Understand the design and selection of drug synthesis process route

Expensive route and best route.

The main targets of the optimization route research include new drugs that will be listed soon, drugs whose compound patents are about to expire, and drugs with large output and wide application.

The optimized route must have the characteristics of reliable quality, economy, efficiency, process safety and environmental friendliness.

The research content of drug synthetic route covers two aspects: the design of synthetic route and the selection of synthetic route.

First, the inverse synthesis analysis method

(1) The basic concepts and main methods of inverse comprehensive analysis.

Inverse synthesis analysis, also known as disconnection method and traceability method, is the most basic and commonly used method for designing organic synthesis routes.

The prominent feature of inverse synthesis analysis method is inverse logical thinking, which deduces the thinking process of simple starting materials from complex target molecules, which is just the opposite of the actual process of chemical synthesis, so it is called "inverse" synthesis or "inverse" synthesis.

The contemporary master of organic synthetic chemistry and Professor E. J. Corey of Harvard University formally put forward the inverse synthetic analysis method in the 1960s. Corey put forward the concepts of disconnection, synthesizer and synthesis equivalence.

The process of reverse synthetic analysis can be simply summarized as: based on the structural analysis of the target molecule, three steps are repeatedly cut off, the synthon is determined, and the synthetic equivalent is found until a suitable starting material is found.

(2) Key links and common strategies of inverse comprehensive analysis.

In the process of designing drug synthesis route by inverse synthesis analysis, the choice of cutting site is the key link to determine the quality of synthesis route.

The choice of cutting site should be based on chemical reaction, that is, "combination can be separated". In the practical work of drug synthesis route design, carbon-hetero bonds or carbon-carbon bonds in molecular skeleton which are easy to construct are usually selected as cutting sites.

The more comprehensive the knowledge of chemical reaction, the broader the design idea of synthetic route.

When designing the process route of drug synthesis, it is usually hoped that the route will be as simple as possible and the construction of drug molecules will be completed with the least reaction steps. However, it should be noted that the pursuit of simple route should not be at the expense of drug quality, and factors such as the length of synthetic route and the difficulty of technological process must be considered on the premise of ensuring key indicators such as drug purity.

In the process of route design, designers are required to fully understand the selectivity of reactions (especially key reactions) and try to use highly selective reactions to reduce the generation of by-products. When necessary, the strategy of protecting groups should be adopted to improve the selectivity of the reaction in order to obtain high-quality products.

Heterocycles are important structural units of organic compounds. Among the known organic compounds, heterocyclic compounds account for about 65%.

Heterocycle is a very common structural fragment in drugs, which is commonly used in the treatment of major diseases such as tumor, infection, cardiovascular disease and diabetes.

In the process of designing the synthetic route of drugs containing heterocyclic rings by inverse synthesis analysis, one way is to introduce heterocyclic rings into molecules as independent structural fragments; The other way is to use heterocyclic ring as cutting target, select specific valence bond in heterocyclic ring as cutting site, and complete the synthesis of target molecule by constructing heterocyclic ring.

(3) The methods and strategies of inverse synthesis analysis using molecular symmetry.

When designing the synthetic routes of these target molecules, we can skillfully use their molecular symmetry to select suitable sites for cleavage, so that two (or several) synthons correspond to the same synthetic equivalent, or one (or several) synthons correspond to the synthetic equivalent with molecular symmetry, thus greatly simplifying the process of inverse synthetic analysis and designing simple and efficient synthetic routes. This synthetic route design method is called molecular symmetry method, which is a special case of inverse synthetic analysis.

(d) Application of inverse synthesis analysis method in semi-synthetic route design.

Most of the existing chemically synthesized drugs are fully synthesized, but semi-synthetic drugs are not uncommon, especially anti-infective drugs, anti-tumor drugs and hormone drugs.

When the semi-synthetic design idea is applied to the reverse synthesis analysis, both the head and the tail should be taken into account, so that the reverse synthesis process can finally point to the raw materials of natural products with wide sources, low prices and reliable quality. Most of these natural products are microbial metabolites, and may also come from plants or animals.

(5) that application of inverse synthesis analysis method in the design of synthetic route of chiral drugs.

In the process of designing the synthetic route of chiral drugs by reverse synthesis analysis, besides the construction of molecular skeleton and the transformation of functional groups, the formation of chiral centers must also be considered!

In the synthesis of chiral drugs, one method is to synthesize raceme first, and then get a single isomer through resolution, and the other method is to synthesize a single isomer directly.

Using racemic resolution, the design process of synthetic route is the same as that of conventional method, but the resolution method used must be efficient and reliable.

The direct synthesis of single isomers mainly includes two technical methods: chiral source synthesis and asymmetric synthesis.

Chiral cell synthesis technology refers to the conversion of cheap natural or synthetic chiral compounds into chiral products through chemical modification.

Compared with chiral raw materials, the configuration of the chiral center of the product can not only be maintained, but also be turned over or transferred.

