Racemic Resolution of Praziquantel and Praziquanamine

 

RXN 010 - Resolution of rac-PZQamine (MNR7-1) with (-)-dibenzoyl-L-tartaric acid (MNR6-1) to obtain R-(-)-PZQamine (MNR3-2)





Hazard and Risk Assessment:
As for MNR2-1

rac-PZQamine (MNR7-1) (13.8 g, 68.23 mmol) and (-)-dibenzoyl-L-tartaric acid. 2IPA (32.65 g, 68.23 mmol) was dissolved in a mixture of isopropanol (280 mL) and water (60 mL) by taking to reflux. The solution was allowed to cool to room temperature and stand overnight. The solid was then filtered and rinsed with IPA/water (5:1).

Crude salt (19.74 g, 35.15 mmol, 103%)


Mother liquor
Solvent was evaporated to give a sticky pale yellow solid - see below.

The salt (19.74 g, 35.15 mmol) was dissolved in a mixture of IPA (200 mL) and water (100 mL) by heating, allowed to cool then placed in an ice bath for two hours. The salt didn't give as nice crystals as before but were filtered off and washed with hexane. The sticky white solid recovered was dried in a vacuum desiccator. (is this recrystallization needed?)

Recrystallized salt:- 15.88 g, 28.33 mmol, 82%

The salt (15.88 g) was mixed with water (80 mL) and taken to pH 11 with the addition of NaOH solution (2M) and extracted with DCM (100 ml x 3). The aqueous layer was pH adjusted to pH2 using 2M HCl - see below. The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give an off white solid (4.09 g, 20.22 mmol, 59 %).

Unsure why this yield is so low?

The combined mother liquor layers were also mixed with water (80 mL) and taken to pH 11 with the addition of NaOH solution (2M)and extracted with DCM (150 ml x 3). The aqueous layer was pH adjusted to pH2 using 2M HCl - see below. The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a white solid (15.28 g, 75.55 mmol, >100 %).

The combined aqueous layers were left to stand overnight nothing crystallized out therefore it was extracted with EtOAc (150 mL x 3). The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a yellow oil (26.21 g, 54.78 mmol, 80 %). - requires recrystallization, also looks like some tartaric acid is still in the enriched product?

Total mass recovered - 45.58 g, 98 %

MNR3-2 [α]D20 = -291.7° (c=1, DCM)

1H NMR NMR3-2

Product used in
N-Cyclohexanoyl-protection of MNR3-2 to give R-PZQ (MNR9-1)

Lab book page complete, MNR