Enantiopure PZQ Analogs

28 Jun
Published by m.robertson

We have now successfully synthesised enantiopure analogs of PZQ bring our library for screening to 12 compound.  If you would like samples of the following compounds for biological screening please get in touch and we can send them to you.

 
As with our previously reported resolution of praziquantel the benzoyl derivatives were accessed via a similar route.  Racemic praziquantel was hydrolysed to give MNR7-5 followed by resolution using (-)-dibenzoyl-L-tartaric acid (MNR6-1) or (+)-dibenzoyl-D-tartaric acid (MNR5-1) or to give MNR3-3 and MNR2-4 respectively.  Subsequent functionalisation of the amines with cyclohexanecarbonyl chloride or benzoyl chloride gave the desired enantiopure products MNR9-1, MNR24-1, MNR1-3 and MNR25-1.

For the dimethoxy analogs, a Ugi reaction followed by a Pictet-Spengler reaction gave the racemic analogs.  The Ugi reaction was carried out using isocyanide MNR4-2 and either cyclohexanecarboxylic acid and benzoic acid to give MNR8-3 or MNR22-2.  Pictet-Spengler cyclisation of the Ugi products gave MNR11-17 and MNR12-6.  The racemic analogs were also produced here KAB1-2 and KAB8-5.

As above, racemic dimethoxy-PZQ (MNR11-17) was hydrolysed to give MNR26-5 followed by resolution using (-)-dibenzoyl-L-tartaric acid (MNR6-1) or (+)-dibenzoyl-D-tartaric acid (MNR5-1) or to give MNR27-1 and MNR30-7 respectively.  Subsequent functionalisation of the amines with cyclohexanecarbonyl chloride or benzoyl chloride gave the desired enantiopure products MNR28-3, MNR31-1, MNR38-1 and MNR39-1.
It should be noted that the resulting salts from the the resolution of dimethoxy-PZQ-amine are not as crystalline as the corresponding PZQ-amine salts.  The salt appear as a white clumpy solid, but after two rounds of crystallisation using mixtures of IPA and water the salt can be isolated with ee's greater than 95%.
 
HPLC traces of the final products can be found in the following files.
 
Chiral HPLC of MNR14, MNR24 and MNR25
Chiral HPLC of KAB1, MNR28 and MNR38
Chiral HPLC of KAB8, MNR31 and MNR39