A short synthesis of praziquantel - Yuste - 1986 - …
Full experimental details for the open process may be found in this paper. Readers are encouraged to review, evaluate and contribute to refining the resolutions online by addressing current weaknesses (e.g., the need for a chlorinated solvent extraction process in the initial PZQ hydrolysis). Both processes show sufficient promise in terms of cost on a lab scale (simple methodology, inexpensive resolving agents, good yields and efficiencies) that costs approaching those needed should be attainable upon scale-up; the processes are therefore being examined by WHO/TDR on a kilogram scale for economic viability. The routes found are quite similar. An advantage of the approach discovered by the CRO is its use of tartaric acid itself, as opposed to a derivative, but the derivatization employed in the open approach is straightforward. Which route is adopted depends to some extent on the method(s) currently employed in the commercial manufacture of the API, and perhaps surprisingly this information is not readily available. The ton-scale availability of 3 implies its use in the synthesis of PZQ, presumably via the original Merck process, yet to the best of our knowledge the CRO manufacturing PZQ for the Schistosomiasis Control Initiative (Shin Poong, South Korea) were employing a different approach that generated PZQamine 2 as an intermediate, implying a similar availability of that material in quantity. The open source approach is the basis of an educational project in which students from around the world are encouraged to collaborate in further optimization. (Interested students and laboratory instructors can view the experiments and collaborate on the relevant website).
The synthesis of praziquantel (1), ..
In the corresponding author's laboratory, PZQamine could be generated with ease, but the enantiomers could not be baseline separated by enantioselective HPLC due to a limited range of chiral stationary phases being available. This precluded a convenient local assay for resolution trials. In addition several attempts to resolve PZQamine with a range of chiral acids had met with mixed success.– To find a suitable chromatographic assay, an appeal for assistance was posted in several online discussion boards. In particular, the Process Chemists Group on LinkedIn furnished multiple offers of help. One company, Syncom B.V., a contract research organization in the Netherlands, additionally offered to perform a free screen of chiral acids for the resolution of PZQamine in order to discover a lead structure for the project. One gram of racemic PZQamine was shipped to Syncom. An effective chiral stationary phase was found, followed by a chiral resolving agent ((–)-di-p-anisoyl-L-tartaric acid) that permitted the isolation of the desired (R)-enantiomer of PZQamine from the mother liquor in ca. 66% ee, which could be increased to 95% ee after one recrystallization.
To effect a resolution, PZQ should be hydrolysed to praziquanamine (PZQamine, ). The process must employ only crystallizations (rather than chromatography) to be practicable. The use of procedures that avoid the synthesis of complex catalysts, chromatographic purifications and NMR-based assessments of purity would also assist laboratories in underdeveloped countries to access enantiopure PZQ locally on smaller scales.
Todd MH (2006) Enantioselective Synthesis of Praziquantel.
Enantiomeric composition of praziquantel can be assayed by a number of enantioselective HPLC columns. For example: Chiralcel OD-H column, hexane/isopropanol/triethylamine solvent system (60400.1), flow rate 0.7 mL per minute. Retention times: 11.6 (R-(–)-PZQ) and 13.7 (S-(+)-PZQ) minutes. ()
a cheap and efficient synthesis of the drug praziquantel
Although effective synthetic methods for the enantioselective preparation of PZQ have been reported , we opted for the direct enantioseparation of the racemate yielding gram quantities of both optical forms. The preparative scale chromatography was performed on microcrystalline cellulose triacetate using methanol as the mobile phase, conditions under which the enantiomer having the negative optical rotation emerged first from the column . After crystallisation from methanol/water, (−)-PZQ was obtained in enantiomeric excess >99%, as determined by HPLC (column used Chiralcel OD-H). No residual other enantiomer (+)-PZQ was detected in this sample. X-ray structural analysis, using Cu-Kα radiation, of a monoclinic crystal in hemi-hydrate form obtained from said fraction by crystallization from methanol/water unequivocally proved the R-configuration of the molecule by measuring Friedel pairs and the Flack parameter (x=−0.1(3)) (). Further details of the crystal structure analysis are available on request from the CCDC () quoting the names of the authors and journal citation.
Enantioselective analysis of praziquantel in plasma ..
There are typically four methods available for the conversion of a racemic synthesis to one that generates a single enantiomer (): 1) Enantioselective synthesis, 2) Chromatographic separation, 3) Stereoablation (destruction and selective reconstruction of the stereocenter) and 4) Resolution. To date, reports of the preparation of enantiopure PZQ either have insufficient detail to allow for their appraisal, or likely do not have the potential for the large-scale production of the drug given the severe price constraint;, – for example with enantioselective chromatographic approaches significant quantities of solvents would be required.
The use of non-enantioselective synthesis of racemic mixtures and ..
We thank Denis Daumerie (WHO/NTD) for a gift of racemic praziquantel, Harald Sekljic (Intervet Innovation GmbH) for a gift of analytically pure samples of (R)- and (S)-PZQ and Donato Cioli (Institute of Cell Biology, Rome) for initial guidance. We thank all the many people who contributed to the open science project on The Synaptic Leap, the Custom Organic Synthesis and Process Chemistry Group at LinkedIn, the Labtrove group at the University of Southampton (particularly Professor Jeremy Frey and Andrew Milsted) and those who contributed by other means. A list of contributors is provided in the supporting information file Contributors. An early draft of this paper was prepared collaboratively online on the following website: