibenzofuran dicarboxylic acid is difficult to synthesize, the cost is high, the decarboxylation conditions are severe, and the yield is low. Benassi Rois et al report the use of 3-formylbenzofuran oxidation (method 2), which uses expensive silver oxide, is not readily available in raw materials, and has low yield. Park Chul Min and the like adopt 3-bromobenzofuran as a raw material, the 3-position of the benzofuran is changed into negative ions by using n-butyl lithium at the temperature of minus 78 ℃, then the benzofuran reacts with carbon dioxide, and the product is obtained after quenching (method 3), the reaction needs low temperature, and a flammable reagent, namely the n-butyl lithium, is used, so that the cost is high, and the method is not suitable for industrial production.

From these literature methods, raw materials are not easily available, the price is high, the reaction conditions are harsh, the reaction yield is low, and the industrial scale-up is not suitable. The authors of the present invention have invented a method for synthesizing a target product by using o-hydroxyphenylacetic acid as a raw material, performing condensation, hydrolysis, ring opening and then ring closing, wherein the whole operation adopts a one-pot method, and the method has the advantages of easily available raw materials, mild reaction conditions, high yield and convenient post-treatment.

Disclosure of Invention

The invention adopts the intermediate 1 as a raw material to synthesize benzofuran-3-carboxylic acid, adopts o-hydroxyphenylacetic acid reported in literature as a raw material, and carries out heating condensation under the conditions of anhydride and orthoformate to obtain the intermediate 1, and the intermediate is directly subjected to alkaline hydrolysis, ring opening and ring closing to prepare the benzofuran-3-carboxylic acid without separation and purification. The method has the characteristics of two-step reaction, namely one-pot reaction, simple operation, high yield and suitability for industrial production.

The synthetic route for this reaction is as follows:

the specific operation steps are as follows:

reacting o-hydroxyphenylacetic acid, anhydride and orthoformate to obtain an intermediate 1, evaporating the solvent and excessive reagents under reduced pressure, adding a proper solvent, controlling the temperature of a reaction solution within a certain range, dropwise adding alkali, heating to react after dropwise adding, adding acid to adjust the pH value, precipitating a large amount of solid, filtering, washing and drying to obtain benzofuran-3-carboxylic acid with the purity of over 98%. The total yield (calculated by o-hydroxyphenylacetic acid) is more than 90 percent.

Wherein the solvent is ethanol, methanol, tetrahydrofuran or their mixed solvent with water; ethanol, methanol, and ethanol/water and methanol/water mixed solvents are preferred. The base to be added here includes hydroxides, carbonates, alkali metal salts of alkoxyls and the like, and is preferably sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate. The dropping temperature is-10-30 deg.C, preferably-5-10 deg.C. The pH is adjusted to 1-5, preferably 2-3.

Detailed description of the invention

The following examples illustrate the invention but are not to be construed as limiting it.

Example 1:

152 g of o-hydroxyphenylacetic acid, 500 g of acetic anhydride and 250 g of trimethyl orthoformate are added into a reaction bottle, and the temperature is raised to 80-100 ℃ for reaction for 6 hours. The solvent was evaporated under reduced pressure to give a yellow solid. Adding 500 g of methanol into the solid, stirring and dissolving, controlling the temperature at 0-10 ℃, dropwise adding 180 g of 30% sodium hydroxide solution, heating to 50-60 ℃ after dropwise adding, and reacting for 3-6 hours. And (3) recovering methanol under reduced pressure, adding 300 g of drinking water into the residue, controlling the temperature of the solution to be below 30 ℃, dropwise adding 160 g of 30% hydrochloric acid to adjust the pH value to be 1-2, cooling to 0-10 ℃, crystallizing for 3 hours, filtering, washing the solid with water, and drying in vacuum to obtain 158 g of white-like solid with the yield of 97.5%.

Example 2:

152 g of o-hydroxyphenylacetic acid, 500 g of acetic anhydride and 250 g of trimethyl orthoformate are added into a reaction bottle, and the temperature is raised to 80-100 ℃ for reaction for 6 hours. The solvent was evaporated under reduced pressure to give a yellow solid. Adding 300 g of 95% ethanol into the solid, controlling the temperature at 10-20 ℃, dropwise adding 500 g of 20% sodium carbonate solution, heating to 80-100 ℃ after dropwise adding, and reacting for 16 hours. Cooling to below 30 ℃, dropping 230 g of 30% hydrochloric acid to adjust the pH value to 3-4, cooling to 10-20 ℃, crystallizing for 3 hours, filtering, washing solid with water, and drying in vacuum to obtain 149 g of white solid with the yield of 92.0%.

