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
    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

 
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