A method for synthesizing p-hydroxymandelic acid

Abstract

The application belongs to the technical field of fine chemical intermediate synthesis, and particularly relates to a synthesis method of p-hydroxymandelic acid, which comprises the following steps: under the atmosphere of inert gas, a catalytic reaction is carried out on a reaction system comprising a water solution of phenol, glyoxylic acid, a catalyst and an alkali metal hydroxide; after the reaction is completed, post-treatment is carried out, and the p-hydroxymandelic acid is obtained; the catalyst is a copper-zinc bimetallic oxide catalyst; and the application reduces the impurity content, and improves the yield and purity.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical intermediate synthesis technology, specifically relating to a method for synthesizing p-hydroxymandelic acid. Background Technology

[0002] Hydroxymandelic acid has significant applications in pharmaceuticals, biochemical research, and organic synthesis. It is an important intermediate in pharmaceuticals such as atenolol and amoxicillin, as well as in fragrances and pesticides. For example, it is used to prepare p-hydroxyphenylacetic acid, a synthetic precursor for the selective β1-receptor antagonist atenolol. Hydroxymandelic acid can also be used to prepare p-hydroxybenzaldehyde, an important intermediate in the pharmaceutical and fragrance industries.

[0003] The main methods for synthesizing p-hydroxymandelic acid include: 1) phenol and glyoxylic acid method; 2) condensation hydrolysis method; 3) cyanohydrin hydrolysis method; 4) p-aminomandelic acid hydrolysis method; and 5) bioenzymatic method. Currently, the phenol-glyoxylic acid method is widely used for synthesizing p-hydroxymandelic acid. However, this method still faces challenges such as the high amount of ortho-hydroxymandelic acid byproducts, the tendency of glyoxylic acid to undergo the Cannizzaro reaction under strongly alkaline conditions, and the easy oxidation and discoloration of phenol under alkaline conditions. Therefore, the continuous development of efficient, low-cost, and green catalytic synthesis processes for hydroxymandelic acid is of great significance.

[0004] Patent application publication number CN113121323A discloses a method for preparing p-hydroxybenzaldehyde, using aluminum salt and / or zinc salt as catalysts to condense phenol with glyoxylic acid under alkaline conditions to obtain 4-hydroxymandelic acid. The method produces a high amount of byproducts, and the product yield and purity need further improvement. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a method for synthesizing p-hydroxymandelic acid, which reduces impurity content and improves yield and purity.

[0006] This invention provides a method for synthesizing p-hydroxymandelic acid. Under an inert gas atmosphere, an aqueous reaction system containing phenol, glyoxylic acid, a catalyst, and an alkali metal hydroxide is subjected to a catalytic reaction. After the reaction, post-treatment is performed to obtain p-hydroxymandelic acid. The catalyst is a copper-zinc bimetallic oxide catalyst.

[0007] Preferably, the catalyst is prepared by mixing the support with an aqueous solution containing copper salt and zinc salt, drying, and then calcining to obtain the catalyst.

[0008] Preferably, in the method for preparing the catalyst, the support is a molecular sieve, the copper salt is copper sulfate, copper nitrate, copper chloride, copper phosphate or their hydrates, the zinc salt is zinc sulfate, zinc nitrate, zinc chloride, zinc phosphate or their hydrates, and the molar ratio of copper to zinc is 2~5:1.

[0009] Preferably, the molecular sieve is ZSM-5, ZSM-35 or SAPO-11, the copper salt is copper nitrate, the zinc salt is zinc nitrate, and the mass ratio of the molecular sieve to copper is 3~10:1.

[0010] Preferably, the drying temperature is 100-120℃ and the calcination temperature is 500-600℃.

[0011] Preferably, the inert gas is nitrogen, argon, or a mixture of gases in any proportion thereof, and the alkali metal hydroxide is sodium hydroxide, potassium hydroxide, or lithium hydroxide.

[0012] Preferably, the molar ratio of phenol to glyoxylic acid is 1~10:1, the molar ratio of copper to glyoxylic acid in the copper-zinc bimetallic oxide catalyst is 0.01~0.1:1, and the molar ratio of alkali metal hydroxide to glyoxylic acid is 0.95~1.05:1.

