Multistep synthesis of rac-PZQ (Ugi route)

Published by jcbradley on 1 June 2010 - 2:57am

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]

Comments

Devil's in the detail- having seen a pre-print of the Agnew Chem paper there are 3 equivalents of various reagents that are used.

See also this poster abstract- 2212, page 4 which claims that he has done it in chiral form.

http://www.astmh.net/AM/Template.cfm?Section=Meeting_Archives&Template=/...

Maybe the imine could be pre-formed as outlined in the paper linked to above using methanol and this amine: http://www.chemspider.com/Chemical-Structure.80987.html
using the method outlined here:
http://pubs.acs.org/doi/abs/10.1021/ol015819b

Bulk starting materials to PZQ in a 3 step synthesis.  In english!
<a href="http://dx.doi.org/10.1002/chem201002046" target="_blank">Cao, H., H. Liu, et al. (2010). "Efficient Multicomponent Reaction Synthesis of the Schistosomiasis Drug Praziquantel." Chemistry-a European Journal 16(41): 12296-12298.  DOI: 10.1002/chem201002046</a> 
 

MatTodd's picture

OK, fine - this was discussed somewhere at some point. Note the way your URLs come out above - you're doing something funny. Can you use the link button instead of manual HTML?
This will give you a clearer idea of the conditions used, and what kinds of conditions lead to the simple isolation of product.
And put the paper in the draft paper on OWW... (in the right place - there's your challenge...)
And add the paper to the Mendeley group...