Example 3:

152 g of o-hydroxyphenylacetic acid, 500 g of acetic anhydride and 250 g of trimethyl orthoformate are added into a reaction bottle, and the temperature is raised to 80-100 ℃ for reaction for 6 hours. The solvent was evaporated under reduced pressure to give a yellow solid. Adding 500 g of anhydrous methanol into the solid, dropwise adding 300 g of 20% sodium methoxide solution at the temperature of-5-0 ℃, and keeping the temperature for reaction for 5 hours after dropwise adding. Dropping 300 g of drinking water, continuing to stir at 30-40 ℃ for 6 hours, recovering methanol under reduced pressure, adding 500 g of drinking water into the residue, cooling to below 30 ℃, dropping 140 g of 30% hydrochloric acid to adjust the pH value of 2-3, cooling for crystallization, filtering, washing solid with water, and drying in vacuum to obtain 156 g of white-like solid with the yield of 96.5%.

Example 4:

152 g of o-hydroxyphenylacetic acid, 500 g of acetic anhydride and 250 g of trimethyl orthoformate are added into a reaction bottle, and the temperature is raised to 80-100 ℃ for reaction for 6 hours. The solvent was evaporated under reduced pressure to give a yellow solid. Adding 500 g of absolute ethyl alcohol into the solid, dropwise adding 300 g of 25% sodium ethoxide solution at the temperature of 0-5 ℃, and keeping the temperature for reaction for 5 hours after the dropwise adding is finished. Dropping 300 g of drinking water, continuing to stir at 20-30 ℃ for 8 hours, recovering ethanol under reduced pressure, adding 500 g of drinking water into the residue, cooling to below 30 ℃, dropping 140 g of 30% hydrochloric acid to adjust the pH value to 4-5, cooling, crystallizing, filtering, washing solid with water, and drying in vacuum to obtain 154 g of white-like solid with the yield of 96%.

Example 5:

152 g of o-hydroxyphenylacetic acid, 500 g of acetic anhydride and 250 g of trimethyl orthoformate are added into a reaction bottle, and the temperature is raised to 80-100 ℃ for reaction for 6 hours. The solvent was evaporated under reduced pressure to give a yellow solid. Adding 500 g of tetrahydrofuran into the solid, dropwise adding 300 g of 20% potassium hydroxide solution at the temperature of 0-10 ℃, and keeping the temperature for reaction for 6 hours after dropwise adding. And continuously heating to 40-50 ℃, stirring for reaction for 6 hours, recovering tetrahydrofuran under reduced pressure, adding 500 g of drinking water into the residue, cooling to below 30 ℃, dropwise adding about 150 g of 30% hydrochloric acid to adjust the pH value to be 2-3, cooling for crystallization, filtering, washing solid with water, and drying in vacuum to obtain 150 g of off-white solid with the yield of 92.6%.

Claims

1. Method for preparing benzofuran-3-carboxylic acid by taking intermediate 1 as raw material

The method is characterized in that: the method comprises the following steps:

1) dropwise adding a proper base into the intermediate 1 at a proper temperature in a proper solvent, and then heating for reaction;

2) after the reaction is finished, adjusting the pH value of the reaction solution, filtering and drying to obtain a product;

in the step 1), the suitable solvent is ethanol, methanol, tetrahydrofuran and a mixed solvent of the ethanol, the methanol and the tetrahydrofuran and water;

in the step 1), the appropriate alkali is sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate and potassium carbonate;

in the step 1), the proper temperature is-10-30 ℃;

in the step 1), the temperature of the heating reaction is 50-100 ℃;

in the step 2), the pH value is 1-5.

2. The method of claim 1, wherein: in step 1), the suitable solvent is ethanol, methanol, and ethanol/water and methanol/water mixed solvent.

3. The method of claim 1, wherein: in step 1), the suitable temperature is-5 to 10 ℃.

4. The method of claim 1, wherein: in the step 2), the pH value is 2-3.