Process for the synthesis of chiral l-2-hydroxy acids in a microchannel reactor

Abstract

The application belongs to the field of chemical synthesis, and particularly relates to a method for synthesizing chiral 2-hydroxy acid by using a micro-channel reactor. 2-hydroxy acid is synthesized by diazotization and hydrolysis of 2-amino acid, and an intermittent reactor is usually used in industrial synthesis, which has low operation safety, and isomers exist in the synthesized product. In the application, the sulfuric acid aqueous solution of L-2-amino acid and the sodium nitrite solution are pumped into a micro-channel reactor to synthesize L-2-hydroxy acid. The micro-channel reaction conditions include: reaction temperature: 40-80 DEG C; residence time: 85-170 s; the set pressure value of the back pressure valve is 6 bar; the flow rate of the amino acid acid solution is controlled to be 9.6-23 g / min; and the flow rate of the sodium nitrite solution is 4.5-9.6 g / min. After the reaction is completed, the pH of the reaction solution is adjusted to be in the range of 1.5-2.5, and the reaction solution is extracted by ethyl acetate to prepare L-2-hydroxy butyric acid. The technical scheme of the application has high operation and equipment safety, can realize accurate control of the diazotization reaction, and the aliphatic L-2-hydroxy acid prepared finally does not contain optical isomers, thereby improving the product quality.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis, specifically relating to a method for synthesizing chiral 2-hydroxy acids using a microchannel reactor. Background Technology

[0002] Chiral 2-hydroxy acids have wide applications in pharmaceuticals, cosmetics, and polymer synthesis. For example, L-2-hydroxybutyric acid is one of the raw materials for the synthesis of pemafibrate, and L-2-hydroxy-3-(4-hydroxyphenyl)propionic acid is one of the raw materials for the non-enzymatic synthesis of the drugs ticaglipza and (S)-(-)-rosmarinic acid. 2-hydroxy-3-methylbutyric acid is an important raw material in the total synthesis of tacalcitol. Compounds such as lactobionic acid, glycolic acid, tartaric acid, lactic acid, citric acid, and malic acid can be used as exfoliating agents, moisturizers, and antioxidants in cosmetics, and are also primary chemical raw materials.

[0003] Currently, the synthesis of chiral 2-hydroxy acids mainly involves enzymatic methods, asymmetric reduction, and chiral resolution. Among these, the synthesis from 2-amino acids via diazotization hydrolysis offers advantages such as high chiral selectivity, inexpensive raw materials, and simple process development, making it the most widely used method in industry. In industrial synthesis, traditional batch reactors such as reaction vessels are often employed. To ensure reaction yield, excess sodium nitrite is added, resulting in the generation of large amounts of nitrogen oxides. The generated diazonium salts are highly decomposed, and the excessive sodium nitrite leads to a violently exothermic reaction, increasing safety risks. Furthermore, prolonged reaction times reduce the optical purity of the product, and optical isomers may still be present in the synthesized product.

[0004] In 2012, Dennls X. Hu et al. used a tubular microchannel reactor to diazotize and hydrolyze some L-2-amino acids. The reaction was carried out at 60°C for 10-60 min. They focused on continuous post-processing of the reaction and obtained yields of 30%-100% through continuous EA extraction. The ee values ​​were between 60%-98%, and isomers were always present. The throughput was 1.0 g per hour, which was limited to laboratory research. Summary of the Invention

[0005] To address the above problems, this invention provides a method for preparing chiral 2-hydroxy acids using a microchannel reactor. This method is safe, efficient, and simple to operate. Furthermore, the prepared product contains few byproducts and no optical isomers, thus reducing the cost required for subsequent isomer removal.

[0006] A microreactor is a micro-channel reactor based on continuous flow, used to replace traditional reactors such as glass flasks, funnels, and reaction vessels commonly used in industrial organic synthesis.

