Novel analgesic-antiinflammatory salicylates

Abstract

5-(2,4-Difluorophenyl)salicylic acid, diflunisal (25), is the best compound, in terms of both efficacy and safety, from over 500 salicylates investigated in our laboratories. It is a chemically distinct, nonacetylating salicylic acid, more active than aspirin as an analgesic and antiinflammatory agent and superior in duration of action and therapeutic index. Some recent clinical and biochemical observations are briefly discussed.

One step synthesis of Diflunisal using a Pd-diamine complex

“…In conventional methods, Diflunisal is prepared in several steps starting from fluorinated aniline. Hannah and co-workers have prepared Dilflunisal in a five step synthesis (Scheme 1) consisting of benzene arylation using a Gomberg-Bachmann-Hey reaction (GBH), FriedelCrafts acylation, Bayer-Villiger oxidation, saponification and finally carbonation of phenol through a KolbeSchmitt reaction achieving Diflunisal in 35.78% yield [3]. In the GBH reaction the aromatic radical formed from aryldiazoniumhydroxide reacts with a different aromatic substrate.…”

“…Hannah et al tried to improve the route and utilized anisole instead of benzene. However, the selectivity of the GBH-reaction was poor and the desired para-isomer was obtained as a minor product [3].…”

“…The biaryl moiety interacts favorably with polar groups such as amides and hydroxyl groups. Because of these unique physicochemical properties it has become a privileged substructure in pharmaceuticals [1,2] The biaryl moiety is present in drugs like Diflunisal 1, Felbinac 2, Flurbiprofen, Fenbufen and Xenbucin [3][4][5]. Also many larger molecules, for example natural cyclic peptide antibiotics including the Biphenomycins A-C [6], anti-HIV agents Chloropeptin I and II [7] and Sartan-type drugs (for example Irbesartan for the treatment of arterial hypertension [8]), contain a biaryl moiety (Fig.…”

“…The compound, also referred to as Dolobid, is a nonacetylated phenyl-derivative of salicylic acid. It is 20 times more effective in a hyperestesia assay and 9 times more effective in adjuvant arthritis than Aspirin [3]. Unlike Aspirin, Diflunisal which is unesterified is chemically incapable of acetylating cyclo-oxygenase and may therefore contribute to better tolerance in humans [9].…”

Palladium-Catalyzed Suzuki–Miyaura Cross-Coupling in Continuous Flow

“…In order to illustrate the synthetic potential of this methodology, Diflunisal [91,92] was obtained in a multi-step sequence [84]. Starting from 4-bromoanisole, the lithiation/borylation followed by Suzuki-Miyaura cross-coupling with 1-bromo-2, 4-difluorobenzene permitted the synthesis of the key intermediate in the production of Diflunisal (Scheme 7).…”