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26th November 2010 @ 00:29
Scale-up of the racemic resolution of rac-PZQamine under (semi) optimized conditions of former experiments

See related experiments:
Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-5 - MW49-11)
Racemic resolution of praziquanamine with (+)-Dibenzoyl-D-tartaric acid (MW49)
Synthesis of (-)-Dibenzoyl-L-tartaric acid (MW10-1-30) -> S-(+)-PZQamine
Diastereomeric salt resolution of praziquanamine with (-)-di-p-anisoyl-L-tartaric acid obtainig S-(+)-PZQamine (MW47-3)


scheme MW49-5.png



Start time: 12:10 PM 26/11/2010
End time: 1:40 PM 26/11/2010

Procedure:
rac-Praziquanamine (1.27 g, 6.27 mmol, M.W. 202.1 g/mol) and (-)-dibenzoyl-L-tartaric acid* 2 i-PrOH (3.00 g, 6.27 mmol, M.W. 478.5 g/mol) were dissolved in a mixture of i-PrOH (60 mL) and water (12 mL) by heating the stirred mixture.

After 90 min at room temperature the crystals were filtered off:
diastereomeric salt: Yield 1.55 g (2.76 mmol, 44%)
m.p. 145.5-147.5°C
[α]D20 = -123° (c = 1, DMSO)
liberated amine: [α]D20 = -242° (c = 1, DCM) -> 82% ee

- After further 3 h the formed crystals were filtered off: 267 mg (8%)
m.p. 145-147°C
- salt [α]D20 = -110° (c = 1, DMSO)
- liberated amine: [α]D20 = -220° (c = 1, DCM) -> 74% ee


mother liquor:
diastereomeric salt: 2.76 g
liberated amine 501 mg (2.48 mmol, 40%)
[α]D20 = +247° (c = 1, DCM) -> 83% ee
1H NMR: Data: 1H NMR MW49-12 remain 1. crystallization.pdf

- M.W. diastereomeric salt = 560.6 g/mol)


2. Crystallization
Start time: 2:40 PM 2/12/2010
End time: 3:30 PM 2/12/2010

The salt (1.33 g, 2.37 mmol) was dissolved in a mixture of i-PrOH (20 mL) and water (10 mL) by heating. After 50 min the precipitate was filtered off.
diastereomeric salt: Yield: 1.20 g (90%, overall: 40%)
m.p. 147-148.5°C
- liberated amine: [α]D20 = -279° (c = 1, DCM) -> 94% ee!!! (100 mg salt for liberation)


3. Crystallization
Start time: 1:20 PM 3/12/2010
End time: 2:30 PM 3/12/2010

The salt (1.08 g, 1.93 mmol) was dissolved in a mixture of i-PrOH (20 mL) and water (10 mL) by heating. After 50 min the precipitate was filtered off.
Yield: 927 mg (86%)
m.p. 147-148.5°C
- liberated amine (865 mg salt): 271 mg (1.34 mmol, 21%)
[α]D20 = -303° (c = 1, DCM) -> 100% ee !!!

Recovering of the resolving agent:
The basic aq. solution (after PZQamine was extracted) was made acidic to pH ~1 by adding 2 N HCl solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated under reduced pressure.

Yield 873 g (7.16 mmol, 57%, M.W. 122.1 g/mol) colorless solid benzoic acid -> hydrolysis of the (-)-Dibenzoyl-L-tartaric acid (under basic conditions)
1H NMR: Data: 1H NMR MW49-12 recovered resolving agent.pdf
13C NMR: Data: 13C NMR MW49-12 recovered resolving agent.pdf
-> too basic conditions / change order of extraction first acidic, then basic


remain 2./3. crystallization, liberated amine 71 mg
Attached Files
1H NMR MW49-12 remain 1. crystallization.pdf
1H NMR MW49-12 recovered resolving agent.pdf
13C NMR MW49-12 recovered resolving agent.pdf