[0007] This invention, based on the work of Dennls X. Hu et al., improves the stereoselectivity and throughput of the reaction by changing the reaction temperature, shortening the reaction time, increasing the concentration of the reaction solution, modifying the post-treatment method, and using a static mixing microchannel reactor, while reducing the amount of solvent used, and simultaneously achieving scale-up synthesis at a scale of 2 kg. After processing with the technical solution of this invention, no optical isomers are present in the 2-hydroxy acid product. The key lies in shortening the reaction time and reducing the configuration inversion of the product at high temperatures.

[0008] Specifically, the present invention is implemented using the following technical solution:

[0009]

[0010] A method for synthesizing chiral 2-hydroxy acids using a microchannel reactor includes the following steps: pumping an aqueous sulfuric acid solution of L-2-amino acid and a sodium nitrite solution into a microchannel reactor for reaction. The microchannel reaction conditions include: reaction temperature: 0–100℃; residence time: 30–180 s; controlling the flow rate of the acid solution of L-2-amino acid to be 5–30 g / min; and the flow rate of the sodium nitrite solution to be 2–15 g / min.

[0011] Furthermore, the reaction temperature was 40–80℃; the residence time was 85–170 s; the flow rate of the acid solution containing L-2-amino acid was controlled at 9.6–23 g / min; and the flow rate of the sodium nitrite solution was 4.5–9.6 g / min.

[0012] In the technical solution of the present invention, the internal pressure of the microchannel reactor outlet is regulated by a back pressure valve, wherein the back pressure valve pressure is 1 to 16 bar; preferably 6 bar.

[0013] After the reaction is complete, the pH of the reaction solution is adjusted to 1.5-2.5, preferably 1.5; the solution is stirred and extracted with one or more organic solvents selected from methyl tert-butyl ether, dichloromethane, ethyl acetate and n-butanol, for 3-8 extractions. The solvent is then removed to obtain L-2-hydroxy acid.

[0014] In the specific experimental scheme of this invention, the organic solvent is ethyl acetate, and the extraction is performed 6 times. During extraction, the total volume of the solvent used in multiple extractions is 0.5 times the volume of the reaction liquid. By repeatedly extracting in small amounts, the product in the reaction liquid is extracted as much as possible, thereby increasing the yield while reducing the amount of solvent used.

[0015] In the technical solution of this invention, the stirring time is generally 12 to 24 hours. Solvent removal refers to removing the liquid from the solution using conventional techniques in the art, thereby obtaining a solid product. These conventional techniques include vacuum distillation, freeze drying, or oven drying.

[0016] In the technical solution of the present invention, the L-2-amino acid is an aliphatic L-2-amino acid; the aliphatic L-2-amino acid is selected from any one of alanine, leucine, isoleucine, L-2-butine, and valine.

[0017] Furthermore, the L-2-amino acid is selected from L-2-butyric acid.

[0018] Furthermore, the acid used in the acid solution of L-2-amino acid is an inorganic acid, while the acid used in the technical solution of the present invention is sulfuric acid.

[0019] In the technical solution of the present invention, the molar ratio of L-2-amino acid to sulfuric acid in the acid solution of L-2-amino acid is 1:0.5 to 1:3.

[0020] Furthermore, the molar ratio of L-2-amino acid to sulfuric acid is 1:0.5 to 1:1.5, preferably 1:1.

[0021] In the technical solution of the present invention, the mass ratio of amino acid to water in the acid solution of L-2-amino acid is 1:3 to 1:15;

[0022] Furthermore, the mass ratio of amino acids to water is 1:4 to 1:10; preferably 1:4.

[0023] The sulfuric acid aqueous solution of the above-mentioned L-2-amino acid was prepared by the following method: At room temperature, L-2-amino acid and water were stirred and mixed at a mass ratio of 1:3 to 1:15. Then, sulfuric acid was slowly added dropwise under ice bath conditions. The molar ratio of L-2-amino acid to sulfuric acid added was 1:0.5 to 1:3.0. After stirring and mixing until completely dissolved, the L-2-amino acid sulfuric acid aqueous solution was obtained and ready for use.

[0024] The aqueous solution of sodium nitrite in this invention is prepared by the following method: dissolving sodium nitrite in 1-5 times its mass of water, stirring to dissolve, and cooling to room temperature to obtain an aqueous solution of sodium nitrite for later use.

