Alternative Approach to the Diamine Precursor

08 Nov
Published by CreativeChemistry

Subject 

Miscellaneous

 We have looked at an alternative process to generate the diamine precursor to PZQ, whose resolution is documented. The process involves reduction of the cyano-imine derived from the published reaction of THIQ with peroxide/tungstate/cyanide. Having been able to reduce 1-cyanoisoquinoline very cleanly using Pd/C we anticipated that it would be possible to do the same here. It would be important, however, to maintain acidic conditions to prevent the retro-addition of the cyanide (well documented for the 1-cyano and 1-(nitromethyl)isoquinolines with a free N-H).
 

 
 
The cyano compound was prepared in 90% yield (95% purity, 0.4mole scale). Attempts to reduce the cyano with either Pd/C or RaNi with 2 eq HCl failed at pressures up to 10 bar. In contrast, the reaction proceeded rapidly with Pt/C (10 bar, 2eq HCl). Unfortunately, even under the acidic conditions, there was a rapid retro-reaction to give a product which contained the diamine and THIQ in a 1:3 ratio as observed by HPLC.
 
It is not known if the ratio can be improved by use of more acidic conditions. Clearly what is needed is a method to reduce the cyano before the imine in order to prevent the retro-reaction.
 
 
 
 

Comments

MatTodd's picture

Interesting. That diamine has always been difficult to isolate for us, too, approaching it from other routes. It's never been well-characterised in the literature.
 
Do you have a reference for that first step?

The cyano compound is documented in Tetrahedron Letters,  1987, 6469. On scale-up, it is not necessary to add the acid to the mixture. It can also get pretty exothermic as well......
 
As for the retro-reactions, there is a summary in J Med Chem, 1983, 507. They solve it by alkylation and LAH reduction!