Racemic Resolution of Praziquantel and Praziquanamine

 

Resolution of MNR26-1 with (+)-dibenzoyl-D-tartaric acid (MNR5-1)





Hazard and Risk Assessment:
As for MNR2-1

MNR26-1 (0.40 g, 1.52 mmol) and MNR5-1 (0.586 g, 1.52 mmol) was dissolved in IPA (4 mL) with heating and water (1 mL) was added. All the reagents went into solution and the mixture was left to stand overnight. No crystals grew over night, IPA (2 mL) was added and mixture allowed to stand for another 8 hours. Again, no crystals grew, hexane (3 mL) was added and mixture left overnight. Some crystals grew and the mixture was left to stand over the weekend. Crystals were washed with IPA:Hex:water (6:3:1) and dried to give fine white crystals which were dried under vacuum for 6 hours.

Salt recovered 0.295 g

Hazard and Risk Assessment:


Procedure:
rac-MNR11-13 (2.00 g, ) was dissolved in a mixture of EtOH (10 mL) and 1M HCl (50 mL) and heated to reflux for 14 h. The solution was allowed to cool to room temperature then cooled in an ice bath, basified with NaOH to pH 12-13 and extracted with DCM (4 x 50 mL). The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a light brown solid.

0.437 g

Very low yield, extracted with EtOAC

0.062 g

total recovered

0.499 g, 35 %

The pH of the aqueous layer was taken to 6 by the addition of conc HCl and extracted with EtOAc

Resolution of MNR26-1 with (+)-dibenzoyl-D-tartaric acid (MNR5-1)

*SM recovered from unsuccessful resolutions in MNR27





Hazard and Risk Assessment:
As for MNR2-1

MNR26-1 (0.60 g, 2.29 mmol) and MNR5-1 (1.1 g, 2.29 mmol) was dissolved in a mixture of IPA (20 mL) and hexane(5 mL) and heated till the reagents went into solution. After standing at room temperature overnight a dark solid was visible but not crystals. This solid was filtered off and washed with IPA:Hex (50:50) to give a light brown solid (0.547 g). A portion of this solid (50 mg) was mixed with water (2 mL) and taken to pH 12 with the addition of NaOH solution (2M) and extracted with EtOAc (4 ml x 3). The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a light brown oil (17 mg) Chiral HPLC analysis of this showed no ee.



*note - there has been problems with the HPLC pump and the pressure is jumping between 200-3000 psi. This is the likely reason for the change in retention times. See the standard below for a better rac trace

Upon standing white crystals had started to form in the original filtrate. This were filtered and washed with IPA:Hex (50:50) to give a white solid (0.063 g). This was mixed with water (2 mL) and taken to pH 12 with the addition of NaOH solution (2M) and extracted with EtOAc (4 ml x 3). The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a clear oil (17 mg) Chiral HPLC analysis of this showed an ee of 70%.

Resolution of MNR26-1 with (+)-dibenzoyl-D-tartaric acid (MNR5-1)





Hazard and Risk Assessment:
As for MNR2-1

MNR26-1 (016 g, 0.61 mmol) and MNR5-1 (0.29 g, 0.61 mmol) was dissolved in a mixture of isopropanol (3 mL) and water (3 mL) and heated till the reagents went into solution. After standing at room temperature overnight no crystals appeared. The reaction mixture was concentrated and taken up in IPA (25 mL) and hexane (15 mL) with heating, allowed to cool to room temperature and left in the freezer overnight. No crystals formed but a small trace of brown solid did. It was filtered off and the solvent was concentrated. The resulting crude was then taken up in IPA (20 mL) and heated to 60 C in a water bath. Hexane (20 mL) was added and the flask was left to stand open at room temperature. After approximately 1 week sitting open in the back of the fume hood crystals started to form, after being left for 3 mores days the crystals were filtered and washed with hexane and EtOAc. More more solid crashed out of this wash and the filtrated was reduced in volume and filtered again, washing with EtOAc.

First crop - fine white solid/crystals 0.055 g
Second crop - off white solid 0.055 g

Both crops were kept separate and mixed with water (2 mL) and taken to pH 11 with the addition of NaOH solution (2M) and extracted with DCM (4 ml x 3). The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give...

Hazard and Risk Assessment:

To a cooled solution of MNR27-1 ( mmol) in DCM (5 mL) at 0°C was added triethylamine (0.21 mL, mol) and benzoyl chloride(0.13 mL, 1.09 mmol). The solution was stirred overnight at room temperature.

The solution was quenched with water (5 mL) and stirred for a further 30 min. The layers were separated and the organic layer was washed with saturated sodium carbonate solution (5 mL), 0.5 M HCl (5 mL) and brine (5 mL). Dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude as an orange oil (0.240 g).

Column:- 50-100 EtOAc/PetEther

Fracs 15-24