Update 19th September

19 Sep
Published by m.robertson

Praziquantel: Racemic Resolution
Based on our recently-developed resolution, I've started producing gram quantities of enantiopure R and S PZQ to have a stock of each ready for any collaborators who might want some (let us know if you'd like some, or want advice on how to run this resolution yourself).  This last week I've made >100 g of both dibenzoyl tartaric acids. Recrystallization was originally troublesome, most likely due to scale and finding the right concentrations, but I eventually found good conditions. In the case of (+)-dibenzoyl-L-tartaric acid I found chloroform to be a better solvent for recrystallizing than toluene – because my NMR sample crystallized...  I carried out the hydrolysis of rac-PZQ in 4 batches (safer and easier working volumes) to produce 28 g of rac-PZQamine in 84 %.  I'm now doing the resolution of both enantiopure PZQamines using the tartaric acid derivatives.  Finally the N-cyclohexanoyl protection needs to be carried out to give enantiopure PZQ and I'm done.
 

Praziquantel: Enantioselective Synthesis via the Pictet-Spengler reaction
I'm then turning to making (R)-PZQ from scratch, using the Pictet-Spengler reaction that Michael started. Right now I'm making the starting materials for the P-S reactions with the intention of screening asymmetric catalysts. Isocyanide was prepared from 3,4-dimethoxyphenethylamine, ethyl formate and POCl3 in 83 %.  It was then taken on in a test Ugi reaction to form the Pictet-Spengler precursor (purification still required).  I'm also planning to make the aromatic derivative by substituting benzoic acid for the cyclohexanecarboxylic acid in the Ugi reaction. We're pretty sure the racemic cyclizations are going to be fine, but we are going to need help in screening catalysts. If you have a catalyst sitting in your fridge that you think might have a shot at catalysing this P-S reaction, let us know, and we can send you some of the precursors. It's quicker to work like this rather than us resynthesising catalysts that have already been made.

 

Comments

ndt228's picture

Hope this doesn't come too late but pls see my posting on PZQAmine characterisation, as it concerns the quality you need to achieve at the tartrate salt resolution, before converting the salt to the free amine.  Pls feel free to discuss further if you wish.
best regards
Nick

m.robertson's picture

Thanks,
At the time of making the amines I never checked the ee of the salt before converting to the free amine.  I was happy with the ee of the amines by optical rotation and the purity of the subsquent PZQ's were found to both be >98% by chiral HPLC.
Maybe I just got lucky but will check the puritiy of the salts if I have to go through this route again.
Thanks again
Murray