Racemic Syntheses of PZQ
This page details the various approaches to rac-PZQ
Multistep synthesis of rac-PZQ (Ugi route)
A new patent application using a multistep reaction (Ugi reaction) for the synthesis of Praziquantel
This recent patent application describes a new method for the synthesis of rac-Praziquantel.[1] The key step in this procedure is a multi-step reaction, also known as the Ugi reaction, which enables the formation of the intermediate 5 up to 89%. [2,3] Under Broensted-acidic conditions a Pictet-Spegler-cyclization yields 6 or Praziquantel 7, depending on the various substituents R2.
[1] “Novel Synthesis of Praziquantel“, A. Dömling, Patent Application 2009, WO 2009/11533(A1), Language: German.
[2] “Multicomponent Reactions with Isocyanides” A. Dömling, I. Ugi, Angew. Chem.2000, 39, 18, 3168 – 3210.
[3] "Recent Developments in Isocyanide Based Multicomponent Reactions in Applied Chemistry", A. Dömling, Chem. Rev. 2006, 106 ,1, 17–89; DOI: 10.1021/cr0505728.
We just tried this exact reaction 2 weeks ago :) http://usefulchem.wikispaces.com/Exp258 [JCB]
Pictet-Spengler route to rac-PZQ
The synthesis of rac-PZQ via the Pictet-Spengler route was developed by the Korean Shin Poong Pharmaceutical Company and obtains very low production costs of US¢7 per 600 mg tablet of the drug.
First step (amide bond formation to give 3)
Second step (attachment of acetal to give 4) - there's also a one-pot procedure to combine the first 2 steps
Third step (cyclization to praziquanamine to give 5)
Fourth step...
Combination of steps 1-3 to give the dimethoxy analog of PZQ
Key references:
[1] Formation of pyrazinoisoquinoline ring system by the tandem amidoalkylation and N-acyliminium ion cyclization: An efficient synthesis of Praziquantel, J. H. Kim, Y. S. Lee, H. Park and C. S. Kim, Tetrahedron 1998, 54, 7395-4000.
[2] Synthesis of Praziquantel via N-Acyliminium Ion Cyclization of Amido Acetals through Several Synthetic, J. H. Kim, Y. S Lee and C. S. Kim, Heterocycles 1998, 48, 11, 2279-2285.
[3] History of Praziquantel: http://www.stanford.edu/group/parasites/ParaSites2006/Praziquantel/history.html
Reissert Approach to rac-PZQ
The most obvious, and known, approach to rac-PZQ is using Reissert chemistry.
This approach has been used in the following publications:
[1] Organic Sonochemistry. Synthesis and Use of Reissert compounds under PTC-Ultrasound, J. Ezquerra and J. Alvarez-Builla, J. Heterocyclic Chem. 1988, 25, 917-925.
[2] Alkylation of isoquinolines via 2-benzoyl-1,2-dihydroisoquinaldonitriles: 1-Benzylisoquinoline, B. C. Uff, J. R. Kershaw and J. L. Neumeyer, Org. Synth. 1988, 6, 115; Org. Synth. 1977, 56, 19.
Child pages from this one detail attempts at this synthesis, and can host comment about it.
Starting Materials for the Synthesis of rac-PZQ
For an inexpensive route to rac-PZQ (and potentially the enantioenriched material), the relevant starting materials (below) are required. While prices may be obtained for these from commercial catalogues, we require realistic prices of these materials on a large (ton) scale to assess whether this approach to PZQ is economically viable. The starting materials are:
Reissert route chemicals:
Isoquinoline
(InChI=1/C9H7N/c1-2-4-9-7-10-6-5-8(9)3-1/h1-7H)
Cyclohexanoyl chloride
(InChI=1/C7H11ClO/c8-7(9)6-4-2-1-3-5-6/h6H,1-5H2)
Cyclohexane carboxylic acid
(InChI=1/C7H12O2/c8-7(9)6-4-2-1-3-5-6/h6H,1-5H2,(H,8,9))
Example price from Sigma-Aldrich = US$59 for 500 g = 12 cents per gram. Bulk?
Thionyl Chloride
(InChI=1/Cl2OS/c1-4(2)3)
Chloroacetyl chloride
(InChI=1/C2H2Cl2O/c3-1-2(4)5/h1H2)
Cyanide sources: KCN (InChI=1/CN.K/c1-2;/q-1;+1)
or NaCN (InChI=1/CN.Na/c1-2;/q-1;+1)
Pictet-Spengler route chemicals:
2-Phenylethanamine
(InChI=1/C8H11N/c9-7-6-8-4-2-1-3-5-8/h1-5H,6-7,9H2)
US$ 96 for 1 L (Sigma-Aldrich)
2,2-Dimethoxyethanamine
(InChI=1/C4H11NO2/c1-6-4(3-5)7-2/h4H,3,5H2,1-2H3 )
US$ 532 for 500 mL (Sigma-Aldrich)
Synthesis of Cyclohexanoyl Chloride from Cyclohexane Carboxylic Acid
An early step in the Reissert approach to PZQ is the synthesis of cyclohexanoyl chloride (InChI=1/C7H11ClO/c8-7(9)6-4-2-1-3-5-6/h6H,1-5H2) from cyclohexane carboxylic acid, (InChI=1/C7H12O2/c8-7(9)6-4-2-1-3-5-6/h6H,1-5H2,(H,8,9)). This step is needed if it is found that the acid chloride is prohibitively more expensive than the acid.
Experimental:
Cyclohexanoyl chloride was prepared by refluxing cyclohexanecarboxylic acid (390 mmol, 50.0 g) and SOCl2 (770 mmol, 56.0 mL, 1.95 eq.) for 4 h with exclusion of moisture. The mixture was allowed to cool. Gas bubbles continued to evolve from the solution and hence the mixture was allowed to stir overnight at rt.
The residue was purified by fractional distillation (1 atm, bp 186°C) to give the acid chloride as a light yellow liquid (47.0 g, 321 mmol, 82%).
1H NMR Cyclohexanoyl chloride
