CN-117164448-B - Method for synthesizing chiral L-2-hydroxy acid by micro-channel reactor

Abstract

The invention belongs to the field of chemical synthesis, and particularly relates to a method for synthesizing chiral 2-hydroxy acid by a micro-channel reactor. 2-hydroxy acid is synthesized from 2-amino acid by diazotization and hydrolysis, batch reactors are mostly adopted in industrial synthesis, the operation safety is low, and isomers exist in synthetic products. The invention synthesizes L-2-hydroxy acid by pumping the sulfuric acid aqueous solution of L-2-amino acid and sodium nitrite solution into a micro-channel reactor. The microchannel reaction conditions comprise a reaction temperature of 40-80 ℃, a residence time of 85-170 s, a back pressure valve set pressure value of 6bar, an amino acid solution flow rate of 9.6-23 g/min and a sodium nitrite solution flow rate of 4.5-9.6 g/min. After the reaction is finished, regulating the pH range of the reaction solution to be 1.5-2.5, and extracting the reaction solution by ethyl acetate to obtain the L-2-hydroxybutyric acid. The technical scheme of the invention has high operation and equipment safety, can realize the accurate control of diazotization reaction, has no optical isomer in the finally prepared aliphatic L-2-hydroxy acid, and improves the product quality.

Inventors

• YANG SHENG
• LIU JIAN
• LI BO
• LIN CHUANHUA
• LIAO JIANYU
• DU ZHENJUN
• HUANG HAOXI
• SU ZHONGHAI

Assignees

• 成都倍特药业股份有限公司

Dates

Publication Date

20260512

Application Date

20220526

Claims (4)

1. 1. The method for synthesizing chiral L-2-hydroxy acid by using a microchannel reactor comprises the following steps of pumping an acid solution of L-2-amino acid and a sodium nitrite solution into the microchannel reactor for reaction, wherein the microchannel reaction conditions comprise a reaction temperature of 80 ℃, a residence time of 85s, a flow rate of a sulfuric acid solution of the L-2-amino acid of 23g/min and a flow rate of a sodium nitrite solution of 9g/min; the L-2-amino acid is L-2-butyryl acid; The molar ratio of the L-2-amino acid to sulfuric acid in the sulfuric acid solution of the L-2-amino acid is 1:1; in the sodium nitrite solution, the mass ratio of the sodium nitrite to the water is 1:1.
2. 2. The method of claim 1, wherein the back pressure valve pressure in the microchannel reactor is 1 to 16bar.
3. 3. The method of claim 2, wherein the back pressure valve pressure in the microchannel reactor is 6bar.
4. 4. The method of claim 1, wherein after the reaction is completed, the pH of the reaction solution is adjusted to 1.5-2.5, the reaction solution is stirred and extracted with one or more solvents selected from methyl tertiary butyl ether, methylene dichloride, ethyl acetate and n-butanol, the extraction times are 2-8, and the solvent is removed to obtain the L-2-hydroxy acid.

Description

Method for synthesizing chiral L-2-hydroxy acid by micro-channel reactor Technical Field The invention belongs to the field of chemical synthesis, and particularly relates to a method for synthesizing chiral 2-hydroxy acid by a micro-channel reactor. Background Chiral 2-hydroxy acid is widely applied in the fields of medicines, cosmetics, polymer synthesis and the like, for example, L-2-hydroxy butyric acid is one of raw materials for synthesizing the pembrofibrate, L-2-hydroxy 3- (4-hydroxyphenyl) propionic acid is one of raw materials for non-enzymatic synthesis of the medicine tiglinide and (S) - (-) -rosmarinic acid, 2-hydroxy-3-methylbutyric acid is taken as an important raw material in the total synthesis of tacalcitol, and compounds such as lactobionic acid, glycolic acid, tartaric acid, lactic acid, citric acid and malic acid can be taken as stripping agents, moisturizers, antioxidants and the like in cosmetics, and simultaneously are also primary chemical raw materials. At present, the synthesis of chiral 2-hydroxy acid mainly comprises a biological enzyme method, an asymmetric reduction method, a chiral resolution method and the like. The method for synthesizing the 2-amino acid by diazotization and hydrolysis has the advantages of high chiral selectivity, low cost of raw materials, simple process development and the like, and is the most widely used method in industry. In industrial synthesis, a reaction kettle and other traditional batch reactors are mostly adopted, and in order to ensure the reaction yield, excessive sodium nitrite is added into the reaction, so that a large amount of nitrogen oxides are generated, the generated diazonium salt is extremely easy to decompose, the excessive sodium nitrite reacts and releases heat severely, the safety risk is increased, meanwhile, the optical purity of the product is reduced by long-time reaction, and optical isomers still exist in the synthesized product. In 2012, dennls x.hu et al used a tubular microchannel reactor to diazotize part of the L-2-amino acid, reacted for 10-60min at 60 ℃ with continuous post-treatment of the reaction, and obtained 30% -100% yields by continuous EA extraction, ee values between 60% -98%, isomers were always present, and hourly throughput of 1.0g, limited to laboratory studies. Disclosure of Invention Aiming at the problems, the invention provides a method for preparing chiral 2-hydroxy acid by a microchannel reactor, which has the characteristics of safety, high efficiency and simple operation, and meanwhile, the prepared product has few byproducts, does not contain optical isomers, and reduces the cost for removing the isomers subsequently. The microreactor is a micro-pipe reactor based on continuous flow, and is used for replacing the traditional batch reactors such as glass flasks, funnels, reaction kettles commonly used in industrial organic synthesis and the like. The invention improves the reaction stereoselectivity and flux by changing the reaction temperature, shortening the reaction time, improving the concentration of the reaction liquid, changing the post-treatment mode and using static mixing micro-channel reactor equipment on the basis of Dennls X.Hu et al, reduces the solvent consumption and simultaneously realizes the 2kg scale amplification synthesis. After the treatment by the technical scheme of the invention, no optical isomer exists in the 2-hydroxy acid product, and the key point is to shorten the reaction time and reduce the configuration inversion of the product at high temperature. Specifically, the invention is realized by adopting the following technical scheme: A method for synthesizing chiral 2-hydroxy acid by a microchannel reactor comprises the following steps of pumping an aqueous solution of sulfuric acid of L-2-amino acid and a sodium nitrite solution into the microchannel reactor for reaction, wherein the microchannel reaction conditions comprise the reaction temperature of 0-100 ℃, the residence time of 30-180 s, the acid solution flow rate of the L-2-amino acid is controlled to be 5-30 g/min, and the sodium nitrite solution flow rate is controlled to be 2-15 g/min. Further, the reaction temperature is 40-80 ℃, the residence time is 85-170 s, the flow rate of the acid solution of the L-2-amino acid is controlled to be 9.6-23 g/min, and the flow rate of the sodium nitrite solution is controlled to be 4.5-9.6 g/min. In the technical scheme of the invention, the internal pressure of the discharge port of the microchannel reactor is regulated by a back pressure valve, wherein the back pressure valve pressure is 1-16 bar, and preferably 6bar. After the reaction is finished, the pH of the reaction solution is adjusted to be 1.5-2.5, preferably 1.5, and the reaction solution is stirred, extracted by one or more organic solvents selected from methyl tertiary butyl ether, methylene dichloride, ethyl acetate and n-butyl alcohol for 3-8 times, and then the solvent is removed to obtain the L-2