Solvent-Free Mechanochemical Modification of Lappaconitine and Piroxicam

Abstract

A mechanochemical procedure of ball milling was applied to a solvent-free synthesis of natural alkaloid lappaconitine derivatives. A mixture of purely solid lappaconitine and 3-Cl-perbenzoic acid reacted to give lappaconitine N(20)-oxide with a good isolated yield (57percnt after workup). The ball milling of solid lappaconitine and N-bromosuccinimide affords N(20)-deethyllappaconitine with an acceptable (42percnt) yield. The mechanochemical approach was also applied for acylation of the anti-inflammatory drug piroxicam to improve its therapeutical properties. Consequently piroxicam 4-nitrobenzoate was obtained under the solvent-free reaction conditions with a moderate yield as a result of mechanical activation of the reaction between piroxicam and 4-nitrobenzoyl chloride in the presence of the aluminum oxide impregnated with thriethylamine. The reaction mixtures were analyzed after ball milling by HPLC in the proposed conditions.

Keywords:

• Lappaconitine N(20)-oxide
• Lappaconitine
• Mechanochemistry
• N(20)-deethyllappaconitine
• Piroxicam 4-nitrobenzoate
• Piroxicam
• Solvent-free synthesis

ACKNOWLEDGMENTS

We thank Dr. Nikolay Gorobets for valuable discussion of the work results. The financial support of this study from the U.S. Civilian Research & Development Foundation, CRDF (Award No. RUX0-008-NO-X1) is gratefully acknowledged. The work was also supported by Russian Ministry of Education and Science, Russian Foundation for Basic Research (No. 05-03-08029), and the RAS Program “Fundamental Science for Medicine.”