When designing the synthetic route of chiral drugs, we must carefully consider the chemical reaction, separation and purification process after the construction of chiral centers to ensure that the configuration of chiral centers will not be destroyed and finally obtain chiral products with higher purity.

Second, analogy method

(A) the basic concepts and main methods of analogy.

In the process of designing the process route of drug synthesis, in addition to the inverse synthesis analysis based on logical thinking, the simulation analogy method with analogy thinking as the core can also be used.

The simulation and analogy method in the design of drug synthesis process route consists of two stages: "simulation" and "analogy"

In the "simulation" stage, firstly, the structure of drug molecules (target compounds) should be accurately and carefully analyzed to find its key structural characteristics; Secondly, it is necessary to use a variety of literature retrieval methods to obtain a variety of analogues and their chemical information with high similarity to the structural characteristics of the target compound; Thirdly, it is necessary to compare, analyze and summarize several synthetic routes of various analogues, and gradually form a broad understanding and profound understanding of the design ideas of synthetic routes of analogues reported in the literature.

In the "simulation" stage, firstly, the process route which is expected to be suitable for the synthesis of the target compound is selected from many simulated synthesis routes; Secondly, the structural characteristics of the target and its analogues are further analyzed to confirm the structural differences between the former and the latter; Finally, the synthetic route of drug molecules is designed with reference to the selected synthetic route of analogues and full consideration of the actual situation of drug molecules themselves.

For a series of drugs with the same target and highly similar chemical structures, the success probability of synthetic route design by analogy is often high. Analogy analogy method can not only be used to construct the molecular skeleton of a series of drugs, but also be extended to construct the chiral centers of a series of chiral drugs.

(B) the scope of application of analogy and matters needing attention

As a reasoning mode with analogical thinking as the core, the analogy method in the design of drug synthesis process route has its inherent limitations.

The synthetic routes of some drug molecules whose chemical structures seem to be very similar are not similar, and sometimes even far apart.

When designing the process route of drug synthesis by analogy, we must do "specific problems, specific analysis". While fully understanding the structural characteristics of various drugs, it is necessary to thoroughly investigate the structural characteristics of each drug molecule itself.

If the intermolecular structure of drugs is dominant, if there is an opportunity to directly design the synthetic process route through analogy, it can be boldly adopted; If the personality factor of a drug molecule plays a key role and cannot directly and comprehensively simulate analogy, it can indirectly and partially simulate analogy, and on the basis of skillfully learning from the successful experience of others, think independently, find another way and create its own novel method.

A, the evaluation criteria of process route

The optimized synthetic route with good industrialization prospect must have the basic characteristics of reliable quality, economic efficiency, process safety and environmental friendliness.

From a technical point of view, the main characteristics of the optimized synthetic route can be summarized as follows: convergence of synthetic strategies, minimum reaction steps, stable source of raw materials, feasible chemical process, reliable production equipment, simplified post-treatment process and minimal environmental impact. The above characteristics are the main technical indexes to evaluate the chemical pharmaceutical process route.

What needs to be pointed out here is that the determination of the final route is obviously restricted by economic factors. Based on the above technical indexes, it is necessary to estimate the comprehensive cost of the process route more accurately, and choose the route with high output and low consumption as the practical process route applied to industrial production.

Compared with linear synthesis method, convergent synthesis method has certain advantages:

The total amount of (1) intermediates is reduced, and less starting materials and reagents are needed, thus reducing the cost;

(2) The required reaction container is small, which increases the flexibility of equipment use;

(3) the synthesis cost of the intermediate is reduced, and once an error occurs in the production process, the loss is relatively small.

2. Minimize the reaction steps.

On the premise that other factors are not much different, the synthetic route with fewer reaction steps often presents the advantages of higher total yield, shorter cycle and lower cost. The simplicity of the synthetic route is the simplest and most intuitive index to evaluate the technical route.

It is an important pursuit of synthetic route design to complete the preparation of the target in as few steps as possible. Simple and effective synthetic routes are usually the result of careful design.

Realizing two (or even more) chemical transformations in one step is one of the common ideas to reduce the number of reaction steps.

The sequence of some reactions can be carefully designed, so that the intermediate produced in the first step can trigger the subsequent transformation and produce series reaction or domino reaction, which greatly reduces the reaction steps and shortens the synthetic route.

Tandem reaction means that two or more reactions belonging to different types are carried out in series and completed in one bottle.

Domino reaction means that one reaction in a series of reactions can trigger another reaction, thus making multi-step reactions continue.

3. The source of raw materials is stable

When evaluating synthetic routes, it is necessary to know the sources, specifications and supply of various raw and auxiliary materials used in each synthetic route, and at the same time, consider the storage and transportation of raw and auxiliary materials.

Some raw and auxiliary materials are temporarily unavailable, so we need to consider self-production.