[0013] Preferably, the molar ratio of phenol to glyoxylic acid is 4~6:1, and the molar ratio of copper to glyoxylic acid in the copper-zinc bimetallic oxide catalyst is 0.01~0.05:1.

[0014] Preferably, the temperature of the catalytic reaction is 20~100℃, and the reaction time is 3~12 hours.

[0015] Preferably, the post-treatment involves filtering the reaction solution, extracting the filtrate with diethyl ether, adding water and acetone to the extracted filtrate, heating under reflux, cooling, and then adding acetone again to obtain p-hydroxymandelic acid salt; adjusting the pH to 5.5–5.8 with acid solution, performing solid-liquid analysis to obtain a crude product; adding a mixture of ethanol and water to the crude product, dissolving it, cooling, crystallizing, separating the solid and liquid phases, and drying to obtain p-hydroxymandelic acid crystals. The beneficial effects of this invention are that it effectively improves reaction selectivity, reduces the proportion of o-hydroxymandelic acid byproducts, and increases product purity and yield; the catalyst of this invention is inexpensive, readily available, and recyclable, thereby more effectively reducing production costs. This invention enables a more economical, greener, more environmentally friendly, and more efficient synthesis of p-hydroxymandelic acid.

[0016] This invention employs a copper-zinc bimetallic catalyst for catalytic reaction, resulting in a high molar proportion of sodium p-hydroxymandelate in the product (98%), while byproducts such as ortho-hydroxymandelate (1.9%) and 2,4-dihydroxymandelate (0.1%) are minimal, exhibiting extremely high selectivity. Analysis of Comparative Example 1 and Comparative Examples 1-3 clearly demonstrates that the introduction of zinc as an auxiliary agent effectively optimizes the active site, forming an excellent synergistic effect and significantly improving the activity and selectivity of the catalyst.

[0017] The catalyst regeneration method of this invention is simple and efficient. When the catalyst becomes deactivated after continuous use, its activity can be restored simply by rinsing with alkaline solution, washing with deionized water until neutral, drying, and calcining. This recyclable characteristic effectively reduces production costs and resource waste, and has extremely high industrial application value. Detailed Implementation

[0018] It should be noted that, unless otherwise specified, the embodiments and features described in this application can be combined with each other. The following embodiments are only used to explain the technical principles of the present invention and are not intended to limit the scope of protection of the present invention. The present invention will be described in detail below with reference to the embodiments.

[0019] Example 1 A method for preparing a catalyst includes the following steps: 1) Weigh 59.08 g (0.315 mol) of copper nitrate and 15.15 g (0.080 mol) of zinc nitrate powder and dissolve them in 300 ml of deionized water. Stir to fully dissolve them to prepare an impregnation solution.

[0020] 2) Weigh 75.00 g of molecular sieve ZSM-5 carrier and add it to the impregnation solution. Stir at 85°C for 6 hours, then sonicate for 60 minutes to ensure uniform distribution of the impregnation solution. Let stand for 12 hours. After rotary evaporation to dryness, place in a constant temperature drying oven at 110°C for 6 hours.

[0021] 3) Then, the sample was calcined in a muffle furnace under the following conditions: 10℃ / min temperature ramp-up; calcination temperature of 550℃; calcination time of 4 hours; the calcined sample was cooled to room temperature and then taken out for use, thus obtaining the molecular sieve supported copper-zinc bimetallic catalyst, designated Cu-Zn / ZSM-5.

[0022] Catalysts with different loadings can be prepared by changing the type and amount of copper or zinc salts.

[0023] This type of catalyst can also be regenerated. Specific regeneration methods are as follows: If the catalyst becomes deactivated after repeated use, rinse the catalyst bed with a 5% NaOH solution until the pH of the washing solution no longer decreases. Then wash with deionized water until the washing solution is neutral. Regenerate the catalyst by vacuum drying at 110℃ for 6 hours. If necessary, it can be placed back into a muffle furnace and calcined at 500℃ for 1 hour in air.

