An Efficient, Green
Chemical Synthesis of the Malaria Drug, Piperaquine
Joseph MD Fortunak1*,
Stephen R Byrn2, Brandon Dyson1,
Zita Ekeocha3, Tiffany Ellison1,
Christopher L King1, Amol A Kulkarni4,
Mindy Lee1, Chelsea Conrad1
and Keeshaloy Thompson1
1Department of Chemistry,
Howard University, Washington, DC, 20059, 2Department
of Industrial and Physical Pharmacy, Purdue University,
West Lafayette, IN 47907 USA, 3St Luke
Foundation – Kilimanjaro School of Pharmacy, Industrial
Pharmacy Training Unit, PO Box 481, Moshi, Tanzania,
4Department of Pharmaceutical Sciences,
Howard University, Washington, DC, USA 20059, 5National
Institute for Pharmaceutical Research & Development,
Federal Ministry of Health, P.M.B. 21, Industrial
Layout, Abuja, Nigeria
*For correspondence:
Email:
jfortunak@comcast.net
Received: 6 July
2012
Revised accepted:
11 June 2013
Tropical Journal of
Pharmaceutical Research, October 2013;
12(5):
791-7
http://dx.doi.org/10.4314/tjpr.v12i5.20
Abstract
Purpose: To provide a robust,
efficient synthesis of the malaria drug piperaquine for
potential use in resource-poor settings.
Methods:
We used in-process
analytical technologies (IPAT; HPLC) and a program of
experiments to develop a synthesis of piperaquine that
avoids the presence of a toxic impurity in the API and
is optimized for overall yield and operational
simplicity.
Results :
A green-chemical synthesis
of piperaquine is described that proceeds in 92 – 93 %
overall yield. The chemistry is robust and provides
very pure piperaquine tetraphosphate salt (> 99.5 %).
The overall process utilizes modest amounts (about 8
kg/kg) of 2-propanol and ethyl acetate as the only
organic materials not incorporated into the API; roughly
60 % of this waste can be recycled into the production
process. This process also completely avoids the
formation of a toxic impurity commonly seen in
piperaquine that is otherwise difficult to remove.
Conclusion:
An efficient synthesis of
piperaquine is described that may be useful for
application in resource-poor settings as a means of
expanding access to and reducing the cost of ACTs.
Keywords: ACTs, Dihydroartemisinin
Piperaquine, Dihydroartemisinin, Green Chemistry,
Malaria, Piperaquine.