[0025] Furthermore, the mass ratio of sodium nitrite to water is 1:1 to 1:2; preferably 1:1.

[0026] Diazotization is a hazardous chemical process under key regulatory oversight (Category 18). This invention utilizes a microchannel reactor for the diazotization hydrolysis of L-2-amino acids. This reactor provides a large specific surface area and extremely high mass and heat transfer efficiency, ensuring inherent safety in diazotization while enabling rapid and efficient production. Furthermore, the microreactor allows for continuous flow instead of batch operation, enabling precise control of reactant residence time. Compared to Comparative Example 1, under conditions achieving similar yield and purity, this invention reduces solvent usage, sodium nitrite and sulfuric acid consumption, and waste generation, thus lowering costs. It also reduces isomerization during diazotization hydrolysis, reducing the cost of subsequent isomer removal. However, Comparative Example 2 shows that when the reaction residence time exceeds the range of this invention, optical isomers will be produced.

[0027] Compared with the prior art, the present invention has the following significant advantages:

[0028] 1. This invention utilizes a microchannel reactor to prepare L-2-hydroxy acids, achieving continuous synthesis and initial scale-up, enabling synthesis on a 2kg scale, thus making production more flexible.

[0029] 2. Due to the high specific surface area of ​​the microchannel reactor, the heat exchange performance of the reaction system is much higher than that of conventional reactors. There is no obvious temperature rise during the reaction process, which avoids local overheating of the reaction system and reduces the reaction risk factor.

[0030] 3. The reactant flows in a laminar state in the microchannel, and mixing is carried out by diffusion. In the microchannel reactor, the materials can be mixed instantly, the reaction rate is accelerated, and the production efficiency is improved. At the same time, by controlling the reaction time, the stereoselectivity and yield are improved.

[0031] In summary, the present invention has a simple process, is easy to operate, and is highly safe, enabling industrial production and possessing significant application value. Attached Figure Description

[0032] Figure 1 This is a schematic diagram of the reaction apparatus. Detailed Implementation

[0033] The embodiments provided below are merely illustrative of the invention and are not intended to limit the invention in any way.

[0034] In the following specific implementation scheme, the microchannel reactor is the Shandong Haomai RMCS1810 microchannel reactor, which is made of silicon carbide or stainless steel. The channel shape is rhomboid, fan-shaped or heart-shaped, the connecting pipeline is made of PFA material, and the total volume of solvent in the channel and connecting pipeline is 45ml.

[0035] Example 1

[0036] (1) Preparation of L-2-aminobutyric acid sulfuric acid aqueous solution: At room temperature, L-2-aminobutyric acid and water are mixed at a mass ratio of 1:10. Then, sulfuric acid is slowly added dropwise under ice bath conditions. The molar ratio of sulfuric acid to L-2-aminobutyric acid is 2:1. After stirring and mixing until completely dissolved, L-2-aminobutyric acid sulfuric acid aqueous solution is obtained and ready for use.

[0037] (2) Preparation of sodium nitrite solution: Dissolve sodium nitrite in 2 times its mass of water, stir to dissolve, cool to room temperature to obtain an aqueous solution of sodium nitrite, and set aside for use.

[0038] (3) Synthesis of L-2-hydroxybutyric acid: L-2-aminobutyric acid sulfuric acid solution and sodium nitrite solution were pumped into the two inlets of the microreactor at flow rates of 9.6 g / min and 6.4 g / min, respectively. The two liquids were mixed in the microchannel reactor at 40 °C. The residence time of the material in the microchannel reactor was 170 s. The internal pressure of the outlet was adjusted by the back pressure valve. The back pressure valve was set to 6 bar. After the system pressure and temperature stabilized, the reaction solution was collected at the outlet for 15 min. The pH of the collected solution was adjusted to 2.5 and stirred overnight. The solution was extracted 6 times with ethyl acetate at 0.5 times the total volume of the reaction solution. After drying, filtration and rotary evaporation, L-2-hydroxybutyric acid was obtained with a yield of 80% and a purity of 90%. No isomers were detected.

