Synthesis method of 2-hydroxycarboxylic acid and derivatives thereof

Abstract

The invention discloses a synthesis method of 2-hydroxycarboxylic acid and derivatives thereof, hydroxycarboxylic acid and ester derivatives thereof are synthesized through mild oxidation reaction by taking a compound A as a raw material, the reaction system is mild in condition, simple and convenient to operate, environment-friendly, high in yield and good in purity, and has wide universality and good industrial application prospects; .

Description

Technical Field

[0001] This invention relates to a method for synthesizing 2-hydroxycarboxylic acids and their derivatives, belonging to the field of chemical synthesis technology. Background Technology

[0002] Alkyds are a class of organic compounds possessing both hydroxyl (-OH) and carboxyl (-COOH) functional groups. Due to their combined chemical properties of alcohols and acids, they exhibit broad application value and development potential in numerous fields. These compounds generally possess good biodegradability and biocompatibility, and most are derived from renewable resources or can be synthesized via green catalytic pathways, aligning with the development concepts of sustainable chemistry and a "zero-carbon" economy. Furthermore, alkyds can serve as important structural modification platforms, providing flexible molecular templates for drug design and functional material construction, exhibiting unique advantages, particularly in the biomedical fields of implantable medical devices and transdermal drug delivery systems.

[0003] Among various alcoholic acids, glycolic acid (HOCH₂COOH), as the simplest α-hydroxy acid, holds a particularly important position. It is a colorless, odorless, and hygroscopic crystalline solid, a widely used and in-demand basic chemical raw material, used in cleaning agents, adhesives, biodegradable polymer monomers, dyeing auxiliaries, and chelating agents. Due to its excellent skin permeability and biodegradability, glycolic acid is also widely used in skin peeling agents and polyester synthesis.

[0004] Currently, the main industrial synthesis methods for glycolic acid include chloroacetic acid hydrolysis, formaldehyde carbonylation, and oxalic acid reduction. However, these methods generally suffer from harsh reaction conditions, high catalyst costs, and numerous byproducts. In recent years, the synthesis of glycolic acid based on the oxidation of ethylene glycol has attracted attention. This reaction is typically carried out in an alkaline medium, where the base catalyzes the reaction; however, strongly alkaline environments easily lead to the deactivation of metal catalysts. Therefore, developing catalysts with both high activity and stability in suitable alkaline media has become a current research hotspot. Overall, existing glycolic acid synthesis methods still have limitations in terms of mild conditions, green processes, and structural diversity, necessitating the further development of efficient, environmentally friendly, and industrially feasible new synthetic routes. Summary of the Invention

[0005] The purpose of this invention is to provide a method for synthesizing 2-hydroxycarboxylic acids and their derivatives from aldehyde compounds via a mild oxidation reaction. The method uses small-molecule alcohols as starting materials and performs an oxidation reaction under normal pressure with ozone blowing to generate corresponding alcoholic acid compounds (such as glycolic acid, propionic acid, butyric acid, etc.), overcoming the main shortcomings of existing technologies.

[0006] The implementation process of this invention is as follows.

[0007] A method for synthesizing 2-hydroxycarboxylic acids and their derivatives includes the following steps:

[0008]

[0009] The R is selected from C1-C10 alkyl, C1-C10 alkoxy, nitro, trifluoromethyl, hydroxy and α-hydroxycarboxylic acids;

[0010] (1) Compound A and an oxidant are added to an organic solvent, and ozone is introduced to react and a precipitate is obtained;

[0011] (2) After adding saturated sodium sulfite solution to quench the ozone, concentrated hydrochloric acid is added to continue the reaction;

[0012] (3) After separating, washing and drying the precipitate, compound B is obtained.

[0013] The R mentioned above is preferably selected from C1-C6 alkyl, C1-C6 alkoxy, nitro, trifluoromethyl, hydroxy and α-hydroxycarboxylic acid.

[0014] In step (1) above, the oxidant is selected from sodium chlorite, potassium permanganate, hydrogen peroxide, periodic acid, and manganese dioxide.

[0015] In step (1) above, the organic solvent is selected from methanol, ethyl acetate, dichloromethane, diethyl ether, tetrahydrofuran, N,N-dimethylformamide, and tert-butanol.

[0016] In step (1) above, the reaction temperature is 25~60℃.

[0017] The method described in this invention can synthesize methanolic acid, propionic acid, butyric acid, pentanic acid, hydroxypropionic acid, 2-hydroxybutyric acid, tartaric acid, methyl glycolate, ethyl glycolate, methyl lactate, butyl lactate, isopropyl glycolate, etc.

[0018] Compared with the prior art, the present invention has the following advantages:

[0019] (1) The reaction conditions are mild and the safety is high.

[0020] The reaction is carried out under normal or slightly positive pressure, with the temperature controlled between 25 and 60°C. No high-pressure equipment is required, making it suitable for conventional laboratories or standard industrial production lines. The equipment requirements are low and the operational risks are minimal.

[0021] (2) Using ozone as an oxidant is green and environmentally friendly.

