Racemic Resolution of Praziquantel and Praziquanamine

 

Testing (+)-dibenzoyl-D-tartaric acid as a resolving agent for the racemic resolution or PZQamine via diastereomeric salt formation

See related experiments:
Diastereomeric salt resolution of praziquanamine with (-)-di-p-anisoyl-L-tartaric acid obtainig S-(+)-PZQamine (MW47-3)
Synthesis of (+)-Dibenzoyl-D-tartaric acid - alternative route (MW10-6)

and subsequent experiments:
Optimizing the racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-14)
Multigram-scale racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-13)
Scale-up: Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-12)
Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-5 - MW49-11)



Start time: 7:30 PM 8/11/2010
End time: 12:30 PM 9/11/2010

Procedure:
rac-Praziquanamine (101 mg, 500 µmol) and (+)-dibenzoyl-D-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)

MW49-1: (previous experiment*)
Solvent: i-PrOH/water 5:1,
*) wrong stoichiometry due to a wrong molecular weight of (+)-dibenzoyl-D-tartaric acid (2 molecules of iPrOH in the crystal weren't considered)

2 mL: no precipitate after 1 day at room temperature and 2 days in the fridge, evaporated solvents in a stream of nitrogen
added 3 mL of solvent - crystallization
- After 15 h at room temperature: 140 mg (250 mmol, 50%) colorless crystals
- salt: [α]D20 = 109° (c = 1, DMSO)
- basic liberation of the amine: 39 mg pale brown solid
- PZQamine: [α]D20 = + 212° (c = 1, DCM) -> 72% ee
[α]D20 = 296° (c=1, DCM) )


MW49-2:
Solvent: EtOH/water 9:1
1 mL: rapid precipitation of a crystals when the mixture cooled down -> added 1 mL and heated to reflux
2 mL: slow crystallization, began after ~10 min standing at room temperature
- After 15 h at room temperature: 213 mg (373 mmol, 75%) colorless precipitate -> added 1 mL of solvent and dissolve the solid by heating
3 mL: crystals after ~15 min, after 4 h solvent was removed: 186 mg (332 mmol, 66%) of a crystalline colorless solid
4 mL: crystals, after 4 h solvent was removed: 163 mg (291 mmol, 58%)
- salt: [α]D20 = 111° (c = 1, DMSO)
- basic liberation of the amine: 48 mg pale brown solid
- PZQamine: [α]D20 = + 183° (c = 1, DCM) -> 62% ee
- mother liquor: [α]D20 = - 33° (c = 1, DMSO)

MW49-3:
Solvent: i-PrOH/water 5:1
1 mL: rapid precipitation of a colorless solid
2 mL: residue couldn't get dissolved by heating
3 mL: slow crystallization, began after ~10 min standing at room temperature
- After 15 h at room temperature: 209 mg (380 mmol, 76%) colorless precipitate -> added 1 mL of solvent and dissolve the solid by heating
4 mL: crystals after ~20 min, after 4 h solvent was removed: 177 mg (316 mmol, 63%) of a crystalline colorless solid
5 mL: crystals, after 4 h solvent was removed: 154 mg (275 mmol, 55%)
- salt: [α]D20 = 110° (c = 1, DMSO)
- basic liberation of the amine: 41 mg pale brown solid
- PZQamine: [α]D20 = + 190° (c = 1, DCM) -> 64% ee
- mother liquor: [α]D20 = - 23° (c = 1, DMSO)

MW49-4:
Solvent: EtOH/water 9:1
3 mL: after 2 h 157 mg

3 mL: after 1 h
- 1. precipitate (106 mg, 38%): [α]D20 = + 112° (c = 1, DMSO),
liberated salt: 92 mg
PZQamine: 30 mg
[α]D20 = 157° (c = 1, DCM)

2. precipitate (73 mg, 26%): [α]D20 = + 83.7° (c = 1, DMSO)
PZQamine: 22 mg
[α]D20 = 79.0° (c = 1, DCM)

mother liquor (113 mg, 40%):: [α]D20 = - 31.8° (c = 1, DMSO)
PZQamine: 33 mg
[α]D20 = -203° (c = 1, DCM)

-> solution is too concentrated (?)

Racemate:
rac-Praziquanamine (32 mg) and (+)-dibenzoyl-D-tartaric acid* 2 i-PrOH were dissolved in a mixture of EtOH and water 9:1 and the solvent was evaporated.
Remain: 102 mg pale yellow solid
[α]D20 = 37.5° (c = 1, DMSO)

Results:
(+)-dibenzoyl-D-tartaric acid shows excellent resolving abilities for PZQamine
(+)-PZQamine can be obtained from (+)-dibenzoyl-D-tartaric acid -> can (-)-PZQamine obtained from (-)-dibenzoyl-L-tartaric acid???
crystallization process is much faster - nice crystals can be obtained after a few minutes when the solution cools down to room temperature (seed crystals?)
Resolving agent (-)-dibenzoyl-L-tartaric acid is cheaper than (+)-di-p-anisoyl-D-tartaric acid! -> naturally occuring L-tartaric acid and more common resolving agent (syntheis costs are lower)