[0039] Example 2

[0040] (1) Preparation of L-2-aminobutyric acid sulfuric acid aqueous solution: At room temperature, L-2-aminobutyric acid and water are mixed at a mass ratio of 1:4. Then, sulfuric acid is slowly added dropwise under ice bath conditions. The molar ratio of sulfuric acid to L-2-aminobutyric acid is 1:1. After stirring and mixing until completely dissolved, L-2-aminobutyric acid sulfuric acid aqueous solution is obtained and ready for use.

[0041] (2) Preparation of sodium nitrite solution: Dissolve sodium nitrite in water of equal mass, stir to dissolve, cool to room temperature to obtain an aqueous solution of sodium nitrite, and set aside for use.

[0042] (3) Synthesis of L-2-hydroxybutyric acid: L-2-aminobutyric acid sulfuric acid solution and sodium nitrite solution were pumped into the two inlets of the microreactor at flow rates of 11.5 g / min and 4.5 g / min, respectively. The two liquids were mixed in the microchannel reactor at 80 °C. The residence time of the material in the microchannel reactor was 170 s. The internal pressure of the outlet was adjusted by the back pressure valve. The back pressure valve was set to 6 bar. After the system pressure and temperature stabilized, the reaction solution was collected at the outlet for 30 min. The pH of the collected solution was adjusted to 2.5 and stirred overnight. The solution was extracted 6 times with ethyl acetate at 0.5 times the total volume of the reaction solution. After drying, filtration and rotary evaporation, L-2-hydroxybutyric acid was obtained with a yield of 84% and a purity of 92.07%. No isomers were detected.

[0043] Example 3

[0044] (1) Preparation of L-2-aminobutyric acid sulfuric acid aqueous solution: At room temperature, L-2-aminobutyric acid and water are mixed at a mass ratio of 1:4. Then, sulfuric acid is slowly added dropwise under ice bath conditions. The molar ratio of sulfuric acid to L-2-aminobutyric acid is 1:1. After stirring and mixing until completely dissolved, L-2-aminobutyric acid sulfuric acid aqueous solution is obtained and ready for use.

[0045] (2) Preparation of sodium nitrite solution: Dissolve sodium nitrite in water of equal mass, stir to dissolve, cool to room temperature to obtain an aqueous solution of sodium nitrite, and set aside for use.

[0046] (3) Synthesis of L-2-hydroxybutyric acid: L-2-aminobutyric acid sulfuric acid solution and sodium nitrite solution were pumped into the two inlets of the microreactor at flow rates of 23.0 g / min and 9 g / min, respectively. The two liquids were mixed in the microchannel reactor at 80 °C. The residence time of the material in the microchannel reactor was 85 s. The internal pressure of the outlet was adjusted by the back pressure valve. The back pressure valve was set to 6 bar. After the system pressure and temperature stabilized, the reaction solution was collected at the outlet for 15 min. The pH of the collected solution was adjusted to 2.5 and stirred overnight. The solution was extracted 6 times with ethyl acetate at 0.5 times the total volume of the reaction solution. After drying, filtration and rotary evaporation, L-2-hydroxybutyric acid was obtained with a yield of 78% and a purity of 89.20%. No isomers were detected.

[0047] Example 4

[0048] (1) Preparation of L-2-aminobutyric acid sulfuric acid aqueous solution: At room temperature, L-2-aminobutyric acid and water are mixed at a mass ratio of 1:4. Then, sulfuric acid is slowly added dropwise under ice bath conditions. The molar ratio of sulfuric acid to L-2-aminobutyric acid is 0.5:1. After stirring and mixing until completely dissolved, L-2-aminobutyric acid sulfuric acid aqueous solution is obtained and ready for use.

[0049] (2) Preparation of sodium nitrite solution: Dissolve sodium nitrite in water of equal mass, stir to dissolve, cool to room temperature to obtain an aqueous solution of sodium nitrite, and set aside for use.

