2023 Author: Bryan Walter | [email protected]. Last modified: 2023-05-21 22:24
Polish researchers have adapted the Chematica synthesis pathway planning software to find synthetic pathways that do not violate existing patents. This became possible thanks to the use of the technique of retrosynthetic analysis and the "blocking" of key chemical bonds described in patents. As an example, researchers have found alternative synthetic routes for three popular drugs. An article describing the method was published in Chem.
Today, synthesis paths are planned not only manually, but also with the help of automated programs. They have access to databases on various reactions, as well as the properties of substances. As a result, the scientist can specify the final substance and find the sequence of necessary reactions for its synthesis. One of these programs, called Chematica, was created in 2012 by a group of scientists led by the author of the new work, Bartosz Grzybowski. However, the presence of a program for searching for synthesis paths does not solve one important problem - many substances used as commercial drugs are protected by patents describing many possible pathways for their synthesis.
Grzybowski and his colleagues at the Institute of Organic Chemistry of the Polish Academy of Sciences have learned to use Chematica to find new synthetic routes not described in patents. To do this, they wrote additional algorithms that can be applied to other similar programs. The researchers used the method of retrosynthetic analysis, in which the final substance is broken down into simpler precursors. Due to the multitude of such subdivisions, the analysis often yields rather simple and inexpensive starting materials suitable for commercially viable synthesis. However, in the case of popular drugs, many of the obvious pathways for the separation of molecules (this term in retrosynthetic analysis is usually called the process of breaking a chemical bond with the subsequent formation of two or more substances) have already been described and may violate patents. As an example, scientists showed all the described pathways for the synthesis of three important drugs: linezolid, used as an antibiotic of the last reserve, sitagliptin, used to treat type 2 diabetes mellitus, and the anti-cancer substance panobinostat.
Aggregate of all patented synthetic routes for linezolid (A), sitagliptin (B), and panobinostat (C)
Writing all exceptions manually is a rather laborious task, which, moreover, may not bring results, because in addition to the precursors and reactions directly described in patents, there are their chemical analogs that will be perceived by the program as suitable, but in fact also will not help to circumvent patents. Instead, scientists have taught an algorithm to determine chemical bonds in substances, the break or connection of which is most often found in patents, and therefore are key in the described synthesis methods, and to exclude them.
Despite the fact that some of the synthesis pathways and precursor substances are inaccessible in this case, the program can still find suitable methods thanks to a database containing data on about 60 thousand types of reactions and 7 million known substances, of which about 200 thousand are known for their price., which allows you to immediately estimate the cost of synthesis. The authors tested the method on three popular drugs - linezolid, sitagliptin and panobinostat - and within a few minutes obtained new synthetic routes for them that do not violate patents.
In 2017, American scientists developed a program that systematizes information on methods for obtaining materials described in scientific publications. In addition, based on this data, it is able to predict the outcomes of similar reactions with similar materials that are not yet in the database.