For the synthetic route to be selected, it is necessary to list the names, specifications and unit prices of various raw materials, calculate the unit consumption (the number of various raw materials needed to produce 1kg products), and then calculate the cost of various raw materials and compare them with the total cost of raw materials.

4. Chemical technology is feasible.

The feasibility of chemical technology is an important index to evaluate the synthesis process.

The optimized process route should be stable and reliable, the probability of accidents is extremely low, and the yield and quality of products have good reproducibility. The reaction conditions in each step are mild, easy to realize and control, and extreme conditions such as high temperature, high pressure or ultra-low temperature are avoided as far as possible.

Platform reaction: the reaction with a wide range of optimization conditions, even if a certain process parameter deviates slightly from the optimal conditions, the yield and quality will not be greatly affected;

Point reaction: the process parameters changed slightly, and the output and quality decreased obviously.

5. Reliable production equipment

In the process of industrial synthesis route selection, the factors of equipment must be considered, and the reliability of production equipment is an important index to evaluate the synthesis process route.

The practical process route should use conventional equipment as much as possible, and avoid using special kinds, materials and models of equipment as much as possible.

6. Simplify the post-treatment process

Post-treatment processes such as separation and purification are an important part of the process route, accounting for about 50% of labor time and 75% of equipment support in industrial production.

In the whole process, reducing the number of post-treatment or simplifying the post-treatment process can effectively reduce the loss of materials, reduce the discharge of pollutants, save working hours, save equipment investment, reduce the labor intensity of operators and reduce their contact time with potentially toxic chemicals.

The common method of compression post-treatment process is that after the reaction, the product directly enters the next step without separation and purification, and several reactions are continuously operated to realize the "one-pot operation" of multi-step reactions.

The prerequisite for using the "one-spoon stew" method is that the solvents and reagents used in the previous step and the by-products produced have little influence on the next reaction, and will not lead to the decrease of the purity of products and key intermediates.

If the "one-spoon stew" method is used properly, it can not only simplify the operation, but also greatly improve the total yield of the whole reaction route.

7. Minimize environmental impact

Environmental protection is China's basic national policy and the fundamental guarantee for sustainable economic and social development.

The traditional chemical pharmaceutical industry produces a lot of waste, which still has a negative impact on the environment after harmless treatment.

The key to solve the pollution problem of chemical pharmaceutical industry is to adopt green technology to minimize its impact on the environment and reduce or even avoid the production of pollutants from the source.

To evaluate the "greenness" of the synthetic route, it is necessary to consider the atomic economy of the whole route, the efficiency of each reaction step and the safety of the reagents used.

Atomic economy is one of the core concepts of green chemistry, which is defined as the ratio of the atomic weight in the final product to the atomic weight of all initiators involved in the reaction.

For the reaction with good atomic economy, the atoms in the raw material molecules should appear in the product molecules as much as possible, and the ratio should be close to 100%.

Second, the choice of process route

(A) the basic ideas and main methods of process route selection

First of all, we should make an objective and accurate evaluation of the advantages and disadvantages of each route according to the main technical indicators of the evaluation route discussed in the previous section;

Then it is necessary to repeatedly compare and weigh the advantages and disadvantages of each route and choose an alternative process route with clear industrialization prospects;

After systematic and rigorous research and demonstration, the optimal route is finally determined for pilot or industrial production.

The selection of process route must be based on technical analysis and guided by market analysis, and the technical analysis and market analysis should be closely combined to obtain the optimized process route with the lowest comprehensive cost.

Only in this way can enterprises exchange less resources for more profit returns and bring considerable economic benefits; At the same time, it provides high-quality and cheap pharmaceutical products for the society, thus producing good social benefits.

(B) Patent issues in the selection of process routes

A patent is an invention protected by legal norms. When an invention-creation applies to the state examination and approval authority for a patent, the patent applicant shall be granted the exclusive right to enjoy the invention-creation within a specified period of time after being examined and approved according to law.

Patent right is an exclusive right with exclusivity. If a non-patentee wants to use the patented technology of others, he must obtain the consent or permission of the patentee according to law.

The patent right granted by a country according to its patent law is only valid within the jurisdiction of that country's law. The legal protection of patent right has timeliness, and patent right is only valid within a specific time range.

The current patent law is the third revised edition promulgated on February 27, 2008.

China's patent law divides patents into three categories, namely invention, utility model and design.

Invention refers to a new technical scheme for a product, method or its improvement, which is mainly embodied in novelty, creativity and practicality.

In the process of chemical pharmaceutical technology research, if it is found that the process route or method is obviously different from others' patents and has the characteristics of novelty, creativity and practicality, we can consider applying for a patent for new process inventions, protect our own inventions, form independent intellectual property rights, and strive to produce economic benefits.

In some cases, in order to avoid the protection scope of others' patents, enterprises may be forced to develop new technical routes.

It takes many years and a lot of money to develop the best process. In order to avoid helping competitors, almost all enterprises are reluctant to disclose any details related to the optimal process.