strategy for the synthesis of N-aminopiperidine (NAPP) was developed using
hydroxylamine-O-sulfonic acid (HOSA). A systematic study of NAPP formation and
degradation reactions was carried out in diluted medium, in order to identify
products and to establish a kinetic modelling. Principal parameters have been
defined, in particular, that obtaining high yields (>90%) requires non
stoichiometric conditions. The extraction and purification processes were also
studied. NAPP isolation and piperidine recycling were optimized after the
establishment of the various solid-liquid-liquid and liquid-vapour implied
phase diagrams. At least, a calorimetric study of solvatation and reaction
enthalpies was undertaken in order to estimate reactor heating temperature in
the case of anhydrous synthesis. The combination of our kinetic, thermodynamic
and calorimetric data allows the establishment of two process schemes: one
using pure piperidine, the other, a 66 w% titrating azeotropic solution in
Cite this paper
E. Labarthe, A. Bougrine, V. Pasquet and H. Delalu, "A New Strategy for the Preparation of N-Aminopiperidine Using Hydroxylamine-O-Sulfonic Acid: Synthesis, Kinetic Modelling, Phase Equilibria, Extraction and Processes," Advances in Chemical Engineering and Science, Vol. 3 No. 2, 2013, pp. 157-163. doi: 10.4236/aces.2013.32019.
 F. Barth and P. Casellas, “Substituted N-Piperidino 3-Pyrazolecarboxamide,” European Patent 0656354, 1995.
 C. G. Kruse, J. H. M. Lange, A. H. J. Herremans and H. H. Van Stuivenberg, “1H-Imidazole Derivatives Having CB1 Agonistic, CB1 Partial Agonistic or CB1-Antagonistic Activity,” International Patent WO03027076, 2003.
 C. G. Kruse, J. H. M. Lange, T. Jacobus, A. H. J. Herremans and H. H. Van Stuivenberg, “Novel 4,5-Dihydro-1H-pyrazole Derivatives Having CB1-Antagonistic Activity,” International Patent WO03026647, 2003.
 A. R. Stoit, J. H. M. Lange, A. P. Den Hartog, E. Ronken, K. Tipker, H. H. Van Stuivenberg, J. A. R. Dijksman, H. C. Wals and C. G. Kruse, “Design, Synthesis and Biological Activity of Rigid Cannabinoid CB1 Receptor Antagonists,” Chemical and Pharmaceutical Bulletin, Vol. 50, No. 8, 2002, pp. 1109-1113. doi:10.1248/cpb.50.1109
 P. E. Finke, S. G. Mills, C. W. Plummer, S. K. Shah and Q. T. Truong, “Substituted Imidazoles as Cannabinoid Receptor Modulators,” International Patent WO03007887, 2003.
 W. K. Hagmann, H. Qi and S. K. Shah, “Substituted Imidazoles as Cannabinoid Receptor Modulators,” International Patent WO03063781, 2003.
 R. A. Smith, S. J. O’Connor, S. N. Wirtz, C. Wong Wai, S. Choi, H. C. Kluender, N. Su, G. Wang, F. Achebe and S. Ying, “Imidazole-4-carboxamide Derivatives, Preparation and Use Thereof for Treatment of Obesity,” International Patent WO03040107, 2003.
 R. A. Smith, H. C. Kluender, N. Su, R. C. Lavoie and J. Fan, “Preparation and Use of Pyrrole Derivatives for Treating Obesity,” International Patent WO03027069, 2003.
 A. L. Hildebrandt, D. M. Kelly-Sullivan and S. C. Black, “Antiobesity Effects of Chronic Cannabinoid CB1 Receptor Antagonist Treatment in Diet-Induced Obese Mice,” European Journal of Pharmacology, Vol. 462, No. 1-3, 2003, pp. 125-132. doi:10.1016/S0014-2999(03)01343-8
 J. M. Wilsterman and A. I. K. Berggren, “Pyrazine Compounds and Pharmaceutical Compositions Containing them,” International Patent WO03051850, 2003.
 A. I. K. Berggren, S. J. Bostrom, S. T. Elebring, P. Greasley, E. Terricabra and J. M. Wilstermann, “5,6-Diaryl-pyrazine-2-amide Derivatives as CB1 Antagonists,” International Patent WO03051851, 2003.
 S. Liu, “N-Substituted 3-Hydroxy-4-pyridinones and Pharmaceuticals Containing Thereof,” International Patent WO03065991, 2003.
 B. S. Muehl, “3-Benzyl-benzothiophenes,” US Patent 6417199, 2002.
 J. Dumas, W. Lee, Y. Chen, L. Adnane, W. Scott, S. Verna, J. Chen, Z. Chen and L. Yi, “Substituted Pyridine Derivatives Useful in the Treatment of Cancer and Other Disorders,” European Patent 1603879, 2005.
 E. Labarthe, A. J. Bougrine, V. Pasquet and H. Delalu, “Kinetic Modelling of Synthesis of N-Aminopiperidine from Hydroxylamine-O-sulfonic Acid and Piperidine,” Kinetics and Catalysis, Vol. 53, No. 1, 2012, pp. 25-35.
 E. Labarthe, A. J. Bougrine, H. Delalu, J. Berthet and J. J. Counioux, “Equilibrium Study between Condensed Phases by Isoplethic Thermal Analysis When a Miscibility Gap Is Observed,” Journal of Thermal Analysis and Calorimetry, Vol. 95, No. 1, 2009, pp. 135-139.
 J. Berthet and J. J. Counioux, “Procédé et Dispositif de Mesure de la Solubilité d'au Moins un Soluté Solide, Liquide ou Gazeux dans un Solvant, Par Analyse Thermique Isopléthique,” French Patent 9313402, 1993.
 E. Labarthe, A. J. Bougrine, J. Berthet and H. Delalu, “Study of the Polythermal Diagram Water-Sodium Sulphate-Piperidine,” Journal of Themal Analysis and Calorimetry, Vol. 100, No. 3, 2010, pp. 1099-1105.
 E. Labarthe, A. J. Bougrine and H. Delalu, “Extraction Optimization of Organic Compounds by Demixing Observed in the H2O-NaOH-Piperidine Ternary Diagram,” Journal of Themal Analysis and Calorimetry, Vol. 102, No. 3, 2010, pp. 1119-1122. doi:10.1007/s10973-010-0744-6