Anti-Narcoleptic Agent Modafinil and Its Sulfone: A Novel Facile Synthesis and Potential Anti-Epileptic Activity

Abstract

We report a facile procedure to synthesize racemic modafinil (diphenylmethylsulfinylacetamide), which is now being used in pharmacotherapy, and its achiral oxidized derivative (diphenylmethylsulfonyl acetamide). Modafinil is of interest more than for its potential anti-narcoleptic activity. It has also been reported to have neuroprotective properties and may potentially be effective in the enhancement of vigilance and cognitive performance. Finally, it may also protect from subclinical seizures that have been implicated as causative factors in autistic spectrum disorders and other neurodegenerative conditions. This agent can now be synthesized simply and in larger amounts than previously, making it more readily available for testing in various research modalities. The described procedure also lends itself to production of several other amides of potential interest. We are currently in the process of synthesizing and testing several new derivatives in this series. The anticonvulsant properties of modafinil and its sulfone derivative have not previously been extensively described in the literature. It may be of interest to note that the oxidized derivative of modafinil is also nontoxic and almost as effective as an anticonvulsant as the parent.

New synthetic route to modafinil drug including desulfobenzhydrylation of sodium carbamoylmethyl thiosulfate: experimental and quantum chemical studies

“…This favorably distinguishes the reaction we have developed from the analogous oxidation of compound 3a in acetic acid, which is accompanied by the formation of consider able amounts of sulfone. 8 Steps B and C can be combined by performing the process without isolation of amide 3a. In this case, the single isolated intermediate product is Bunte salt 6a, and the overall yield of compound 1 after two one pot steps is 74%.…”

“…Amide 3a is further oxidized to modafinil (1) with hydrogen peroxide in ace tic acid. 7, 8 Sulfoxide 1 can also be obtained from compound 2 following Scheme 1 via intermediate for mation of benzhydrylsulfinylacetic acid (4) and its ethyl ester (5). 9,10…”

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“…(XII). CID of all sulphoxides (MASO (I), ADSO (IV), MOSO (V) and ESTSO (XI)) did not produce intense protonated molecular ions due to the fact that the sulphoxide functionality did not render the a-protons sufficiently acidic [19]. Sulphides (MAS (III),…”

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“…It is furthermore used for the treatment of depression [17], attention-deficit hyperactivity disorder [18], Parkinson's disease [19], and epilepsy [20]. Moreover, it is a memory-improving and mood-brightening psychostimulant [21].…”