[0024] Example 2 A method for synthesizing p-hydroxymandelic acid includes the following steps: 1) Under nitrogen protection, add 200 ml of deionized water and 4.08 g of sodium hydroxide to a 250 ml three-necked flask, stir to dissolve, and then add 56.4 g of phenol and 0.75 g of the molecular sieve-supported copper-zinc bimetallic catalyst Cu-Zn / ZSM-5 prepared in Example 1 while stirring continuously. Raise the temperature to 70 °C, and add 9.2 g of glyoxylic acid monohydrate in 20 equal batches over 3 hours. Stir the reaction for another 3 hours to complete the reaction.

[0025] 2) Cool the reaction solution to room temperature, filter, and wash the filter residue with deionized water to recover the catalyst. Extract the filtrate three times with diethyl ether, 35 ml each time, to recover excess phenol; take a sample of the filtrate and use ion chromatography to confirm that the molar ratio of sodium p-hydroxymandelate, sodium o-hydroxymandelate, and sodium 2,4-dihydroxymandelate is 98%:1.9%:0.1%.

[0026] 3) After the filtrate is desolvated, add 10 ml of water and 40 ml of acetone, heat under reflux and stir for 10 min, cool to room temperature, add 100 ml of acetone, and precipitate solid to obtain sodium p-hydroxymandelate (content 98%, yield 95%).

[0027] 4) Add the above-mentioned sodium 4-hydroxymandelic acid to 30 ml of deionized water, adjust the pH value to 5.5-5.8 with 50% sulfuric acid solution to allow the crystals to gradually precipitate, keep warm for 1 hour to grow crystals, and start solid-liquid separation with centrifugation to obtain crude p-hydroxymandelic acid monohydrate crystals.

[0028] 5) Add the entire batch of the crude product to a recrystallization reaction flask, then add a mixture of 12 ml of ethanol and 12 ml of water. Heat to a clear solution, then slowly cool with ice-salt water, controlling the stirring speed from high to low. When crystals are observed to precipitate, adjust the stirring speed to low. When the temperature gradually decreases to 0-5℃, maintain the temperature for crystal growth for 2 hours, then use a centrifuge for solid-liquid separation to obtain p-hydroxymandelic acid monohydrate crystals. Drying at a constant temperature of 60℃ in a vacuum oven for 24 hours yields 15.8 g of p-hydroxymandelic acid monohydrate crystals, with a yield of 85%. High-performance liquid chromatography (HPLC) analysis showed an effective component content of 99.0%. Nuclear magnetic resonance (NMR) analysis using heavy water as a solvent showed chemical shifts of 7.32 (d), 6.91 (d), and 5.01 (s) ppm, consistent with the standard. After desolventizing the mother liquor from the above crystallization, continue recrystallization with ethanol and water, followed by post-treatment drying, to obtain another 1.5 g of p-hydroxymandelic acid monohydrate crystals with a purity of 99%. The total yield was 93%.

[0029] Comparative Example 1 Comparative Example 1 used a molecular sieve supported copper metal catalyst, designated Cu / ZSM-5, which, compared to Example 1, only used copper nitrate. The specific preparation method of the catalyst is as follows: 1) Weigh 59.08 g (0.315 mol) of copper nitrate and dissolve it in 300 ml of deionized water. Stir to fully dissolve the copper nitrate to prepare an impregnation solution.

[0030] 2) Weigh 75.00 g of molecular sieve ZSM-5 carrier and add it to the impregnation solution. Stir at 85°C for 6 hours, then sonicate for 60 minutes to ensure uniform distribution of the impregnation solution. Let stand for 12 hours. After rotary evaporation to dryness, place in a constant temperature drying oven at 110°C for 6 hours.

[0031] 3) Then, the sample was calcined in a muffle furnace under the following conditions: a programmed temperature increase of 10℃ / min, a calcination temperature of 550℃, and a calcination time of 4 hours. After calcination, the sample was cooled to room temperature and then taken out for use. This yielded a molecular sieve supported copper metal catalyst, designated Cu / ZSM-5.

[0032] A method for synthesizing p-hydroxymandelic acid includes the following steps: 1) Under nitrogen protection, add 200ml of deionized water and 4.08g of sodium hydroxide to a 250ml three-necked flask, stir to dissolve, and then add 56.4g of phenol and 0.75g of molecular sieve supported copper metal catalyst Cu / ZSM-5 while stirring continuously. Raise the temperature to 70℃, and add 9.2g of glyoxylic acid monohydrate in 20 equal batches over 3 hours. Stir the reaction for another 3 hours to complete the reaction.

