Applicable methods in trifluoromethoxylation for high value compounds and 18F-PET Imaging – Ap-PET-I

The research program consists in three independent modules.
The first work module tackles the development of scalable, non-expensive accesses to the trifluoromethoxide anion (or the OCF3 radical), either by in situ construction of the F3CO– anion from the F– anion, or by developing 2,4-dinitro(trifluoromethoxy)benzene (DNTFB) as a commercially available and affordable OCF3 source, and implementing them both in batch and in continuous flow trifluoromethoxylation processes.
The second module extends the previously developed strategy to a vast variety of substrates and reactions aiming at general methods. Another task will be to develop the access to trifluoromethoxylated stereogenic centers.
The third module is specifically dedicated to applying the results of the 2 previous modules to an efficient preparation of [18F]F3CO-containing radiotracers and application in 18F PET imaging.

Fluorine chemistry is at the heart of activities that are highly competitive academically and economically.
The objective of the Ap-PET-I project is to create original molecules incorporating the emerging fluorinated group OCF3 in order to obtain new molecular building blocks that will be at the origin of future agrochemical or pharmacological ingredients. This emerging fluorinated group may have novel physico-chemical and biological properties and constitute an alternative to the CF3 group. Finally, this emerging fluorinated group may eventually lead to an improved biological activity or even a new mode of action with a minor impact on the environment.
The Ap-PET-I project is at the forefront of innovation in modern fluorine organic chemistry and its socio-economic interests are multiple: 1) to significantly increase the international visibility and performance of French R&D in chemistry in important fields for the pharmaceutical and agrochemical industries but also materials; 2) to allow innovation in synthesis methods in a highly competitive field at the international level; 3) to ensure, at a relatively early stage of potential industrial exploitation, many possible applications in the short term; 4) to allow the development of new therapeutic or agrochemical molecules, potentially more effective, more benign for the environment, and involved in new modes of action paving the way for new treatments; 5) to propose an innovative way to obtain radiolabeled molecules with fluorine-18 for medical imaging applications.

The chemistry of organofluorinated compounds is today an important element of life science research and the development of new methodologies for the introduction of fluorinated groups remains a central issue. From an industrial point of view, OCF3 is quite rarely encountered and there is an urgent need to develop viable academic and industrial approaches to introduce this emerging fluorinated substituent (EFS). This EFS could confer new reactivities and functions to molecules created by man, and could also eventually lead to an improvement in biological activity or even a new mode of action. In addition, this type of EFS would avoid patent restrictions and thus provide a competitive advantage, which is of capital importance for the chemical industry. Thus, the discovery of innovative molecules with emerging fluorinated groups is a major challenge for leading companies in this field.
The project is at the forefront of innovation in the field of modern organofluorinated chemistry. In addition to innovation in synthesis methods in a highly internationally competitive field, at a relatively early stage of potential industrial exploitation, many possible short-term applications will be generated by this project.
This project will contribute to orienting other research themes by offering new tools leading to applications in areas that are essential assets for the industrial revival of our country.
The three main objectives of a company are : (1) to obtain a means of rapid access to specific technologies in the field of fluorine chemistry; (2) to obtain a clear advantage over its competitors in this field and (3) to have a library of unique elementary bricks not available from competitors.

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Recent years witnessed an increasing interest in compounds bearing emergent fluorinated substituents like ?-fluorinated ethers. Among them, the most largely described ones are based on aromatic scaffolds, more rarely on heteroaromatic ones, and even more scarcely on aliphatic ones, with, in exceptional cases, control of the absolute configuration of the newly formed C*-OCF3 stereocenters.
The overall objective of the Ap-PET-I project is to devise new and efficient nucleophilic trifluoromethoxylation methods on a broad substrate scope which have not been described to this day. The protocols should be robust enough for application, on the one hand, in medicinal and agrochemical R&D especially, which would truly unlock the access to new reactivity and functions to man-made molecules but also eventually lead to improved biological activity or even a novel mode of action with a minor impact on the environment; and, on the other hand, in more delicate processes such as the preparation of radiotracers for 18F PET imaging.
We therefore envisage to tackle the following work packages:
WP1 – Developing scalable, non-expensive accesses to the trifluoromethoxide anion (or the OCF3 radical), and implementing them in batch and in continuous flow trifluoromethoxylation processes;
WP2 – Exploring the substrate and reaction scopes of these processes aiming at general methods and developing the access to trifluoromethoxylated stereogenic centers;
WP3 – Applying the results of WP1–2 to an efficient preparation of [18F]F3CO-containing radiotracers and application in 18F PET imaging.
Based on preliminary results by Partner 1, dealing with the in situ generation and direct use of AgOCF3 from rather cheap starting materials (triphosgene, KF) and AgF, we firstly intend in WP1, Task 1.1 to further investigate reaction parameters under "batch conditions". In Task 1.2, an alternative method for generation of the trifluoromethoxide anion or trifluoromethoxyl radical will be developed based on previous studies of Partner 2 dealing with DNTFB as source of OCF3. We seek to better understand the reactivity of DNTFB towards F3CO– (or F3CO•) by means of an accurate mechanistic study. These batch conditions will then be transposed in Task 1.3 to a continuous flow process, which offers appealing advantages of efficiency, scalability and tuning of the reaction setup, especially where liquid and gaseous phases are implied, as in our case.
While in WP1 we develop more cost-effective methods for OCF3 anions or radical production and assess them in the trifluoromethoxylation of a handful of model substrates, the aim of WP2 will first be to demonstrate the applicability of these methods in terms of substrates for a given reaction as well as of reaction types . Second, we will also look for alternative active F3CO-transfer species. We wish to develop species based on bismuth, which is cheap and whose reactivity is versatile. Moreover, chiral Bi complexes would allow controlling the stereochemical course of the C–OCF3 bond formation, a challenge that has barely been addressed so far.
In WP3, we envisage to generate a [18F]F3CO– anion by applying the results of WP1 and WP2 to the in situ formation of [19F or 18F]difluorophosgene and reaction with [18F]AgF, the latter being used for the first time in labeling through a direct trifluoromethoxylation. This will be based on an original method recently developed by Partner 2 to obtain [18F]AgF directly from the cyclotron-produced fluorine-18 through an ion exchange cartridge.