[0050] (3) Synthesis of L-2-hydroxybutyric acid: L-2-aminobutyric acid sulfuric acid solution and sodium nitrite solution were pumped into the two inlets of the microreactor at flow rates of 22.4 g / min and 9.6 g / min, respectively. The molar ratio of L-2-aminobutyric acid to sodium nitrite was controlled at 1:2. The two liquids were mixed in the microchannel reactor at 80°C. The residence time of the material in the microchannel reactor was 85 s. The internal pressure of the outlet was adjusted by the back pressure valve. The back pressure valve was set to 6 bar. After the system pressure and temperature stabilized, the reaction solution was collected at the outlet for 15 min. The pH of the collected solution was adjusted to 2.5. After stirring overnight, it was extracted 6 times with ethyl acetate at 0.5 times the total volume of the reaction solution. After drying, filtration and rotary evaporation, L-2-hydroxybutyric acid was obtained with a yield of 82% and a purity of 90.19%. No isomers were detected.

[0051] Example 5

[0052] (1) Preparation of L-2-aminobutyric acid sulfuric acid aqueous solution: At room temperature, L-2-aminobutyric acid and water are mixed at a mass ratio of 1:4. Then, sulfuric acid is slowly added dropwise under ice bath conditions. The molar ratio of sulfuric acid to L-2-aminobutyric acid is 1:1. After stirring and mixing until completely dissolved, L-2-aminobutyric acid sulfuric acid aqueous solution is obtained and ready for use.

[0053] (2) Preparation of sodium nitrite solution: Dissolve sodium nitrite in water of equal mass, stir to dissolve, cool to room temperature to obtain an aqueous solution of sodium nitrite, and set aside for use.

[0054] (3) Synthesis of L-2-hydroxybutyric acid: L-2-aminobutyric acid sulfuric acid solution and sodium nitrite solution were pumped into the two inlets of the microreactor at flow rates of 23.0 g / min and 9.0 g / min, respectively. The two liquids were mixed in the microchannel reactor at 80 °C. The residence time of the material in the microchannel reactor was 85 s. The internal pressure of the outlet was adjusted by the back pressure valve. The back pressure valve was set to 6 bar. After the system pressure and temperature stabilized, the reaction solution was collected at the outlet for 15 min. The pH of the collected solution was adjusted to 1.5 and stirred overnight. The solution was extracted 6 times with ethyl acetate at 0.5 times the total volume of the reaction solution. After drying, filtration and rotary evaporation, L-2-hydroxybutyric acid was obtained with a yield of 91% and a purity of 88.25%. No isomers were detected.

[0055] Example 6

[0056] (1) Preparation of L-2-aminobutyric acid sulfuric acid aqueous solution: At room temperature, L-2-aminobutyric acid and water are mixed at a mass ratio of 1:4. Then, sulfuric acid is slowly added dropwise under ice bath conditions. The molar ratio of sulfuric acid to L-2-aminobutyric acid is 1:1. After stirring and mixing until completely dissolved, L-2-aminobutyric acid sulfuric acid aqueous solution is obtained and ready for use.

[0057] (2) Preparation of sodium nitrite solution: Dissolve sodium nitrite in water of equal mass, stir to dissolve, cool to room temperature to obtain an aqueous solution of sodium nitrite, and set aside for use.

[0058] (3) Synthesis of L-2-hydroxybutyric acid: L-2-aminobutyric acid sulfuric acid solution and sodium nitrite solution were pumped into the two inlets of the microreactor at flow rates of 23.0 g / min and 9.0 g / min, respectively. The two liquids were mixed in the microchannel reactor at 80 °C. The residence time of the material in the microchannel reactor was 85 s. The internal pressure of the outlet was adjusted by the back pressure valve. The back pressure valve was set to 6 bar. After the system pressure and temperature stabilized, the reaction solution was collected at the outlet for 24 h. The pH of the collected solution was adjusted to 1.5 and stirred overnight. The solution was extracted 6 times with ethyl acetate at 0.5 times the total volume of the reaction solution. After drying, filtration and rotary evaporation, L-2-hydroxybutyric acid was obtained with a yield of 99.48% and a purity of 82.23%. No isomers were detected.

