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

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Abstract

A new synthetic route to 2-benzhydrylsulfinylacetamide (1), a nootropic drug modafinil, is described. The synthesis includes the alkylation of sodium thiosulfate with chloroacetamide to sodium carbamoylmethyl thiosulfate, the desulfobenzhydrylation of the latter by benzhydrol in formic acid to form benzhydrylthioacetamide (3a), and the further oxidation of this thioamide with hydrogen peroxide. According to B3LYP/6-31G** DFT calculations, the key step of the synthesis, namely, desulfobenzhydrylation of salt 6a, occurs only insignificantly due to the energetically unfavorable direct attack of this salt by benzhydryl formate; the reaction mainly involves the attack by the benzhydrilium carbocation Ph2CH+. The oxidation of sulfide 3a to sulfinylacetamide 1 is efficiently catalyzed by side proton-donor molecules (constituents of the transition states of the reaction). The oxidant can be the anionic form of the reactant (HO2 - ion), which reacts with sulfide 3a via the unusual noncatalytic mechanism. At the step of transition state formation, this mechanism resembles the SN 2 substitution.

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Authors and Affiliations

  1. Southern Scientific Center, Russian Academy of Sciences, 41 ul. Chekhova, 344006, Rostov-on-Don, Russian Federation

    A. V. Bicherov

  2. Research Institute of Physical and Organic Chemistry, Southern Federal University, 194/2 prosp. Stachki, 344090, Rostov-on-Don, Russian Federation

    A. R. Akopova, V. I. Spiglazov & A. S. Morkovnik

Authors
  1. A. V. Bicherov
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  2. A. R. Akopova
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  3. V. I. Spiglazov
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  4. A. S. Morkovnik
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Correspondence to A. S. Morkovnik.

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Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 92–102, January, 2010.

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Bicherov, A.V., Akopova, A.R., Spiglazov, V.I. et al. New synthetic route to modafinil drug including desulfobenzhydrylation of sodium carbamoylmethyl thiosulfate: experimental and quantum chemical studies. Russ Chem Bull 59, 91–101 (2010). https://doi.org/10.1007/s11172-010-0049-8

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  • DOI: https://doi.org/10.1007/s11172-010-0049-8

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