Racemic Resolution of Praziquantel and Praziquanamine

 

Testing (-)-dibenzoyl-L-tartaric acid as a resolving agent for the racemic resolution or PZQamine via diastereomeric salt formation to obtain R-(-)-PZQamine

See related experiments:
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)





Start time: 13:45 PM 17/11/2010
End time: 13:45 PM 17/11/2010

Procedure:
rac-Praziquanamine (101 mg, 500 µmol) and (-)-dibenzoyl-L-tartaric acid* 2 i-PrOH(239 mg, 0.5 mmol) were dissolved in a various solvents (mixtures) by heating the stirred mixture.

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

MW49-5:
Solvent: EtOH/water 9:1, 3 mL
- formation of crystals after 5 min
- after 1 h: 185 mg (66%)
- salt: [α]D20 = -100° (c = 1, DMSO)

MW49-6:
Solvent: EtOH/water 9:1, 4 mL
- formation of crystals after 5 min
- after 1 h: 159 mg (57%)
- salt: [α]D20 = -103° (c = 1, DMSO)

MW49-7:
Solvent: EtOH/water 9:1, 5 mL
- formation of crystals after 15 min
- after 1 h: 128 mg (46%)
- salt: [α]D20 = -110° (c = 1, DMSO)
- 118 mg recrystallized from EtOH/water (2 mL, 9:1), after 50 min: 90 mg (76%, 32% over-all)
Diastereomeric salt: [α]D20 = -117° (c = 1, DMSO)
m.p. = 149-150.5°C

PZQamine: 24 mg
[α]D20 = -257° (c = 1.71, DCM) -> 87% ee (calculation error -> c=1 ?)


-> crystallization too fast, lower concentration should slow down the crystallization



Further experiments:

Start time: 6:15 PM 17/11/2010
End time: 7:40 PM 17/11/2010

MW49-8:
Solvent: EtOH/water 9:1, 6 mL
(former MW49-6, - 10.4 mg for optical rotation)
- after 90 min: 127 mg (45%)
Diastereomeric salt: [α]D20 = -118° (c = 1, DMSO) [not consistent ???]
m.p. = 144-145°C

PZQamine: 36 mg
[α]D20 = -198° (c = 1, DCM) 67% ee

MW49-9:
Solvent: EtOH/water 9:1, 7 mL
(former MW49-5, - 12.3 mg for optical rotation)
- after 90 min: 72 mg (26%)
Diastereomeric salt: [α]D20 = -115° (c = 1, DMSO)
m.p. = 147-148°C

PZQamine: 16 mg
[α]D20 = -210° (c = 1, DCM) -> 71% ee

Results:
- rising melting point of the diastereomeric salt
- deviations of the optical rotation (not consistent)
- crystallisation with another solvent / solvent mixture (higher content of water or i-PrOH/water)


MW49-10:
Start time: 10:30 PM 24/11/2010
End time: 13:00 PM 24/11/2010

Solvent: EtOH/water 9:1, 5 mL
- at first no crystals, stirring -> precipitate
- heated again - formation of crystals after 30 min
- after 3 h: 155 mg (55%)
m.p. = 136-138°-c
- salt: [α]D20 = -103° (c = 1, DMSO)

2. Crystallization: Solvent: EtOH/water 2:1, 3 mL
Start time: 9:00 PM 24/11/2010
End time: 9:30 PM 24/11/2010

after 1 h: 110 mg (39%)
- salt: [α]D20 = -115° (c = 1, DMSO)
- PZA: [α]D20 = -246° (c = 0.90, DCM) -> 83% ee



MW49-11:
Start time: 10:30 PM 24/11/2010
End time: 11:00 PM 24/11/2010

Solvent: i-PrOH/water 5:1, 3 mL
- crystallization too fast

Solvent: i-PrOH/water 5:1, 4 mL
- crystallization after 5 min, after 30 min separated: 172 mg (61%)
- salt: m.p. = 135-137°C, [α]D20 = -115° (c = 1, DMSO)

2. Crystallization:
Start time: 9:00 PM 24/11/2010
End time: 9:20 PM 24/11/2010

Solvent: i-PrOH/water 2:1, 3 mL
- complete precipitation

Solvent: i-PrOH/water 2:1, 4 mL
- after 1 h: yield: 99mg (35%)
- salt: [α]D20 = -121° (c = 1, DMSO)
[α]D20 = -262° (c = 1.09, DCM) -> 89% ee