[0059] Comparative Example 1

[0060] 103.12 g of L-2-aminobutyric acid was added to a 5 L four-necked flask equipped with a thermometer, a constant pressure dropping funnel, and a mechanical stirrer. 1031.2 g of purified water was added, and then 300.0 g of sulfuric acid was added dropwise while stirring at 0 °C. Separately, 414.0 g of sodium nitrite was dissolved in 600.0 g of purified water and slowly added dropwise to the four-necked flask, keeping the temperature below 5 °C for 2 hours. During the process, a large amount of reddish-brown gas was generated, with significant exothermic reaction. After the addition was completed, the temperature was raised to 20 °C, and the reaction was observed on a TLC plate until the starting material was completely reacted. Sodium chloride was added until saturation. The mixture was extracted six times with 800 ml of ethyl acetate. The ethyl acetate layer was dried, filtered, and evaporated to dryness to obtain L-2-hydroxybutyric acid with a yield of 66.6%, a purity of 89.5%, and 0.73% isomers.

[0061] Comparative Example 2

[0062] (1) Preparation of L-2-aminobutyric acid sulfuric acid aqueous solution: At room temperature, L-2-aminobutyric acid and water are mixed at a mass ratio of 1:4. Then, sulfuric acid is slowly added dropwise under ice bath conditions. The molar ratio of sulfuric acid to L-2-aminobutyric acid is 1:1. After stirring and mixing until completely dissolved, L-2-aminobutyric acid sulfuric acid aqueous solution is obtained and ready for use.

[0063] (2) Preparation of sodium nitrite solution: Dissolve sodium nitrite in water of equal mass, stir to dissolve, cool to room temperature to obtain an aqueous solution of sodium nitrite, and set aside for use.

[0064] (3) Synthesis of L-2-hydroxybutyric acid: L-2-aminobutyric acid sulfuric acid solution and sodium nitrite solution were pumped into the two inlets of the microreactor at flow rates of 2.9 g / min and 1.1 g / min, respectively. The two liquids were mixed in the microchannel reactor at 40 °C. The residence time of the material in the microchannel reactor was 680 s. The internal pressure of the outlet was adjusted by the back pressure valve, which was set to 6 bar. After the system pressure and temperature stabilized, the reaction solution was collected at the outlet for 2 h. The pH of the collected solution was adjusted to 1.5 and stirred overnight. The solution was then extracted 6 times with ethyl acetate at 0.5 times the total volume of the reaction solution. After drying, filtration and rotary evaporation, L-2-hydroxybutyric acid was obtained with a yield of 97.28%, a purity of 73.22%, and 2.46% isomers.

[0065] The above description, in conjunction with specific embodiments, provides a further detailed explanation of the present invention. However, it should not be construed that the specific embodiments of the present invention are limited to these descriptions. For those skilled in the art, various deductions or substitutions can be made without departing from the concept of the present invention, and all such modifications or substitutions should be considered within the scope of protection of the present invention.

Claims

1. A method for synthesizing chiral L-2-hydroxy acids using a microchannel reactor, comprising the following: An acidic solution of L-2-amino acid and a sodium nitrite solution were pumped into a microchannel reactor for reaction. The microchannel reaction conditions included: reaction temperature: 80℃; residence time: 85s; the flow rate of the sulfuric acid solution of L-2-amino acid was controlled at 23g / min; and the flow rate of the sodium nitrite solution was controlled at 9g / min. The L-2-amino acid is L-2-butyric acid; In a sulfuric acid solution of L-2-amino acid, the molar ratio of L-2-amino acid to sulfuric acid is 1:

1. In a sodium nitrite solution, the mass ratio of sodium nitrite to water is 1:

1.

2. The method according to claim 1, characterized in that, The back pressure valve in the microchannel reactor is 1–16 bar.

3. The method according to claim 2, characterized in that, The back pressure valve in the microchannel reactor is 6 bar.

4. The method according to claim 1, characterized in that, After the reaction is complete, the pH of the reaction solution is adjusted to 1.5–2.5; the mixture is stirred and extracted with one or more solvents selected from methyl tert-butyl ether, dichloromethane, ethyl acetate, and n-butanol; the extraction is performed 2–8 times; the solvent is removed to obtain L-2-hydroxy acid.

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