[0033] 2) Cool the reaction solution to room temperature, filter, and wash the filter residue with deionized water to recover the catalyst. Extract the filtrate three times with 35 ml of diethyl ether each time to recover excess phenol; take a sample of the filtrate and use ion chromatography to confirm that the molar ratio of sodium p-hydroxymandelate, sodium o-hydroxymandelate, and sodium 2,4-dihydroxymandelate is 86%:13%:1%.

[0034] Comparative Example 2 The catalyst used in Comparative Example 2 was a molecular sieve-supported copper-aluminum metal catalyst, designated Cu-Al / ZSM-5. Compared to Example 1, zinc nitrate was replaced with aluminum nitrate. The specific preparation method of the catalyst is as follows: 1) Weigh 59.08 g (0.315 mol) of copper nitrate and 0.080 mol of aluminum nitrate powder and dissolve them in 300 ml of deionized water. Stir to fully dissolve them to prepare an impregnation solution.

[0035] 2) Weigh 75.00 g of molecular sieve ZSM-5 carrier and add it to the impregnation solution. Stir at 85°C for 6 hours, then sonicate for 60 minutes to ensure uniform distribution of the impregnation solution. Let stand for 12 hours. After rotary evaporation to dryness, place in a constant temperature drying oven at 110°C for 6 hours.

[0036] 3) Then, the sample was calcined in a muffle furnace under the following conditions: a programmed temperature increase of 10℃ / min, a calcination temperature of 550℃, and a calcination time of 4 hours. After calcination, the sample was cooled to room temperature and then taken out for use. The molecular sieve supported copper-aluminum metal catalyst was obtained and designated as Cu-Al / ZSM-5.

[0037] A method for synthesizing p-hydroxymandelic acid includes the following steps: 1) Under nitrogen protection, add 200ml of deionized water and 4.08g of sodium hydroxide to a 250ml three-necked flask, stir to dissolve, and then add 56.4g of phenol and 0.75g of molecular sieve-supported copper-aluminum metal catalyst (Cu-Al / ZSM-5) while stirring continuously. Heat to 70℃, and add 9.2g of glyoxylic acid monohydrate in 20 equal batches over 3 hours. Stir the reaction for another 3 hours to complete the reaction.

[0038] 2) Cool the reaction solution to room temperature, filter, and wash the filter residue with deionized water to recover the catalyst. Extract the filtrate three times with 35 ml of diethyl ether each time to recover excess phenol; take a sample of the filtrate and use ion chromatography to confirm that the molar ratio of sodium p-hydroxymandelate, sodium o-hydroxymandelate, and sodium 2,4-dihydroxymandelate is 88%:11%:1%.

[0039] Comparative Example 3 The catalyst used in Comparative Example 3 was a molecular sieve-supported copper-iron metal catalyst, designated Cu-Fe / ZSM-5. Compared to Example 1, zinc nitrate was replaced with iron nitrate. The specific preparation method of the catalyst is as follows: 1) Weigh 59.08 g (0.315 mol) of copper nitrate and 0.080 mol of ferric nitrate and dissolve them in 300 mL of deionized water. Stir to fully dissolve them to prepare an impregnation solution.

[0040] 2) Weigh 75.00 g of molecular sieve ZSM-5 carrier and add it to the impregnation solution. Stir at 85°C for 6 hours, then sonicate for 60 minutes to ensure uniform distribution of the impregnation solution. Let stand for 12 hours. After rotary evaporation to dryness, place in a constant temperature drying oven at 110°C for 6 hours.

[0041] 3) Then, the sample was calcined in a muffle furnace under the following conditions: a programmed temperature increase of 10℃ / min, a calcination temperature of 550℃, and a calcination time of 4 hours. After calcination, the sample was cooled to room temperature and then taken out for use. The resulting molecular sieve supported copper-iron metal catalyst was designated Cu-Fe / ZSM-5.

