IceCube Application Notes

The following application notes show the wide range of chemical reactions and synthetic methods which can be implemented with our IceCube Flow Reactor system.

1.

Continuous Ozonolysis as a Key Step of the Darunavir Synthesis Using the IceCube™ Flow Reactor

AIDS is one of the most threatening diseases spread across the planet, affecting about 35 million people worldwide. To improve the quality of life of those affected by HIV, a number of antivirals were developed, such as Darunavir. This molecule has a complex bicyclic core, the synthesis of which is well documented in the literature.

State of the art: An approach described by Ghosh and his co-workers includes an ozonolysis step, which is performed under batch conditions resulting in the desired ketone with 98% yield after 3 hours. However, handling the gaseous ozone and working at a very low temperature (78°C) is inconvenient. Adapting the synthesis to a continuous flow system provides a safe and rapid alternative solution by using in-situ generated ozone, a closed system, and higher temperatures. In this application note, we demonstrate that continuous flow ozonolysis can easily be carried out utilizing the IceCube™ Flow Reactor, developed by ThalesNano, in a safe and efficient way.

2.

Cryogenic applications in flow chemistry enabled by the IceCube Flow Reactor – Swern oxidation

In this application note we are about to demonstrate a classical Swern oxidation, conducted in ThalesNano’s novel IceCube Flow Reactor, as an example of performing high energy reactions safely and selectively.

3.

Multistep azo-dye formation in the IceCube continuous flow reactor

Diazotization and azo-coupling reactions are chemical processes that lead to industrially important azo-dyes and other intermediary molecules. The formed intermediate diazonium salts are unstable above 5°C and might explode when they are left to dry. Both diazotization and azo-coupling reactions are always carried out with high precautions in the lab on any scale. The need for a safe and high capacity process for diazotization and azo-coupling made us develop these reactions in a flow manner.

4.

Performing highly exothermic reactions safely in minutes

Exothermic reactions, by their very nature, often progress rapidly through unstable intermediates. Maintaining a firm control over parameters such as temperature and pressure is problematic, so their utilization is limited in synthetic practice. However, flow techniques have the potential of keeping such reactions under control via their improved heat and mass transfer capabilities, allowing one to exploit untapped or avoided chemistries such organometallic chemistry, nitration and ozonolysis.

5.

Safe and fast ozonolysis using the IceCube Flow Reactor

Ozonolysis is a fundamentally important oxidation reaction, which has never been fully adopted due to the safety concerns with performing the process. Its main importance stems from the fact that you can selectively oxidize double or triple bonds to form hydroxyl groups, aldehydes or carboxylic acids in the presence of other oxidizable groups. Other conventional oxidative methods are not so selective, are slower to react, require addition of water or need purification to eliminate side products leading to lower yields or need the use of metal catalysts. Compared to other methodologies, ozonolysis is considered as a greener way of oxidation. Ozonolysis has been used frequently in major drug syntheses such as (+)-Artemisinin, Indolizidine 251F, and D,L-Camptothecin and with fine-chemical syntheses such as L-Isoxazolylalanine and Prostaglandin endoperoxides.

6.

Simple, fast and safe continuous flow nitrations with the IceCube Flow Reactor

Nitration of aromatics is one of the oldest and industrially most important reactions. A reaction between an organic compound and a nitrating agent leads to the introduction of a nitro group onto a carbon, nitrogen or oxygen atom of that organic compound. Nitro derivatives of aromatic compounds are used in a variety of basic and specialty chemicals that are employed in dyes, perfumes, pharmaceuticals, explosives, intermediates, colorants, and pesticides. Almost 65% of APIs require at least one nitration step in the whole process.