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Radiopharmaceuticals for Diagnostics
Published in Michael Ljungberg, Handbook of Nuclear Medicine and Molecular Imaging for Physicists, 2022
Nucleophilic 18F is produced in the form of [18F]fluoride ([18F]F-). [18F]F- is produced from 18O-enriched water. However, before [18F]F- can react with precursor molecules, it must be dried and a phase-transfer catalyst must be added to allow [18F]F- to dissolve in organic solvents that are required to perform nucleophilic substitution reactions. Dried [18F]F- acts as a nucleophilic particle to attack carbon atoms that are slightly positively charged because of a neighbouring electron-withdrawing group.
Chemistries of Chemical Warfare Agents
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Terry J. Henderson, Ilona Petrikovics, Petr Kikilo, Andrew L. Ternay Jr., Harry Salem
In the 1980s, however, a new synthetic route became available based on the reaction of 4-piperidone hydrochloride with phenethyl bromide via phase-transfer catalysis (PTC) to give N-phenethyl-4-piperidone (NPP), which is then converted to fentanyl in three additional reactions (Zee et al., 1981):
Radiochemistry for Preclinical Imaging Studies
Published in George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, Handbook of Small Animal Imaging, 2018
The nucleophilicity of [18F]F− can, however, be increased. For instance, potassium carbonate is added with potassium acting as a counter-cation to fluoride. The counter-cation can be complexed by a phase transfer catalyst such as Kryptofix. This creates the so-called naked fluoride and improves both its reactivity and solubility in the organic reaction solvent. Other phase-transfer systems can be used to modulate the strength of the base in case of sensitive labeling substrates. These [18F]F− methods may rely on potassium bicarbonate, cesium carbonate, oxalate, tetrabutylammonium bicarbonate, 18-crown-6 ether, and others. Fluoride will preferably react with the protons of water and form [18F]HF with no nucleophilic activity. Therefore, in the classical protocol, any macroscopic amount of water will have to be carefully removed by concentration with solid-phase extraction on an ion exchange resin. This is followed by an azeotropic distillation using acetonitrile. This process serves also as the foundation for the preparation of 2-deoxy-2-[18F]fluoro-d–glucose (Figure 16.15).
Covalent drug discovery using sulfur(VI) fluoride exchange warheads
Published in Expert Opinion on Drug Discovery, 2023
Developments in covalent drug discovery using SuFEx electrophiles have and will continue to rely heavily on innovations in their synthetic preparation. The pioneering synthesis of sulfonyl fluorides was achieved by Steinkopf in 1927 through the fluorosulfonylation reaction of benzene in the presence of fluorosulfonic acid [61]. Due to the high toxicity and corrosivity of fluorosulfonic acid, the synthesis of sulfonyl fluorides through halogen exchange from sulfonyl chlorides by KF was developed by Davis and Dick in the 1930s (Figure 4a, formula 2) [62]. Since then, sulfonyl chlorides have been widely used for the synthesis of sulfonyl fluorides. In 2014, the Sharpless group reported the use of biphasic reactions to afford sulfonyl fluorides by adding aqueous KFHF to an acetonitrile solution of sulfonyl chlorides (Figure 4a, formula 3) [16]. Importantly, the ‘on-water’ method removed the requirement for 18-crown-6 ether phase transfer catalysis that had been developed previously [63]. Recently, Bare reported a further optimization of this conversion through the use of KF in water/acetone, which further expanded substrate tolerability, to include phenols, anilines and multiple heteroaryl groups (Figure 4a, formula 4) [64].
Asymmetric organocatalysis in drug discovery and development for active pharmaceutical ingredients
Published in Expert Opinion on Drug Discovery, 2023
(S)-Pregabalin is a well-known drug marketed as LyricaTM (originally developed by Parke-Davies) that is an a2d2 protein inhibitor of the voltage-gated calcium channels. Annual sales are in the region of 5 billion dollars, making it a blockbuster drug. Many industrial routes to this API are known, such as asymmetric catalytic reduction (Pfizer) and biocatalytic methods (Matrix Ltd, Pfizer, and Sandoz) [38]. A number of organocatalytic routes have been devised for this drug. The route employed by Hayashi and coworkers involved the use of 6 at a loading of 10 mol% to catalyze the key Michael addition of nitromethane with the Michael acceptor 11 to afford the adduct 12 in high yields and 91% ee (Figure 2, D). In 2013, Kelada Pharmachem developed an alternative phase-transfer-catalysis (PTC) route to this API, which involved another Michael addition with nitromethane to the nitro-isoxazole Michael acceptor 13 using a cinchona-based quaternary ammonium salt (quinine derived) as the catalyst 14 (3 mol%), giving the adduct 15 in excellent yield and 86% ee, this intermediate was then converted to the target after further steps) [38]. The synthesis could be performed at multi-kg scale. The catalyst could be later immobilized to a polymer support and reused up to 10 times. This provided the target in 54% yield in 6-steps [39]. Asymmetric phase transfer catalysis (PTC) basically works on the basis of ion-pairing and hydrogen-bonding effects. In fact, Hughes highlighted the importance of asymmetric PTC in the pharmaceutical industry [31]. Moreover, quaternary ammonium cinchona catalysts have been used for over two decades to afford important chiral non-racemic API targets [24,40].
Synthesis, antitumor activity, and molecular docking study of 2-cyclopentyloxyanisole derivatives: mechanistic study of enzyme inhibition
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Walaa M. El-Husseiny, Magda A.-A. El-Sayed, Adel S. El-Azab, Nawaf A. AlSaif, Mohammed M. Alanazi, Alaa A.-M. Abdel-Aziz
The synthetic strategies used to obtain the target compounds are presented in Schemes 1–3. The O-alkylation of isovanillin (1) with bromocyclopentane was successively conducted in the presence of K2CO3 and a phase transfer catalyst tetrabutylammonium bromide (TBAB) in THF to obtain the key intermediate 3-cyclopentyloxy-4-methoxybenzaldehyde (2) that provided the core structure of phosphodiesterase-4 inhibitors37. Tetrabutylammonium bromide successively exhibited the character of phase transfer catalyst in an environmentally friendly procedure under mild conditions37.