Application and optimization strategy of biocatalysis technology in green synthesis of pharmaceutical intermediates

With the deepening of the goal of "double carbon" and the increasingly strict environmental protection regulations, green synthesis has become the core direction of the transformation and upgrading of pharmaceutical intermediate industry, and the traditional synthesis process with high pollution, high energy consumption and low atomic utilization rate has been gradually eliminated. As one of the core technologies in the field of green synthesis, biocatalysis technology has been widely used in the synthesis of pharmaceutical intermediates with its advantages of high efficiency, high selectivity, environmental friendliness and mild reaction conditions, and has become the key driving force to promote the green transformation of the industry. Based on years of research, development and production practice of pharmaceutical intermediates, Changsha Fuzhen Bio-technology deeply discussed the application points and optimization strategies of biocatalysis technology in the green synthesis of pharmaceutical intermediates, and provided reference for industrial technology upgrading.

Biocatalysis technology is a synthetic technology that uses biocatalysts (mainly enzymes) to realize chemical transformation under mild conditions (normal temperature, normal pressure and near neutral pH). Its core advantage lies in accurately controlling reaction sites, reducing side reactions, improving product yield and purity, avoiding the use of toxic and harmful organic solvents and catalysts, and reducing the discharge of "three wastes", which is in line with the development concept of green synthesis. At present, biocatalysis technology has been widely used in the synthesis of amino acids, heterocyclic compounds, steroids and other pharmaceutical intermediates, especially in the synthesis of chiral pharmaceutical intermediates, showing irreplaceable advantages.

In the synthesis of pharmaceutical intermediates, biocatalysis technology has a variety of application scenarios, among which the most representative ones include enzyme-catalyzed redox reaction, enzyme-catalyzed condensation reaction and enzyme-catalyzed hydrolysis reaction. In the synthesis of amino acid pharmaceutical intermediates, by selecting specific transaminase and dehydrogenase as biocatalysts, the efficient synthesis of amino acids can be realized. Compared with traditional chemical synthesis methods, not only the reaction conditions are mild, but also the use of heavy metal catalysts can be avoided, and the purity of products can reach over 99.5%, which greatly reduces the difficulty of subsequent separation and purification. For example, in the synthesis of common amino acid intermediates such as alanine and glutamic acid, the reaction yield can be increased to more than 95% and the waste discharge can be reduced by more than 80% by using biocatalysis technology.

In the synthesis of heterocyclic pharmaceutical intermediates, biocatalysis technology can effectively solve the problems of many side reactions and low product purity in traditional synthesis processes. Heterocyclic structure is one of the most common structural types in pharmaceutical intermediates, and its synthesis process often involves complex cyclization reactions. Traditional chemical synthesis methods are prone to produce a variety of isomer impurities, while the high selectivity of biocatalysts can accurately control the site and three-dimensional configuration of cyclization reactions, effectively reducing isomer formation. In the production of heterocyclic pharmaceutical intermediates, Fuzhen Bio used biocatalysis technology to optimize the synthesis process, which reduced the by-product content of a certain six-membered heterocyclic intermediate from 5% to below 0.5%, and significantly improved the product quality.

Although biocatalysis technology has obvious advantages in the green synthesis of pharmaceutical intermediates, in the actual application process, it still faces problems such as insufficient activity, poor stability, high cost and poor adaptability of reaction system, which restricts its large-scale application. Combined with the technical practice of Fuzhen Bio-technology, the application effect of biocatalysis technology can be improved through the following optimization strategies.

The first is the modification and screening of biocatalysts. Through genetic engineering, protein engineering and other technologies, the enzyme was modified to optimize the active center structure of the enzyme, improve the catalytic activity, stability and substrate compatibility of the enzyme, and reduce the use cost of the enzyme. For example, by modifying lipase by site-directed mutation technology, its catalytic activity in organic phase can be improved by 3-5 times, its stability can be significantly enhanced, and its service life can be prolonged. At the same time, an efficient enzyme screening system was established, and biocatalysts with strong adaptability and high catalytic efficiency were screened according to the synthetic requirements of pharmaceutical intermediates to improve the reaction efficiency.

The second is the optimization of reaction system. Biocatalytic reaction requires high parameters such as pH, temperature and solvent of the reaction system. Optimizing the reaction system can significantly improve the catalytic effect. For example, the mixed water-organic phase system is selected to replace the traditional pure organic phase system, which not only ensures the solubility of the substrate, but also maintains the activity of the enzyme; The pH of the reaction system was stabilized by adding buffer, and the reaction temperature was controlled within the optimum temperature range of the enzyme to reduce the inactivation of the enzyme. In addition, cocatalyst can be added to promote the reaction and improve the reaction yield.

The third is the large-scale adaptation of catalytic process. Aiming at the difference between laboratory biocatalysis process and industrial production, the parameters of catalytic process were optimized to realize the large-scale amplification of the process. For example, the continuous biocatalysis process is used to replace the traditional batch reaction, which improves the production efficiency and reduces the production cost; Optimize the immobilization technology of enzyme, realize the recycling of enzyme, further reduce the catalytic cost, and promote the application of biocatalysis technology in the large-scale production of pharmaceutical intermediates.

In the future, with the continuous innovation and development of biocatalysis technology, its application in the green synthesis of pharmaceutical intermediates will be more extensive. Changsha Fuzhen Bio will continue to increase investment in research and development of biocatalysis technology, focus on key technologies such as catalyst modification and reaction system optimization, promote the deep integration of biocatalysis technology and pharmaceutical intermediate synthesis process, continuously improve the green and refined level of products, and contribute technical strength to the green transformation of the industry.