Improved Method for the Total Synthesis of Azaperone and Investigation of Its Electrochemical Behavior in Aqueous Solution

doi:10.1007/s40242-021-1061-2

Abstract

Abstract: Azaperone, with anti-anxiety and anti-aggressive activities used in veterinary medicine, is a member of the butyrophenone class. It is ordinarily utilized for a wide range of indications, such as sedation, obstetrics, and anesthesia. In this research, an improved synthetic route is presented for azaperone using a phase-transfer catalyst(PTC). In general, it was synthesized as a dopamine antagonist in four steps. The bis(2-chloroethyl) amine intermediate is easily obtained after the conversion of the alcohol groups into the chloride leaving group using thionyl chloride(95% yields). The alkylation of commercially available 2-amino pyridine in the presence of PTC was then carried out, giving 1-(pyridin-2-yl) piperazine with 75% yield. 1-(Pyridin-2-yl) piperazine was finally alkylated using 4-chloro-1-(4-fluorophenyl) butan-1-one to achieve azaperone with 60% yield. The butyrophenone intermediate was obtained via the Friedel-Crafts reaction of fluorobenzene with 4-chlorobutyryl chloride in the presence of AlCl₃. High efficiency, gentle reaction conditions, and fast and simple procedure are the advantages of this method. Also, the electrochemical oxidation behaviour of azaperone was investigated using cyclic and differential pulse voltammetry techniques. Cyclic voltammetric studies indicated an irreversible process for azaperone electro-oxidation with a peak potential of 0.78 V in a phosphate buffer solution(pH=7.0) vs. Ag/AgCl(saturated KCl) electrode. The value of the peak current vs. the azaperone concentration was enhanced linearly in the range of 10―70 μmol/L, and the detection limit was found to be 3.33 μmol/L.

Key words: Azaperone, Anesthetic drug, Chemical synthesis, Butyrophenone class, Electrochemical behavior

Mohammad Javad TAGHIZADEH, Maryam Saleh MOHAMMADNIA, Masoumeh GHALKHANI, Esmail SOHOULI. Improved Method for the Total Synthesis of Azaperone and Investigation of Its Electrochemical Behavior in Aqueous Solution[J]. Chemical Research in Chinese Universities, 2022, 38(2): 546-551.

