Anti-Narcoleptic Agent Moda?nil and Its Sulfone: A Novel
Facile Synthesis and Potential Anti-Epileptic ActivityNithiananda Chatterjie, James P. Stables, Hsin Wang, and George J. AlexanderNeurochemical Research, Vol. 29, No. 8, August 2004 (© 2004), pp. 1481–1486Abstract:We report a facile procedure to synthesize racemic moda?nil (diphenylmethylsul?nylacetamide), which is now being used in pharmacotherapy, and its achiral oxidized derivative (diphenylmethylsulfonyl acetamide). Moda?nil 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 moda?nil 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 moda?nil is also nontoxic and almost as effective as an anticonvulsant as the parent.
ExperimentalDiphenylmethylthioacetic Acid (3)Benzhydryl bromide (14.78 gm, 0.059 mole) was dissolved in 75 ml of acetone in a 250-ml round-bottomed ?ask. To this solution was added dropwise sodium mercaptoacetate (6.59 g, 0.058 mole) in about 60 ml of H2O; the mixture was stirred under N2 for 2 h at room temperature and was thereafter warmed at about 60–70°C for 1 h. The reaction mixture was evaporated to dryness and taken up in CH2Cl2 and saturated aqueous NaHCO3. The organic extract was rejected, and the aqueous phase was treated with acid to pH 2 and chilled. Suction ?ltration gave the 6.9 g of the acid (3, 46%), mp 125°C. Rf 0.2. Recrystallization from MeOH/H2O gave mp 126–128°C.
Diphenylmethylthioacetamide (4)Diphenylmethylthioacetic acid (19.5 g, 0.076 mole)
in 114 ml of dry benzene was taken in a 250-ml roundbottomed
?ask attached to a re?ux condenser, under N2 gas. To this was added thionyl chloride (19.5 ml, 0.097 mole) with a dropping funnel. The mixture was stirred at room temperature with a magnetic stirrer and re?uxed for 1 h. Thereafter, the mixture was evaporated under low pressure to give a yellow oil that was taken up in about 100 ml of CH2Cl2 and ?ltered to yield a clear orange solution. This was chilled in ice water and added slowly to an ice-cold solution of concentrated NH4OH in H2O (40:40 ml). The ensuing mixture was stirred for 1 h and shaken well in a separatory funnel. The organic layer was dried (Na2SO4) and evaporated to dryness to give 14.39 g (54%) of the amide (4), mp 108–109°C (lit2 110°C). Rf 0.8. Recrystallization from CH3OH/H2O gave mp 109–110°C.
Diphenylmethylsul?nylacetamide (moda?nil, 1)Diphenylthioacetamide (3.46 g, 0.013 mole) was taken in glacial acetic acid (14 ml) with stirring; to this was added 1.34 ml of 30% H2O2 with chilling in ice water. The mixture was left in the refrigerator for 4 h and thereafter worked up by treating it with 70 ml of ice-cold water. The precipitated material was ?ltered under suction and washed with ice-cold water to give 1.5 g of white crystals (43%), mp 159–160°C. Rf 0.6. Recrystallization from hot MeOH gave mp 161–162°C
Diphenylmethylsufonylacetamide (2)Diphenylmethylthioacetamide (2.5 g, 0.009 mole) (reg. No. 118779-53-6) was dissolved in about 12 ml of glacial acetic acid and 3 ml of 30% H2O2 and set aside overnight (16 h or more). The next day, the mixture was diluted with 100 ml of H2O and set aside to cool in the refrigerator. Upon ?ltration and drying, 2.1 g (80%) of 2 was obtained as a white powder. Rf 0.89. The melting point of sample after recrystallization from absolute EtOH was 195–197°C.
One aspect of our preparation of moda?nil needs further mention. When diphenylmethylthioacetamide (4) is being oxidized by H2O2, care must be taken to keep the reaction mixture cool, and workup should be done in a timely manner. Allowing the reaction to go to 24 h or longer at room temperature results in the formation of the sulfone (2). The paper by Mu et al. (3) does not discuss this possibility. In our hands, the procedure stated therein led to the higher melting sulfone and not the moda?nil. Our NMR data for the newly prepared moda?nil preparation are in consonance with the data of the patented commercial product. It should be noted that the methylene protons in moda?nil are geminally
coupled and appear as a pair of doublets. This is due to the fact that the adjacent sulfoxide moiety is chiral, and therefore the methylene protons adjacent to it wind up being diastereotopic with different chemical shifts and coupling. In the sulfone 2, the methylene protons appear as a singlet due to the fact that the adjacent sulfone moiety is achiral, thus making the two protons equivalent. Moda?nil 1 is, however, an equal mixture of enantiomers, as in the reported patent and publication (2,3).
RESULTSThe chemical pathway leading to moda?nil may be
represented in Scheme 1.
see pdf for further information and references,
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