Racemic Resolution of Praziquantel and Praziquanamine

 

Testing a resolution method for (+)-PZQamine with (-)-di-p-anisoyl-L-tartaric acid following a resolution method for (+)-PZQamine with (-)-di-p-anisoyl-L-tartaric acid developed by Syncom B.V.

See:

Diastereomeric salt resolution of praziquanamine with (+)-di-p-anisoyl-D-tartaric acid (MW47-1)

Upscale: Diastereomeric salt resolution of praziquanamine with (+)-di-p-anisoyl-D-tartaric acid (MW47-2)

and Synthesis of (-)-Di-p-anisoyl-L-tartaric acid (MW46-4)

Start time: 4:10 PM 27/10/2010
End time: 10:00 AM 28/10/2010

Procedure:
rac-Praziquanamine (505 mg, 2.50 mmol) and (-)-di-p-anisoyl-L-tartaric acid (1.07 g, 2.50 mmol) [link to the procedure for purified resolving agent...] was dissolved in a mixture of isopropanol (10 mL) and water (2.0 mL) by heating. The solution was allowed to cool to room temperature and stand over night.

After 18 h the mother liquor was pipetted off and the remaining pale yellow solid was dried in a gentle stream of nitrogen.

Diasteromeric salt (1. precipitation):
656 mg (1.08 mmol, 43%) of a pale yellow amorphous solid (M.W. diastereomeric salt = 606.6 g/mol)

[α]D20 (diasteromeric salt) = - 1.4° (c = 1, DMSO)

- Liberation of the diasteromeric salt:
The salt (101 mg, 167 µmol) was dissolved in 2 N NaOH and extracted with DCM (3 x 5 mL), dried over sodium sulfate, evaporated:
Yield of S-(+)-PZQamine: 22 mg (117 mmol, 30% overall yield) of a colorless solid.
[α]D20 = 260° (c = 1, DCM) -> 85% ee (for [α]D20 = 296° (c=1, DCM) )

Recrystallization of the diastereomeric salt (1. precipitation):
The salt (504 mg, 830 µmol) was dissolved in a mixture of i-propanol and water 2:1 (8 mL) by heating to reflux and stirring the solution until all solid got dissolved.


Salt: [α]D20 = 15.3° (c = 1, DMSO)
Liberated salt (361 mg) yield: 101 mg colorless solid
[α]D20 = 274° (c = 1, DCM) -> 90% ee
1H NMR: Data: MW47-3 recrystallized from i-PrOH_water 2_1.pdf

Recrystallization of the diastereomeric salt (2. precipitate) after 3 d in the fridge: 245 mg colorless solid

Mother liquor after 10 h at room temperature (after 1. precipitation): 491 mg (809 µmol, 32%) yellow crystalline precipitate

Salt: [α]D20 = -140° (c = 1, DMSO)
Liberated salt (460 mg): 184 mg yellow oil
[α]D20 = -191° (c = 1, DCM) -> 65% ee

Mother liquor (2. precipitate) after 3 d in the fridge: 310 mg pale yellow solid