[0042] A method for synthesizing p-hydroxymandelic acid includes the following steps: 1) Under nitrogen protection, add 200ml of deionized water and 4.08g of sodium hydroxide to a 250ml three-necked flask, stir to dissolve, and then add 56.4g of phenol and 0.75g of molecular sieve-supported copper-iron metal catalyst (Cu-Fe / ZSM-5) while stirring continuously. Heat to 70℃, and add 9.2g of glyoxylic acid monohydrate in 20 equal batches over 3 hours. Stir the reaction for another 3 hours to complete the reaction.

[0043] 2) Cool the reaction solution to room temperature, filter, and wash the filter residue with deionized water to recover the catalyst. Extract the filtrate three times with diethyl ether, 35 ml each time, to recover excess phenol; take a sample of the filtrate and use ion chromatography to confirm that the molar ratio of sodium p-hydroxymandelate, sodium o-hydroxymandelate, and sodium 2,4-dihydroxymandelate is 89%:10%:1%.

[0044] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of protection of this application is limited to these examples; within the framework of this application, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of different aspects of one or more embodiments of this application as described above, which are not provided in detail for the sake of brevity.

[0045] One or more embodiments in this application are intended to cover all such substitutions, modifications, and variations that fall within the broad scope of this application. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of one or more embodiments in this application should be included within the protection scope of this application.

Claims

1. A method for synthesizing p-hydroxymandelic acid, characterized in that, in In an inert gas atmosphere, an aqueous reaction system containing phenol, glyoxylic acid, a catalyst, and an alkali metal hydroxide is subjected to a catalytic reaction. After the reaction is completed, post-treatment is performed to obtain p-hydroxymandelic acid. The catalyst is a copper-zinc bimetallic oxide catalyst.

2. The synthesis method as described in claim 1, characterized in that, The catalyst is prepared by mixing the support with an aqueous solution containing copper salt and zinc salt, drying, and then calcining to obtain the catalyst.

3. The synthesis method as described in claim 2, characterized in that, In the method for preparing the catalyst, the support is a molecular sieve, the copper salt is copper sulfate, copper nitrate, copper chloride, copper phosphate or their hydrates, the zinc salt is zinc sulfate, zinc nitrate, zinc chloride, zinc phosphate or their hydrates, and the molar ratio of copper to zinc is 2~5:

1.

4. The synthesis method as described in claim 3, characterized in that, The molecular sieve is ZSM-5, ZSM-35 or SAPO-11, the copper salt is copper nitrate, the zinc salt is zinc nitrate, and the mass ratio of the molecular sieve to copper is 3~10:

1.

5. The synthesis method as described in claim 2, characterized in that, The drying temperature is 100-120℃, and the calcination temperature is 500-600℃.

6. The synthesis method according to any one of claims 1-5, characterized in that, The inert gas is nitrogen, argon, or a mixture of gases in any proportion, and the alkali metal hydroxide is sodium hydroxide, potassium hydroxide, or lithium hydroxide.

7. The synthesis method according to any one of claims 1-5, characterized in that, The molar ratio of phenol to glyoxylic acid is 1~10:1, the molar ratio of copper to glyoxylic acid in the copper-zinc bimetallic oxide catalyst is 0.01~0.1:1, and the molar ratio of alkali metal hydroxide to glyoxylic acid is 0.95~1.05:

1.

8. The synthesis method as described in claim 7, characterized in that, The molar ratio of phenol to glyoxylic acid is 4~6:1, and the molar ratio of copper to glyoxylic acid in the copper-zinc bimetallic oxide catalyst is 0.01~0.05:

1.

9. The synthesis method according to any one of claims 1-5, characterized in that, The catalytic reaction is carried out at a temperature of 20~100℃ for 3~12 hours.

10. The synthesis method according to claim 1, characterized in that, The post-treatment involves filtering the reaction solution and extracting the filtrate with diethyl ether. Water and acetone are added to the extracted filtrate, which is then heated under reflux. After cooling, acetone is added again to obtain p-hydroxymandelic acid. The pH of the p-hydroxymandelic acid is adjusted to 5.5–5.8 with acid, and solid-liquid analysis is performed to obtain a crude product. The crude product is then added to a mixture of ethanol and water, dissolved, cooled, and crystallized. Solid-liquid separation is performed, and the product is dried to obtain p-hydroxymandelic acid crystals.