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Preparation Method and Related Synthesis Process of Chiral Drug

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At present, chiral drugs have occupied an important position in the global pharmaceutical market. Chiral drugs have high technical barriers, good economic benefits, high curative effect, low toxic and side effects, and low dosage. The research and development of chiral drugs has become an important development direction of the pharmaceutical industry.

Preparation method of chiral drugs

There are three main ways to prepare chiral drugs:

  • One is: extracting chiral drugs or chiral intermediates from natural products;

  • The second is: the separation of racemic chiral drugs or their chiral intermediates by the resolution method, which mainly includes crystallization resolution, chemical resolution, kinetic resolution, chromatographic resolution and biological enzymatic resolution. Classification, etc.;

  • The third is: the use of asymmetric reactions to synthesize chiral drugs or their chiral intermediates, mainly including chemical synthesis and biosynthesis.

    Medicilon can undertake the synthesis of special reagents, intermediates and molecular fragments, preparation of standard products, synthesis design and preparation of impurities or metabolites, synthesis of stable isotope internal standards and synthesis of tritiated compounds.

    Or for extraction from natural products, this method is mainly to separate and extract natural or biotransformed chiral compounds from animals and plants. For example, the chiral anticancer drug paclitaxel was first extracted from yew. However, natural raw materials are usually limited, and a large amount of low-priced drugs cannot be obtained through extraction, so this method has greater limitations.

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    In addition, the mechanism of extraction from natural products is more complicated, and in addition to separation and extraction, the control of its process is different from the usual resolution or synthesis methods, so this chapter will mainly focus on the second and third approaches. Explain. The separation of racemates of chiral compounds is a classic separation method, which has been in industrial production for more than 100 years, and is currently the most commonly used method for obtaining chiral drugs. The principle of the resolution method is to separate the racemates into single isomers by physical, chemical or biological methods under the action of chiral additives.

    The resolution method is simple to operate and has good reproducibility, but its biggest disadvantage is that the theoretical yield of the product is only 50%. Therefore, sometimes it is necessary to eliminate the non-target enantiomers at the same time as the resolution. Rotation, so that it is continuously converted into the required enantiomers, thereby improving the utilization of raw materials and the separation yield of products.

    Asymmetric synthesis, also known as chiral synthesis, is the most direct way to obtain chiral drugs. The asymmetric synthesis of chiral drugs includes the synthesis of target chiral products from chiral molecules, or the transformation of potential chiral compounds into one or more chiral compounds under the action of chiral reagents, catalysts or auxiliary agents and other chiral substrates. Sex center compound.

    For successful asymmetric synthesis, the metrics include:

    ① Whether the product has a high enantiomeric excess (e.e.%);

    ② Whether the chiral adjuvant is easy to prepare and recycle;

    ③ Whether any one of the enantiomers can be obtained;

    ④ The reaction is best to be catalytic synthesis, because asymmetric catalysis (including chemical catalysis and biocatalysis) is the only chiral synthesis method with chiral amplification.

    Technical guidelines for the research of chiral drug synthesis technology

    Before the 1980s, due to technical limitations, chiral drugs were all marketed in the form of racemates. However, some racemate drugs have serious side effects during the use process, such as the “Thalidomide” incident in Europe in 1960. Many mothers took the sedative-Thalidomide during pregnancy. Diamine, as a result, about 8,000 to 12,000 deformed babies are born worldwide, and about 5,000 to 7,000 babies have died of deformities before they are born.

    The reason for this tragedy is that the S-isomer of racemic thalidomide is teratogenic, and this incident has also prompted people to pay more attention to the corresponding research on the different isomers of chiral drugs. In 1992, the U.S. Food and Drug Administration (FDA) issued the guidelines for chiral drugs for the first time, requiring all racemate drugs marketed in the U.S. to explain the respective pharmacological effects, toxicity, and toxicity of the isomers contained in them. Clinical effect.

    Since then, the drug regulatory authorities of various countries (regions) have made similar regulations for the research and development of chiral drugs, and they have made similar regulations on the market to standardize and guide the research and development of chiral drugs. The research work required for the confirmation of the synthesis process structure of chiral drugs and the quality control research has made standard requirements, and clarified the basic thinking of the pharmaceutical research of chiral drugs in my country.