[0022] No traditional heavy metal oxidants (such as Cr, Mn) are used 7+ Ozone (O4) is used as the oxidant only. The main byproducts are water and trace amounts of peroxide intermediates, which significantly reduces the generation of toxic liquid and solid waste.

[0023] (3) The raw materials are cheap and readily available, making it economical.

[0024] The raw materials are low-carbon alcohols (such as methanol, ethanol, butanol, etc.), which are widely available, inexpensive, and are commodity solvents with a mature supply chain. The overall raw material cost is significantly lower than that of traditional haloacid hydrolysis or bio-fermentation processes.

[0025] (4) The process is simple and easy to scale up and continue.

[0026] The reaction system is a one-pot liquid-phase reaction, which does not require stepwise feeding or complex solvent replacement. The steps only include mixing, stirring, oxygenation and cooling separation, which facilitates automated control and modular process design.

[0027] (5) High reaction selectivity and few byproducts

[0028] The catalyst system and mild oxidation conditions can effectively inhibit the excessive oxidation of aldehydes and avoid the formation of byproducts such as acetic acid and oxalic acid. The reaction yield is generally 75-88%, and the chromatographic purity of the main product can reach over 95%, without the need for complex purification.

[0029] (6) The product is easy to separate and has good crystallinity.

[0030] The target products are mostly low molecular weight hydroxy acids or their esters (such as glycolic acid, ethyl lactate, and methyl glycolate), which are often white crystals or transparent liquids. They can be directly separated by concentration, cooling crystallization, solvent extraction, etc., and the post-processing is simple. Detailed Implementation Plan

[0031] To better illustrate the embodiments of the present invention, the following will further describe them in conjunction with specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of protection of the present invention. Experimental methods not specifically specified in the examples are generally performed under conventional operating conditions or with reference to the recommended conditions provided by the manufacturers of the reagents and instruments used.

[0032] Example 1

[0033]

[0034] In a 250 mL three-necked flask, 20 mmol of ethylene glycol was added as the substrate, followed by 40 mL of ethyl acetate as the solvent. Then, 3 mmol of sodium chlorite was added and stirred until homogeneous. The reaction mixture was heated to 25 °C and ozone was introduced. After 24 hours, the reaction solution turned pale pink and a large amount of precipitate formed. 10 mL of saturated sodium sulfite solution was then added to quench the ozone, followed by 5 mL of concentrated hydrochloric acid and stirring for 30 minutes. The precipitate was collected by filtration and washed twice with 5 mL of ethyl acetate. The product was then collected. After cooling the filtrate for a period of time, a significant amount of product precipitated. The filtrate was filtered to obtain glycolic acid. The precipitate obtained before filtration was mixed with the crystallized product and dried to obtain a product with a yield of 84%. 1 H NMR (500 MHz, CDCl3) δ4.12 (d, J = 6.1 Hz, 2H), 3.07 (t, J = 6.0 Hz, 1H). 13 C NMR (125 MHz, CDCl3) δ176.87, 60.27.

[0035] Example 2

[0036]

[0037] 1,2-Propanediol (20 mmol) was added to a 250 mL three-necked flask, followed by 40 mL of dichloromethane as a solvent, and then 3 mmol of potassium permanganate. After stirring and mixing thoroughly, the reaction was heated to 35 °C and ozone was introduced. After 24 hours, the reaction solution turned pale pink and a large amount of precipitate appeared. Then, 10 mL of saturated sodium sulfite solution was added to quench the ozone, followed by 5 mL of concentrated hydrochloric acid and stirring for 30 minutes. The precipitate was filtered, washed twice with 5 mL of ethyl acetate, and the product was collected. After cooling the filtrate for a period of time, a large amount of product precipitated. The filtrate was filtered to obtain the product. The precipitate obtained before filtration was mixed with the crystallized product and dried to obtain a product with a yield of 67%. 1 H NMR (500 MHz, CDCl3) δ 4.25 (qd, J = 6.8, 5.5 Hz, 0H), 3.96 (d, J = 5.5 Hz, 0H), 1.35 (d, J = 6.8 Hz, 1H). 13 C NMR (125 MHz, CDCl3) δ 176.95, 66.75, 20.49.

[0038] Example 3

[0039]

[0040] 1,2-Butanediol (20 mmol) was added to a 250 mL three-necked flask, followed by 40 mL of diethyl ether as a solvent, and then 3 mmol of hydrogen peroxide. After stirring and mixing thoroughly, the reaction was heated to 45 °C and ozone was introduced. After 24 hours, the reaction solution turned pale pink and a large amount of precipitate formed. Then, 10 mL of saturated sodium sulfite solution was added to quench the ozone, followed by 5 mL of concentrated hydrochloric acid and stirring for 30 minutes. The precipitate was filtered, washed twice with 5 mL of ethyl acetate, and the product was collected. After cooling the filtrate for a period of time, a significant amount of product precipitated. The filtrate was filtered to obtain the product. The precipitate obtained before filtration was mixed with the crystallized product and dried to obtain a product with a yield of 72%. 1 H NMR (500 MHz, CDCl3) δ 4.18-4.09(m, 1H), 1.92-1.73 (m, 1H), 1.00 (td, J = 7.4, 1.1 Hz, 1H). 13 C NMR (125 MHz, CDCl3) δ 177.21, 72.09, 26.79, 9.70.

