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
 
Scheme1
 
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]

Reissert Approach to rac-PZQ

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Starting Materials for the Synthesis of rac-PZQ

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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
    Isoquinoline
    (InChI=1/C9H7N/c1-2-4-9-7-10-6-5-8(9)3-1/h1-7H)
 
Cyclohexanoyl chloride
   Cyclohexanoyl chloride
   (InChI=1/C7H11ClO/c8-7(9)6-4-2-1-3-5-6/h6H,1-5H2)
 
 
Cyclohexanecarboxylic acid   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
    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

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1H NMR Cyclohexanoyl chloride.pdf88.3 KB

Subject 

Miscellaneous

 
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
 1H NMR Cyclohexanoyl chloride