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Racemic Resolution of Praziquantel and Praziquanamine
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10th January 2011 @ 07:15
Final step of the mulitgram scale resolution of rac-PZQ:
Conversion of enantiopure R-(-)-Praziquanamine (PZQamine), obtained from the Multigram-scale racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-13) to R-(-)-PZQ

See also:
N-Cyclohexanoyl-protection of the enantiopure R-(-)-PZQamine (MW48-3)
From R-(-)-Praziquanamine to R-(-)-Praziquantel (MW48-1): N-Cyclohexanoyl-protection of the enantiopure PZQamine
From S-(+)-Praziquanamine to S-(+)-Praziquantel (MW48-2): N-Cyclohexanoyl-protection of the enantiopure PZQamine

Scheme R-PZQamine MW48-1

Hazard and Risk Assessment:

Start time: 6:00 PM 10/01/2011
End time: 8:10 PM 11/01/2011

To a cooled solution of R-(-)Praziquanamine (3.27 g, 16.2 mmol; M.W. = 202.1 g/mol) in DCM (80 mL) at 0°C was added triethylamine (2.45 g, 3.38 mL, 24.3 mmol, 1.5 eq.; M.W.=101 g/mol, density=0.726g/mL) and cyclohexanoyl chloride (2.62 g, 2.39 mL, 17.8 mmol, 1.1 eq.; M.W.=147 g/mol, density=1.096g/mL). The solution was stirred for 14 h at room temperature.

- the reaction was quenched with water (10 mL) and stirred for 1 h
- seperation of the layers
- organic layer was washed with sodium carbonate solution, 0.5 M HCl solution, then with brine
- dried over MgSO4
- evaporated under reduced pressure and high vac

crude yield: 5.36 g (17.2 mmol, 106%) yellow oil
[M.W.=312.4 g/mol]

- further step: cystallization from acetone/hexane, EtOAc/Hexane or EtOH [2,3,4]

- first recrystallizations from acetone/hexane and EtOAc/Hexane weren't sucessful
- evaporation of the solution under high vac -> oil, which formed a foam under high vac
- the foam was cooled with liquid nitrogen under high vac, powedered in frozen state and left for a few h under high vac -> solid

The pale yellow solid was dissolved in a mixture of acetone/hexane (~35 mL, 1:1 mixture) heating to reflux. After adding a seed crystal to the warm solution (~40°C) R-(-)-PZQ started to crystallize. The solution was placed in the fridge over night at +5°C. The mother liquor was removed and the residue was washed with a cold mixture of acetone/hexane.

Yield (1. crystallization): 3.52 g (11.3 mmol, 70%) colorless crystals
m.p. 113.5 - 114.5°C
Data: 1H NMR MW48-4-1.pdf
[α]D20 = -136° (c=1, EtOH) -> ee 98%
Ref: [α]D20 = -139° (c=1, EtOH), determined for enantiopure R-(-)-PZQ Optical rotation of R-(-)-PZQ and S-(+)-PZQ

HPLC: R-(-)PZQ 98.5% -> 97%ee
Chiralcel OD-H, hexane/iso-propanol/Et3N = 60/40/0.1, 0.7 ml/min flow rate, RT: (R-(-)PZQ): 11.1 min, S-(+)PZQ: 13.6 min
HPLC MW48-4.jpg

The mother liquor was concentrated under reduced pressure. The residue was recrystallized a 2. time from acetone/hexane and stored in the fridge over night.
Yield (2. crystallization): 778 mg (2.49 mmol, 15%) colorless crystals
m.p. 113.0 - 114.5°C
Data: 1H NMR MW48-4-2.pdf
HPLC MW48-4 fr2.jpg

Remain: 1.02 g (3.27 mmol, 20%) pale yellow oil
Yield (3. crystallization): 265 mg (851 µmol, 5%)
HPLC MW48-4 fr3.jpg

90% yield of R-(-)-PZQ for the cyclohexanoyl-protection of PZQamine and recrystallization (2 times concentrated mother liquor)
Resolution obtained 98% R-(-)-PZQ

Calculation overall yield of the resolution procedure...

[1] "Enantioselective synthesis of (R)-(−)-praziquantel (PZQ)", P. Roszkowski J. K. Maurin and Zbigniew Czarnocki, Tetrahedron: Asymmetry,2006, 17, 9, 15, 1415-1419. (doi:10.1016/j.tetasy.2006.04.023)

[2] "4-Acyl-2,6-dioxo-1-phenethyl piperozines, United States Patent US 4523013
US Patent Application (2002), US 2002/0151717A1.

[3] "A short synthesis of praziquantel", F. Yuste, Y. Pallás, H. Barrios, B. Ortíz and R. Sánchez-Obregón, J. Heterocyclic Chem. 1986, 23, 1, 189–190. (DOI: 10.1002/jhet.5570230139)

[4] TheSynyptic leap: Recrystallization of PZQ

See also: Optical rotation of R-(-)-PZQ and S-(+)-PZQ
Linked Posts
Attached Files
1H NMR MW48-4-1.pdf
1H NMR MW48-4-1 JCAMP-DX.dx
1H NMR MW48-4-2.pdf
1H NMR MW48-4-2 JCAMP-DX.dx
HPLC MW48-4.jpg
HPLC MW48-4.jpg
HPLC MW48-4 fr2.jpg
HPLC MW48-4 fr3.jpg