[0041] Example 4

[0042]

[0043] 1,2-Pentanediol (20 mmol) was added to a 250 mL three-necked flask, followed by 40 mL of tetrahydrofuran as a solvent, and then periodic acid (3 mmol). After stirring and mixing thoroughly, the reaction was heated to 45 °C and ozone was introduced. After 24 hours, the reaction solution turned pale pink and a large amount of precipitate formed. Then, 10 mL of saturated sodium sulfite solution was added to quench the ozone, followed by 5 mL of concentrated hydrochloric acid and stirring for 30 minutes. The precipitate was filtered, washed twice with 5 mL of ethyl acetate, and the product was collected. After cooling the filtrate for a period of time, a significant amount of product precipitated. The filtrate was filtered to obtain the product. The precipitate obtained before filtration was mixed with the crystallized product and dried to obtain a product with a yield of 76%. 1 H NMR (500 MHz, CDCl3) δ 4.37 (d,J = 5.5 Hz, 1H), 4.18 (td, J = 6.6, 5.5 Hz, 1H), 1.91-1.76 (m, 2H), 1.51-1.35(m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13 C NMR (125 MHz, CDCl3) δ177.68, 70.39, 35.33, 18.26, 13.67.

[0044] Example 5

[0045]

[0046] In a 250 mL three-necked flask, 20 mmol of 2,3,4-trihydroxy-1-butyric acid was added, along with 40 mL of ethyl acetate as a solvent. Sodium chlorite (3 mmol) was then added, and the mixture was stirred until homogeneous. The reaction was heated to 45 °C, and ozone was introduced. After 24 hours, the reaction solution turned pale pink and a large amount of precipitate formed. 10 mL of saturated sodium sulfite solution was then added to quench the ozone, followed by 5 mL of concentrated hydrochloric acid and stirring for 30 minutes. The precipitate was filtered, washed twice with 5 mL of ethyl acetate, and the product was collected. After cooling the filtrate for a period of time, a significant amount of product precipitated. The filtrate was filtered to obtain the product. The precipitate obtained before filtration was mixed with the crystallized product and dried to obtain a product with a yield of 80%. 1 H NMR (500 MHz, CDCl3)δ 5.30 (d, J = 6.0 Hz, 1H), 4.45 (d, J = 5.9 Hz, 1H). 13 C NMR (125 MHz, CDCl3) δ174.49, 73.65.

[0047] Example 6

[0048] Similar to the synthesis methods in Examples 1-5 above, the target compounds can still be synthesized by changing the types of substrates, oxidants, and organic solvents (as shown in Table 1).

[0049]

[0050] Within the scope of this invention, the above-described technical features and the technical features specifically described in the embodiments can be combined with each other to form new or preferred technical solutions. Furthermore, any feature disclosed in the specification can be replaced by an alternative feature capable of achieving the same, equivalent, or similar function.

Claims

1. A method for synthesizing 2-hydroxycarboxylic acids and their derivatives, characterized in that... Includes the following steps: ； The R is selected from C1-C10 alkyl, C1-C10 alkoxy, nitro, trifluoromethyl, hydroxy and α-hydroxycarboxylic acids; (1) Compound A and an oxidant are added to an organic solvent, and ozone is introduced to react and a precipitate is obtained; (2) After adding saturated sodium sulfite solution to quench the ozone, concentrated hydrochloric acid is added to continue the reaction; (3) After separating, washing and drying the precipitate, compound B is obtained.

2. The method for synthesizing 2-hydroxycarboxylic acids and their derivatives according to claim 1, characterized in that: R is selected from C1-C6 alkyl, C1-C6 alkoxy, nitro, trifluoromethyl, hydroxy, and α-hydroxycarboxylic acids.

3. The method for synthesizing 2-hydroxycarboxylic acids and their derivatives according to claim 1, characterized in that: In step (1), the oxidant is selected from sodium chlorite, potassium permanganate, hydrogen peroxide, periodic acid, and manganese dioxide.

4. The method for synthesizing 2-hydroxycarboxylic acids and their derivatives according to claim 1, characterized in that: In step (1), the organic solvent is selected from methanol, ethyl acetate, dichloromethane, diethyl ether, tetrahydrofuran, N,N-dimethylformamide, and tert-butanol.

5. The method for synthesizing 2-hydroxycarboxylic acids and their derivatives according to claim 1, characterized in that: In step (1), the reaction temperature is 25~60℃.

6. The method for synthesizing 2-hydroxycarboxylic acids and their derivatives according to claim 1, characterized in that: Compound B is methanolic acid, propionic acid, butanolic acid, pentanolic acid, hydroxypropionic acid, 2-hydroxybutyric acid, tartaric acid, methyl glycolate, ethyl glycolate, methyl lactate, butyl lactate, or isopropyl glycolate.

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