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Racemic Resolution of Praziquantel and Praziquanamine
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1st February 2011 @ 03:53
Derivatization of R-(-)-PZQamine from Optimizing the racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-14) in order to determine the ee obtained from the racemic resolution

Repetition of:
N-Cyclohexanoyl-protection of the enantiopure R-(-)-PZQamine in a multigram scale (MW48-4)

Scheme R-PZQamine MW48-1


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

Hazard and Risk Assessment:
HIRAC MW48


Start time: 3:00 PM 1/02/2011
End time: 9:00 PM 2/02/2011

To a cooled solution of R-(-)Praziquanamine (202 mg, 1.00 mmol; M.W. = 202.3 g/mol) in DCM (20 mL) at 0°C was added triethylamine (151 mg, 209 µL, 1.50 mmol, 1.5 eq.; M.W.=101 g/mol, density=0.726g/mL) and cyclohexanoyl chloride (162 mg, 148 µL, 1.10 mmol, 1.1 eq.; M.W.=147 g/mol, density=1.096g/mL). The solution was stirred for 18 h (over night) at room temperature.

Work-up:
- 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: 334 mg (1.07 mmol, 107%) colorless oil
[M.W.=312.4 g/mol]
- recrystallized from acetone/hexane (1:1)
Yield: 259 mg (830 µmol, 83%)

HPLC: R-(-)PZQ 99.2% -> 98.4%ee
Chiralcel OD-H, hexane/iso-propanol/Et3N = 60/40/0.1, 0.7 ml/min flow rate, RT: (R-(-)PZQ): 9.43 min, S-(+)PZQ: 11.45 min.
MW48-5.jpg
HPLC MW48-5 + rac-PZQ.jpg
HPLC rac-PZQ.jpg

HPLC1: MW48-5; HPLC2: MW48-5 + 10% rac-PZQ; HPLC3: rac-PZQ

Results:
The racemic resolution of rac-PZQamine obtained a yield of 31% and an ee of 98%.

References:
[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
Attached Files
MW48-5.jpg
HPLC MW48-5 + rac-PZQ.jpg
HPLC rac-PZQ.jpg