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27th January 2011 @ 00:47
5g-scale racemic resolution of rac-PZQamine
- Optimizing yield and ee by reducing amount of solvent and add another crystallization step

See related experiments:
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)
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: 11:30 AM 27/01/2011
End time: 2:30 PM 27/01/2011

Procedure:
rac-Praziquanamine (5.0 g, 24.7 mmol, M.W. 202.3 g/mol) and (-)-dibenzoyl-L-tartaric acid* 2 i-PrOH (11.9 g, 24.7 mmol, M.W. 478.5 g/mol) were dissolved in a mixture of i-PrOH (208 mL) and water (42 mL) by heating the stirred mixture. The solution was allowed to cool to room temperature and after 2 h the crystalline precipitate was filtered off. Yield: 6.12 g (10.9 mmol, 44%).
The filtrate was cooled to 0°C and a second precipitate was filtered off (260 mg)

Yield: 6.38 g (11.4 mmol, 46%)
[M.W. diastereomeric salt = 560.6 g/mol]

2. Crystallization:
The salt (6.38 g, 11.4 mmol) was dissolved in a minimum of a mixture of i-PrOH and water (135 mL, isopropanol:water = 2:1) by heating. The solution kept at room temperature over night and the precipitate was filtered off and dried.

Yield: 5.35 g (9.54 mmol, 39%)
m.p. = 146 - 147.5°C
1H NMR:Data: 1H NMR MW49-14 diastereomeric salt

3. Crystallization:
Start time: 5:00 PM 28/01/2011
End time: 9:00 AM 31/01/2011
The salt (5.35 g, 9.54 mmol) was dissolved in a minimum of a mixture of i-PrOH and water (120 mL, isopropanol:water = 2:1) by heating. The solution kept at room temperature for 2 days and the precipitate was filtered off and dried.

Yield: 4.80 g (8.56 mmol, 35%)
m.p. = 147.3 - 148.5°C

Liberation of R-(-)-PZQamine:
3.30 g (5.88 mmol) of the diastereomeric salt were dissolved in a 12% aq. solution of K2CO3 (~50 mL) (pH 10 - 11). The solution was extracted 4 times with DCM (15 mL), the combined organic layers were dried over NaSO4 and evaporated.
Yield: 1.05 g (5.19 mmol, 88% yield for the liberation, 31% overall yield) colorless solid
m.p. = 122.6 - 123.9°C
[α]D20 = -305.5° (c=1, DCM)
(1.50 g, 2.68 mmol salt were seperated for further crystallization)

Liberation of L-(+)-PZQamine:
The combined mother liquors from the crystalization were concentrated under reduced pressure and the solid (aq. suspension) was made basic with 12% aq. solution of K2CO3 (~50 mL) (pH 10 - 11). The solution was extracted 4 times with DCM (20 mL), the combined organic layers were dried over NaSO4 and evaporated.
Yield: 3.03 g (15.0 mmol, 61% yield) pale yellow solid
[α]D20 = +158° (c=1, DCM)

Recovery the resolving agent:
The combined basic solutions were neutralized by adding concentrated hydrochloric acid dropwise and when a permanent solid was formed the the pH was adjusted to pH 2-3 by adding 2 M HCl solution. The suspension was cooled by an ice bath and kept for 1 h at 0°C then the colorless precipitate was filtered off and dried (high vac while heating).
Yield: 16.5 g (43.8 mmol, 176%) colorless solid, which turns pale red after heating under high [M.W. (dibenzoyltartaric acid * H2O)= 376.3 g/mol]
1H NMR: dibenzoyl-tartaric acid with small imputities, no isopropanol or water signals! Compound is sparingly soluble in DMSO -> salt impurities, also no isopropyl signals
Data: 1H NMR MW49-14 resolving agent.pdf
-> purification/recrystallization
Recrystallized DBTA: 2.80 g (5.85 mmol, 24%)
- lots of unsoluble residue - monoprotonated tartaric acid. precipitated before protonation (?) -> extract acidic solution with ethyl acetate.

Note: The resolving agent must not be left for a long time in basic solution -> hydrolysis of the ester

Results:
The resolution obtained a yield of 31% and an ee of 98% (determined by chiral HPLC of (R)-PZQ, see: N-Cyclohexanoyl-protection of the enantiopure R-(-)-PZQamine to PZQ (MW48-5))

-> better results were received with the previous procedure: Multigram-scale racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-13)


References:
[1] "Novel processes for the preparation or (R)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol", Daugs et al. US Patent Application (2002), US 2002/0151717A1. [Example 20, p. 27-28]
Attached Files
1H NMR MW49-14 diastereomeric salt
1H NMR MW49-14 resolving agent.pdf