Mechanochemical Path to NO-Releasing Drugs

Mechanochemical Path to NO-Releasing Drugs

Author: European Journal of Organic Chemistry

Iminosydnones are mesoionic heteroaromatic compounds. This type of heterocycle is found in several drugs such as the vasodilators molsidomine (pictured above) and linsidomine, the stimulant and Parkinson’s drug candidate mesocarb, or the stimulant feprosidnine. These types of compounds can be unstable—or be metabolized to unstable derivatives—and release NO. This high reactivity can make the synthesis and isolation of iminosydnones challenging. Mechanochemistry can be a useful approach to tackle this problem. By using mechanical forces to promote chemical reactions, it enables transformations in essentially solvent-free conditions. Reactions are often faster and more efficient than in solution, and they can provide a cleaner crude mixture, which facilitates purification.

Frederic Lamaty, Université de Montpellier, France, and colleagues have combined ball-milling and the use of environmentally friendly 1,1′-carbonyldiimidazole (CDI) as an activating agent for straightforward and high-yielding syntheses of molsidomine and of a mesocarb analogue. The team first reacted an alcohol or an amine as a nucleophile with CDI, leading to a carbonylimidazole intermediate. This intermediate was reacted with a mechanochemically prepared iminosydnone hexafluorophosphate salt to obtain the desired product (reactions pictured below).



Full conversion was observed for the synthesis of molsidomine from the corresponding educts over twelve cycles of 40 min in a planetary ball mill with EtOAc as an additive. For the synthesis of a demethylated mesocarb analog, the team used a vibratory ball mill and obtained a yield of 75 % after 1 h, also using liquid-assisted grinding with EtOAc. Overall, the developed mechanosyntheses are straightforward, efficient, and environmentally friendly, and the work could be a step toward the easier preparation of other iminosydnones.


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