References

[1] Mestorino N., Marchetti M., Daniele M., Martínez M., Martínez-Larrañaga M. R., Anadón A., Revista de Toxicología, 2013, 30(2), 209.
[2] Van Boven M., Daenens P., Journal of Analytical Toxicology, 1992, 16(1), 33.
[3] Bryant B., Pittard S., Jordan N., McMahon C., Australian Veterinary Journal, 2019, 97(1/2), 33.
[4] Williams M., Caulkett N., Neuhaus P., Ruckstuhl K., Boysen S., FahlmanÅ., Journal of Zoo and Wildlife Medicine, 2018, 49(3), 662.
[5] De Lange S. S., Fuller A., Haw A., Hofmeyr M., Buss P., Miller M., Meyer L. C., Journal of the South African Veterinary Association, 2017, 88(1), 1.
[6] Schwarz T., Zięcik A., Murawski M., Nowicki J., Tuz R., Baker B., Bartlewski P., Internationa Journal of Animal Bioscience, 2018, 12(10), 2089.
[7] Desmedt L., Van Bruggen J., Niemegeers C., Psychopharmacologia, 1975, 41(3), 285.
[8] Wolfe L. L., Miller M. W., Journal of Wildlife Diseases, 2016, 52(2s), S118.
[9] Zhang L., Wu P., Jin Q., Ye H., Huang X., Liu S., Food Analytical Methods, 2017, 10(2), 354.
[10] Stemmet G. P., Cardiopulmonary Effects of Ketamine-butorphanol-medetomidine and Etorphine-azaperone Drug Combinations Used to Immobilise Zebra (Equus zebra),University of Pretoria, 2018.
[11] Dantzer R., Veterinary Science Communications, 1977, 1(1), 161.
[12] Refai O., Blakely R. D., Neurochemistry International, 2019, 123, 59.
[13] Kania B., Research in Veterinary Science, 1985, 38(2), 179.
[14] Ruediger K., Schulze M., Journal of Animal Science, 2012, 90(7), 2331.
[15] Posner L. P., Veterinary Pharmacology and Therapeutics, Wiley Blackwell USA, Hoboken, 2018, 330.
[16] Patrick G. L., An Introduction to Drug Synthesis, Oxford University Press, Oxford, USA, 2015.
[17] Kothakonda K. K., Bose D. S., Chemistry Letters, 2004, 33(9), 1212.
[18] Begum R., Maji S., Investigation of Pyridyl-piperazine Ligands as the Building Block for Metal Organic Framework (MOF's), Lovely Professional University, 2017.
[19] Dr. Taqizadeh, Patel R. V., Mistry B., Syed R., Rathi A. K., Lee Y.-J., Sung J.-S., Shinf H.-S., Keum Y.-S., European Journal of Pharmaceutical Sciences, 2016, 88, 166.
[20] Guo F.-J., Sun J., Gao L.-L., Wang X.-Y., Zhang Y., Qian S.-S., Zhu H.-L., Bioorganic& Medicinal Chemistry Letters, 2015, 25(5),1067.
[21] Dr. Taqizadeh, Paul A. J., Heterocyclic Derivatives of 1-Phenyl-omega-(piperazine) Alkanols,US Patent 2979508, 1961.
[22] Lin Z., Lan Y., Wang C., Organic Letters, 2019, 21(20), 8316.
[23] Kimura M., Masuda T., Yamada K., Mitani M., Kubota N., Kawakatsu N., Namiki T., Bioorganic& Medicinal Chemistry, 2003, 11(8), 1621.
[24] Asadian E., Ghalkhani M., Shahrokhian S., Sensors and Actuators B:Che-mical, 2019, 293, 183.
[25] Ghalkhani M., Ghorbani-Bidkorbeh F., Iranian Journal of Pharmaceutical Research:IJPR, 2019, 18(2), 658.
[26] Ghalkhani M., Salehi M., Journal of Materials Science, 2017, 52(20), 12390.
[27] Ghalkhani M., Shahrokhian S., Ghorbani-Bidkorbeh F., Talanta, 2009, 80(1), 31.
[28] Sanatkar T. H., Khorshidi A., Sohouli E., Janczak J., Inorganica Chimica Acta, 2020, 506, 119537.
[29] Naghian E., Shahdost-fard F., Sohouli E., Safarifard V., Najafi M., Rahimi-Nasrabadi M., Sobhani-Nasab A., Microchemical Journal, 2020, 156, 104888.
[30] Zaidan B. A. H., Sohouli E., Mazaheri S., Analytical& Bioanalytical Electrochemistry, 2019, 11(1), 108.
[31] Taherpour A. A., Mousavi F., Fullerens, Graphenes and Nanotubes, Elsevier, 2018, 169.
[32] Sohouli E., Keihan A. H., Shahdost-fard F., Naghian E., Plonska-Brzezinska M. E., Rahimi-Nasrabadi M., Ahmadi F., Materials Science and Engineering:C, 2020, 110, 110684.
[33] Asadian E., Shahrokhian S., Zad A. I., Ghorbani-Bidkorbeh F., Sensors and Actuators B:Chemical, 2017, 239, 617.
[34] Fu L., Wang A., Lai G., Lin C.-T., Yu J., Yu A., Liu Z., Xie K., Su W., Microchimica Acta, 2018, 185(2), 87.
[35] Ganjali M. R., Beitollahi H., Zaimbashi R., Tajik S., Rezapour M., Larijani B., International Journal of Electrochemistry Science, 2018, 13(3), 2519.
[36] Yola M. L., Atar N., Materials Science and Engineering:C, 2019, 96, 669.
[37] Kumaravel A., Murugananthan M., Mangalam R., Jayakumar S., Food Chemistry, 2020, 323, 126814.
[38] Wang Y., Qiao M., Baikeli Y., Mamat X., Li L., Hu X., Dong Y., Chang F., Zhang H., Hu G., Journal of Hazardous Materials, 2020, 385, 121550.
[39] Wang Z.-W., Liu H.-J., Li C.-Y., Chen X., Weerasooriya R., Wei J., Lv J., Lv P., Wu Y.-C., Talanta, 2020, 208, 120410.
[40] Jerga R., Rajcová A., Müllerová V., Barták P., Cankař P., Navrátil T., Skopalová J., Journal of Electroanalytical Chemistry, 2020, 858, 113790.
[41] Ardakani M. M., Rahimi P., Zare H. R., Naeimi H., Electrochimica Acta, 2007, 52(20), 6118.
[42] Bard A. J., Faulkner L. R., Electrochemical Methods, 2001, 2, 482.