Russian researchers from HSE University and the Russian Academy of Sciences Nesmeyanov Institute of Organoelement Compounds have come up with a new method of enhancing the chemical reaction involved in producing gamma-aminobutyric acid (GABA) analogues used in sedative drugs. Adding fluoride to the catalyst more than doubled the yield of the pure product and increased the total reaction yield by 2.5 times. This approach is expected to make the production of certain drug components more efficient and less costly. The study has been published in the Journal of Organic Chemistry.
Certain organic molecules exist as two symmetrical structures which are mirror images of each other, like a person's left and right hand. This phenomenon is called isomerism, and the two compounds are called enantiomers. Isomerism can occur in molecules consisting of a carbon atom bonded to four different atoms (eg hydrogen) or group of atoms, such as a carboxyl group (COOH).
While both optical isomers share the same physical and chemical properties, there may be differences between them in biological activity and thus in their effect on people. This factor must be considered when manufacturing medicines from molecules with optical isomers. There have been incidents with drugs in which one of the molecule's mirror-image forms has medicinal properties while the other one is highly toxic. This was what happened with the drug thalidomide in the US in 1957. Marketed as a sedative and hypnotic as well as a drug for treating morning sickness in pregnant women, thalidomide resulted in serious birth defects in infants due to one of its isomer components being teratogenic.
Therefore, when developing new drugs, scientists aim for selective synthesis, ie producing just one of the mirror-image isomers with the right properties. Whether such selectivity has been achieved is measured by enantiomeric excess, or the excess of one enantiomer (mirror-image isomer) in a mixture over the other, expressed in percentages. The higher the percentage, the more optically pure the mixture.
A team of Russian scientists have proposed a new way to improve the selectivity of the Michael addition reaction used to produce gamma-aminobutyric acid (GABA) analogues. Certain GABA analogues are found in medicines (such as phenibut and baclofen) prescribed for mental health problems such as anxiety, insomnia, and others. Since GABA analogues can exist in the form of optical isomers, their synthesis must be selective in favour of just one of the two isomers. The Russian chemists proposed adding fluoride to the standard nickel bromide and diimine catalysts to improve selectivity.
There are several approaches to influencing the course of a chemical reaction. One way is to produce a more complex catalyst, but this would require changes to the manufacturing process and the production facilities. Another option is to find a suitable additive capable of modifying the catalyst's properties. The latter approach is similar to just 'adding salt' and is thus lest costly for the industry.
The fluoride additive modified the catalyst's behaviour and increased both the reaction yield and the enantiomeric excess. Without the additive, the maximum values were 35% for the yield and 50% for the enantiomeric excess. The fluoride additive increased the minimum yield to 75% and the enantiomeric excess to 84%.
According to the researchers, this modification will reduce the cost of molecule synthesis by producing a better yield of a cleaner product. This will probably make sedatives cheaper to manufacture.
The study findings provide proof of the principle that the proposed strategy of using fluoride-activated catalysts really works. We hope that this simple approach will be noticed and applied to other types of catalysts and reactions, both in laboratory syntheses and in industry.
Text author: Ekaterina Korchagina