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Chromatographic and Computational Study of Hydrophobic Properties of Ring Substituted Pyrazinecarbonitriles and Acetylpyrazines
* 1 , 2 , 1 , 1 , 2 , 2
1  Department of Pharmaceutical Chemistry and Drug Control, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, 500 05 Hradec Kralove, Czech Republic
2  Zentiva a. s., U kabelovny 130, 102 37 Prague 10, Czech Republic

Abstract: Pyrazinecarbonitriles and acetylpyrazines have widely been used as intermediates in the synthesis of various heterocyclic derivatives. Acetylpyrazines also serve as food and tobacco flavourants. In our laboratory, the title compounds have been used as synthetic intermediates for the preparation of potential antifungal and antimycobacterial drugs. Homolytic alkylation of commercially available pyrazine-2-carbonitrile yielded a series of 5-alkylpyrazine-2-carbonitriles that were then converted to the corresponding 1-(5-alkylpyrazin-2-yl)-1-ethan-1-ones (5-alkylpyrazine-2-acetylpyrazines) via the Grignard reaction. Homolytic acetylation of pyrazine-2-carbonitrile yielded 5-acetylpyrazine-2-carbonitrile. By means of the same procedure 3-acetyl-5-tert-butylpyrazine-2-carbonitrile was obtained using 5-tert-butylpyrazine-2-carbonitrile as a starting material. The hydrophobicity of all the pyrazinecarbonitriles and acetylpyrazines was determined using the reversed phase high performance liquid chromatography (RP-HPLC) method (isocratic elution with methanol as an organic modifier in the mobile phase, end-capped non-polar C18 stationary RP column). Experimentally derived Log K values (the logarithm of capacity factor K) were that compared with Log P values calculated by commercially available programmes (CS ChemOffice Ultra ver. 7.0 and ACD/Log P ver. 1.0).
Keywords: pyrazinecarbonitriles; acetylpyrazines; RP-HPLC lipophilicity determination; lipophilicity calculations