nir-vana innovation network

BACKGROUND

Many drugs contain fluorinated functional groups in order to add advantageous properties. Fluorinated functional groups are more likely to withstand metabolic oxidation and, thus, are less prone to rapid degradation. The fluorination also increases the lipophilicity, which is one of the tuning factors for the bioavailability of the drug.
A common approach is the fluorination of the methyl group (CH3) to trifluoromethyl (CF3). Related groups like the pentafluorosulfanyl (SF5) group have additional benefits because of their size and hydrolytic stability. The main problem with the SF5 group is its synthetic accessibility as a functional group in aromatic moieties (Ar-SF5). Today’s methods for preparing Ar-SF5 compounds are harsh, limited in substrate scope and based on explosive oxidants such as silver(II) fluoride (AgF2), xenon difluoride (XeF2) or hazardous gases (fluorine gas, F2). The state of the art synthesis uses corrosive chlorine gas (Cl2). All of this requires specialized, expensive equipment and strict safety precautions.

INVENTION

This invention by the Swiss university provides a gas reagent-free approach to Ar-SF5 compounds via Ar-SF4Cl intermediates with substrate scopes and product yields that are equal or better than the state of the art.
A great variety of Ar-SF5 and heteroaryl-SF5 compounds can be synthesized under mild and gas reagent-free conditions, which are easily manageable. Using this new approach, solid trichloroisocyanuric acid, a cheap chlorine gas source that is easy to store and transport (used as a common disinfectant in swimming pools), a metal fluoride (KF) and catalytic acid react with a diaryl disulfide to form the key aryl-SF4Cl intermediate in the first step. The second step (chlorine/fluorine exchange), which is well established, yields the Ar-SF5 compound. A high functional group tolerance was successfully demonstrated with sensitive substrates. Even highly sensitive, ester- and ketone-containing Ar-SF4Cl intermediates were obtained for the first time that would not be directly accessible with the state of the art method. The intermediate Ar-SF4Cl can also act as a precursor for Ar-SF4-R compounds, where R represents an organic group.

POTENTIAL PRODUCT AND MARKET

There are promising applications in medicinal-, agrochemistry and material science. For example, SF5 analogues of mefloquine (anti-malarial), norfenfluramine (serotonin uptake inhibitor), fipronil (insecticide), trifluralin (herbicide), various liquid crystals and inhibitors of trypanothione reductase (drug target against protozoal parasites such as leishmania) have demonstrated advantageous properties over their existing trifluoromethyl-substituted CF3 counterparts.

DESIRED COOPERATION

A licensing partner is sought who is well established in the pharmaceutical or agrochemical industry. The licensing partner would use this invention to introduce the SF5 group to (hetero-) aromatic moieties for improving the performance of a given drug candidate.

Advantages & innovations

The proposed synthetic procedure for the oxidative polyfluorination and/or chlorofluorination of aromatic drug compounds has the following advantages compared with today’s methods: - wide substrate scope - yields equal or better than state of the art - saves crucial steps over traditional Ar-SF5 synthesis - low-cost, safe, easy-to-handle

Stage of development

Prototype available for demonstration

Partner sought

The specific area of activity of the partner: The partner is well established in the pharmaceutical or agrochemical industry. The tasks to be performed by the partner sought: The industry partner wants to improve the performance of their drug candidate by introducing the SF5 group in their compound using the proposed synthetic procedure.