    Synthesis process control of chiral drugs

    For the preparation method of any kind of chiral drug, in addition to following the existing pharmaceutical research technical guidelines, it is also necessary to study the characteristics of the chiral drug, especially the optical purity of the chiral center at each stage of drug synthesis. Strict control.

    First of all, when studying the preparation process of chiral drugs, effective process control methods should be adopted according to the attractive method of the chiral center to strictly control the optical purity of the chiral raw material and the reaction product of each step, and the various reactions after the introduction of the chiral center The intermediate should also be combined with the reaction mechanism to effectively separate and control the possible stereoisomer impurities. In this way, it can be combined with the quality control of the final product to achieve the purpose of comprehensive control of the optical purity of the product.

    Control of starting materials

    According to the “Guiding Principles of Chiral Drug Quality Control Research Technology”, “The chiral center in the final product is drawn from the pure starting materials or reagents. In the subsequent preparation process, the hand is no longer involved. The configuration changes of the sex center or the configuration changes involved are controllable.

    Therefore, the optical purity of the final product mainly depends on the following two aspects: the optical purity of the starting materials or reagents; whether the subsequent reaction process will affect the existing chiral centers, resulting in the possibility and degree of racemization. So when conducting process research.

    First of all, it is necessary to use stereospecific analysis methods to strictly control the optical purity of starting materials or reagents, and to establish reasonable and feasible limits for chiral impurities.

    Secondly, according to the mechanism of the subsequent reaction. Fully analyze whether the subsequent reaction will affect the configuration of the existing chiral center. If it may affect, the process conditions should be studied and optimized to avoid or reduce the generation of racemization as much as possible.

    Due to the possibility of configuration changes in subsequent reactions, it is not enough to control only the optical purity of the starting materials or reagents in the preparation process, especially when there are multiple chiral centers in the final product, and it is difficult to determine the final product. To effectively control all the stereoisomer impurities in the product, it is necessary to combine the process control in the process to comprehensively control the optical purity of the final product.

    This requires the detection of stereoisomer impurities in the intermediates of each step of the reaction after the introduction of the chiral center during process research, analysis and monitoring of the possibility of racemization. If racemization does not occur , You only need to strictly control the process operating parameters in the preparation process according to the results of process optimization and verification; if partial racemization may occur, in addition to strictly controlling the process operating parameters, reliable indicators are also required To control the optical purity of the intermediate, that is, to strictly control the stereoisomeric impurities in the reaction intermediate. “

    Confirmation of Product Structure

    Since chiral drugs have a three-dimensional structure, and under achiral conditions, the enantiomers generally have the same melting point and solubility chromatographic retention behavior, infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (Nuclear Mag-netic Resonance, NMR), Therefore, the confirmation of the structure of chiral drugs has a certain degree of particularity. In addition to the general principles of structural confirmation, special attention should be paid to the research and confirmation of its configuration.

    Preparation and Process Control

    The overall goal of chiral drug preparation research is the same as that of common chemical drugs, but the difference is that the configuration of chiral drugs must be kept unchanged during the research process. The stability of the configuration of chiral drugs is also an important factor that needs to be considered when choosing the dosage form of chiral drug preparations, such as its stable pH range, the stability of the configuration in solid and liquid state, the stability of factors such as light, heat, and air.

    If the research shows that the configuration of chiral drugs is not stable enough in the solution state, and the configuration can change, it is not suitable to choose liquid dosage forms such as injections and oral solutions.

    Quality Research and Quality Standard Control

    When conducting quality research on chiral drugs, the process and the stability of each chiral center should be combined to determine the stereoisomer impurities that need to be studied and controlled, and attention should be paid to verifying the stereospecificity of various chiral analysis methods; when formulating quality standards, The research data of all aspects should be integrated to monitor the optical properties and optical purity of the product reasonably and effectively; in the stability study, a sensitive three-dimensional specific optical purity detection index should be set up to monitor the stability of the configuration

    Stability Research

    According to different research purposes, the content of stability research can be divided into influencing factor tests, accelerated tests, and long-term retention sample tests. The basic principles and methods of chiral drug stability research are generally the same as those of common chemical drugs, but the stability test of chiral drugs It is also necessary to focus on the stability of the drug configuration, that is, by setting up appropriate optical purity inspection items and adopting sensitive and stereospecific inspection methods (such as stereoisomer inspection, etc.), investigating the quality of chiral drugs in APIs or preparations Changes in optical purity or the proportion of three-dimensional purchased bodies.

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