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Chiral Drug Synthesis

2021-11-11
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Chiral drugs refer to drugs that contain chiral centers (including chiral carbon, chiral nitrogen, chiral sulfur, etc.) in their molecular structure. In January 1992, the FDA promulgated the “Development of Stereoisomer Drugs” technical research guidelines, giving guidance on the work that needs to be done in the research of stereoisomer drugs. In December 2006, the CFDA issued the “Technical Guidelines for the Quality Control of Chiral Drugs”, which provided detailed guidance on the research work that needs to be carried out in the synthesis process, structural confirmation and quality control research of chiral drugs, and indicated for the research of chiral drugs. Up the direction.

As a special kind of chemical drugs, chiral drugs should not only follow the “Guiding Principles for the Research of Chemical Drug Preparation Processes”, but also combine the introduction of chiral centers to establish appropriate process control indicators for monitoring. The configuration changes during the reaction process are mainly summarized into the following three situations:


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1) Directly Introduce from the Starting Materials

The starting material should meet the following two conditions: one is that it has a commercial source, and the other is that its chemical structure, physical and chemical properties, preparation methods, and impurities have clear information. The optical purity of the final product mainly depends on the optical purity of the starting material and the possibility and extent of the configuration change of the chiral center in the subsequent reaction process. Therefore, it is necessary to establish a three-dimensional specific analysis method of the starting material, strictly control the optical purity, and establish reasonable and feasible limits. For example, in the synthesis of the lipid-lowering drug atorvastatin calcium, an outsourcing key side chain is used as one of the starting materials (the structure is as shown in the figure below), which contains two chiral carbons, and the optical quality control of the starting material needs to be established Indicators, otherwise it will affect the evaluation of the quality of the final product.

Due to the possibility of configuration changes in the subsequent reaction process, it is necessary to combine the process control in the process to detect the stereoisomers in the intermediates of each reaction, analyze and monitor the possibility of configuration changes.

2) Asymmetric Synthesis Process

Using stereoselective or specific reactions (including enzyme-catalyzed reactions) to introduce chiral centers of the desired configuration into the molecule, the optical purity of the final product directly depends on the stereoselectivity of the asymmetric synthesis reaction. Before determining the process, it is necessary to consult relevant literature as much as possible to fully understand the reaction mechanism, reaction conditions, stereoselectivity, etc. of different reactions in order to select the appropriate reaction. Some reactions have greater stereoselectivity due to steric hindrance of the substrate, and the desired configuration may be the dominant configuration obtained from the reaction. For example, in the synthesis process of the antihypertensive drug eplerenone, the epoxidation step of the C-C double bond has very high stereoselectivity due to the steric hindrance of the substrate.

The stereoselectivity of the asymmetric synthesis reaction has a crucial impact on the quality of the final product and is one of the key steps of the entire synthesis process. Therefore, process parameters must be screened and optimized, and sufficient risk assessment must be performed to determine key process parameters. For the intermediates introduced into the chiral center as the key intermediate for chiral control, internal control standards for the intermediates should be established, focusing on and monitoring the possible stereoisomers after the introduction of the chiral center. For example, in the synthesis of the antiepileptic drug eslicarbazepine acetate, a chiral metal Ru catalyst is used to enantioselectively reduce the ketone to the alcohol to obtain the desired configuration, and then react with acetic anhydride to obtain the final product.

After the introduction of the chiral center, configuration changes may still occur during subsequent reactions. The stereoisomers in the subsequent intermediates are also required to be detected. According to the difficulty of quality control of the final product, reasonable intermediate optical isomers can be determined Control limits.

In addition, some of the more commonly used chiral catalysts, such as ruthenium, rhodium, etc., are highly toxic. You can refer to the guidelines for the limit of metal catalysts or metal reagent residues issued by the European Union EMEA for quality control of heavy metal residues.

3) Resolution of Racemate

The more commonly used is still to use chiral resolution reagents to form salts with racemic intermediates or final products, separate and purify to obtain the required diastereomers, and then remove the resolution agent to obtain the desired configuration. Compound. Attention should be paid to choosing cheap, easily available, and high optical purity resolution reagents; secondly, the obtained diastereomers should be purified as much as possible, which is a key step to control optical purity; if it is to resolve racemic intermediates, It is also necessary to consider whether the subsequent reaction steps will cause configuration changes, and quality control of the optical purity of the intermediate is also required. For example, in the synthesis of the antidepressant escitalopram oxalate, a chiral acid is used as a resolving agent to obtain an optically pure chiral intermediate, and the target product is obtained through steps such as condensation and salt formation.

In short, no matter how the chiral center is introduced, in the research of its synthesis process, it is necessary to select practical analytical methods to detect and control the optical purity of the product, and to fully reflect it in the drug application data.

Related Articles:

Pharmacokinetics and Bioanalysis of Chiral Drugs

Preparation Method and Related Synthesis Process of Chiral Drug

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