Racemic Resolution of Praziquantel and Praziquanamine

 

Synthesis of a chiral acid as a potential resolving agent for Praziquanamine following a previous procedure for the Synthesis of (-)-Dibenzoyl-L-tartaric acid (MW10-1-30)

See also:
Synthesis of (+)-Dibenzoyl-D-tartaric acid (MW10-5)
Scale-up: Synthesis of (-)-Dibenzoyl-L-tartaric acid (MW10-7)





Hazard and Risk Assessment:


Start time: 6:00 PM 19/10/2010
End time: 10:00 PM 19/10/2010

A mixture D-(-)-tartaric acid (4.50 g, 30 mmol) and benzoyl chloride (14.8 g, 12.2 mL, 105 mmol) was heated to 130°C for 4 h. After which time a pale yellow solid was formed and the mixture was cooled to room temperature. The solid was washed with cold Et2O and recrystallized from toluene (100 mL) affording a fine crystalline colorless solid. The solid was dried in a air stream.
The solvent of resulting mother liquor was evaporated: remaining solid 5.4 g (crude 15.1 mmol) -> recrystallizing a 2. time from toluene: 1.40 g of a colorless solid: benzoic acid
1H NMR: Data: 1H NMR MW 10-6 remain.pdf


Yield: 8.40 g (23.4 mmol, 78%) of a fine crystalline colorless solid, small impurity/trace (signal at 6.70 ppm - anhydride?), broad water / OH-peak.
1H NMR:Data: 1H NMR MW 10-6.pdf
IR:Data: IR MW10-6.pdf no OH/COOH bands!? -> compare with MW10-5
[α]D20 = -104° (c=1, EtOH)
Correction: Yield for the anhydride: 8.40 g (24.7 mmol, 82%)

m.p. = 191-192°C (lit. XX)
154-156 °C (Sigma-Aldrich - monohydrate?)
Scifinder: range from 86-88°C to 183-184°C

-> anhydride??


Hydrolysis of the anhydride:
1. Trial:
The anhydride (1.00 g, 2.93 mmol) was dissolved in a mixture of Aceton (10 mL) and water (0.5 mL) and heated to reflux. After 2 h the solvent was evaporated and the water was removed by azeotropic distillation with toluene -> no solid was obtained
-recrystallized from chloroform: no crystals, but a colorless solid
Yield: 1.05 g (2.93 mmol, 100%) colorless solid
1H NMR: Data: 1H NMR MW 10-6a.pdf
IR: Data: IR MW10-6a.pdf: IR matches with literature [xx]
m.p. 112-116°C

2. Trial: [1]
The anhydride (1.00 g, 2.93 mmol) dissolved in a minimum of a mixture of acetone and water 20:1 (~ 5 mL) and heated to reflux. After 10 min the mixture was allowed to cool to room temperature - no precipitate; slowly remove of the solvent in a gentle stream of nitrogen -> oil

3. Trial:
The anhydride (1.00 g, 2.93 mmol) was dissolved in a minimum amount of hot toluene (~25 mL), water (500 µL) was added and stirred for 30 min
IR: Data: IR MW10-6c: no OH/acid bands in IR
-> anhydride

4. Trial:
The anhydride (1.00 g, 2.93 mmol) was dissolved in a minimum amount of hot ethanol(~ 8 mL), water (500 µL) was added and heated to reflux for 10 min -> oil

5. Bulk:
The anhydride (6.74 g, 19.8 mmol) was dissolved in a mixture of Aceton (20 mL) and water (1.0 mL) and heated to reflux. After 2 h the solvent was evaporated, dissolved in Et2O, dried over sodium sulfate and evaporated while heating to 50°C. The solid residue was obtained with impurities of the solvent (no crystallization).

Yield: 7.37 g (20.6 mmol, 104%) colorless solid

Recrystallization:

ethyl acetate -
ethyl acetate/ hexane -
CHCl3 -
toluene -
toluene / CHCl3 -
isopropanol ?

See: Sucessful recrystallization (MW10-5)

Recrystallization from i-PrOH/hexane 1:2 (~ 9.0 g in 75 mL solvent)
Yield: 5.14 g colorless crystaline solid
remain in mother liquor: 3.80 g pale yellow oil

Analytical data:
m.p. 98-101°C.
[α]D20 = -85.1° (c=1, EtOH).
Data: 13C NMR MW10-6


References:
[1] “The Reduction of Various Sugar Acids to Glycitols with Lithium Aluminum Hydride”, R. K. Ness, H. G. Fletcher and C. S. Hudson, J. Am. Chem Soc. 1951, 73, 10, 4759-4761.

[2] “Relative Stereoselectivity of the Reactions of (2R,3R)- and (2R,3S)-Dibenzoyloxysuccinic Anhydrides with Chiral Amines and Alcohols”, K. H. Bell, Aust. J. Chem. 1987, 40, 399-404. doi:10.1071/CH9870399.