Notice: Undefined index: NAME in /home/www/hosts/www.ourexperiment.org/lib/functions_blog.php on line 123

Notice: Undefined index: NAME in /home/www/hosts/www.ourexperiment.org/lib/functions_blog.php on line 123

Notice: Undefined index: NAME in /home/www/hosts/www.ourexperiment.org/lib/functions_blog.php on line 123
Racemic Resolution of Praziquantel and Praziquanamine
All Notebooks | Help | Support | About
28th January 2011 @ 06:40
rac-PZQamine and R-(-)-PZQamine were purified by recrystallisation from toluene for performing a binary phase diagram via DSC by Nick (Almac Sciences)


rac-PZQamine
Synthesis: Hydrolysis of rac-PZQ (MW2-14)
Purification: recrystallized two times from toluene

m.p. = 119.0 - 119.8°C. (colorless to pale orange solid)
Further analytical data: http://www.thesynapticleap.org/node/296
NMR: http://www.thesynapticleap.org/node/294 (see attachment)

R-(-)-PZQamine (97% ee)
Synthesis, see: Multigram-scale racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-13)
Purification: recrystallized two times from toluene
Quantification of the enantiomeric excess, see: N-Cyclohexanoyl-protection of the enantiopure R-(-)-PZQamine in a multigram scale (MW48-4)

m.p. 121.1 - 122.0°C. (colorless to pale orange solid)
[α]D20 = -305° (c=1, DCM).
1H NMR: Data: 1H NMR MW49-13 (-)-PZQamine.pdf
Chiral 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. Data: HPLC MW48-4.jpg

Note: PZQamine degenerates slowly at room temperature (turns yellow - orange)

References:
[1] Formation of Pyrazinoisoquinoline Ring System by the Tandem Amidoalkylation and N-Acyliminium Ion Cyclization: An Efficient Synthesis of Praziquantel, J. H. Kim, Y. S. Lee, H. Park and C. S. Rim, Tetrahedron 1998, 54, 7395-7400.(DOI: doi:10.1016/S0040-4020(98)00401-3)

[2] Synthesis of “Trioxaquantel”(R) Derivatives as Potential New Antischistosomal Drugs, S. A.-L. Laurent, J. Boissier, F. Coslédan, H. Gornitzka, A. Robert and B. Meunier, Eur. J. Org. Chem. 2008, 895-913. (DOI: 10.1002/ejoc.200700975)

[3] The Resolution of Praziquantel, M. Woelfle, J.-P. Seerden, J. de Gooijer, K. Pouwer, P. Olliaro and M. H. Todd1, www.openwetware.org, 2011
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
24th January 2011 @ 06:58
Preparation of starting material for a scaled-up racemic resolution of PZQamine

See: Hydrolysis of rac-PZQ (MW2-13)
Following the optimized conditions for rac-PZQ: see Optimizing the acid cleavage conditions II

MW2-13.png


Hazard and Risk Assessment:
Data: HIRAC MW2

Start time: 6:30 PM 24/01/2011
End time: 8:50 AM 25/01/2011

Procedure:
rac-PZQ (20.0 g, 64.0 mmol) was dissolved in a mixture of EtOH (150 mL) and 1N HCl (600 mL, 53.0 mL of 11.3 N HCl solution (35%) in 547 mL water) and heated to reflux for 14 h. Reaction monitored by TLC showed a complete consumption of PZQ (TLC, EA/hexane 1:1, Rf = 0.15 for PZQ).

Work-up:
Solution was cooled to room temperature, washed with EtOAc (4 times 15 mL), basified with NaOH solution (5 N) to ph 12, extracted with DCM (5 x 30 mL), washed with brine, dried over NaSO4, evaporated under reduced pressure.
pale yellow oil turned into a solid after freezing the oil with liquid nitrogen under high vac and warmed to room temperature.

Yield:
11.1 g (52.0 mmol, 86%) pale yellow solid
[M.W. = 202.1 g/mol]
m.p. = 116.5 - 118.5°C
Linked Entries
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:
HIRAC MW48


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.

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: 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]
See: http://www.thesynapticleap.org/node/275

Recrystallization:
- 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


Result:
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...


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
Linked Posts
Attached Files