Racemic Resolution of Praziquantel and Praziquanamine

 

Preparation of a resolving agent for the racemic resolution of PZQ via diastereomeric salt formation

Repetition of the experiment: Scale-Up: Synthesis of (+)-Di-p-anisoyl-D-tartaric acid (MW46-5)

See also:
Synthesis of (-)-Di-p-anisoyl-L-tartaric acid (MW46-4)
Repetition of the Synthesis of (+)-Di-p-anisoyl-D-tartaric acid (MW46-3)
Synthesis of (+)-Di-p-anisoyl-D-tartaric acid (MW46-2)
Synthesis of (-)-Di-p-anisoyl-L-tartaric acid (MW46-1)



Hazard and Risk Assessment:


Start time: 8:30 PM 3/11/2010

Procedure: [1]
A mixture of p-methoxy benzoic acid (33.6 g, 253 mmol, M.W. 152.1 g/mol) and SOCl2 (82 g, 691 mmol 50 mL, 2.72 eq., d=1.64 g/mL, M.W. 119.0 g/mol) was stirred for 13 h at room temperature -> still unreacted starting material (no clear solution)
Heat it to reflux for 3 h and evaporate excess of SOCl2 (high vac condensing with liquid nitrogen to remove trace of SOCl2)
- added 2S,3S-D(-)-tartaric acid (12.5 g, 83.0 mmol, M.W. 150.1 g/mol) and heated to 140°C for 1 h till a pale yellow solid was formed, then the mixture was heated to 160°C for 1 h. When the mixture was cooled to 100°C toluene (100 mL) was added and another time toluene (50 mL) was added when it was cooled to room temperature. The colorless solid was filtered off and rinsed with a small amount of toluene.

The dried solid was dissolved in a mixture acetone (150 mL) and water (10 mL) and heated to reflux for 2 h. After addition of water (100 mL) acetone was evaporated and another time water (100 mL) was added. The colorless precipitate was filtered off and dried in an air stream.

65.3 g (156 mmol, 94%) colorless solid, wet (M.W. 418.4 g/mol)
1H NMR: (+)-Di-p-anisoyl-D-tartaric acid and p-methoxybenzoic acid 1:08.5 : Data: 1H NMR MW46-6 after hydrolysis.pdf

1. heating with toluene (100 mL)
31.5 g (75.3 mmol, 91%) colorless solid
1H NMR: Data: 1H NMR MW46-6 1. heating with toluene.pdf - remaining p-methoxybenzoic acid

2. heating with toluene (100 mL)
27.3 g (65.2 mmol, 79%) colorless solid
1H NMR: Data: 1H NMR MW46-6 2. heating with toluene.pdf - remaining p-methoxybenzoic acid

3. heating with toluene (100 mL)
21.5 g (51.4 mmol, 62%) colorless solid
m.p. 187-189 °C
1H NMR:Data: 1H NMR MW46-6 3. heating with toluene.pdf - remaining p-methoxybenzoic acid (~ 10 mol%)

4. heating with toluene (100 mL)
19.9 g (47.6 mmol, 57%) colorless solid
m.p. 195-197 °C
1H NMR: Data: 1H NMR MW46-6 4. heating with toluene.pdf no more remaining p-methoxybenzoic acid!!!
Data: 1H NMR MW46-6 JCAMP-DX.dx

Analytical data:
[α]D20 = 169° (c=1, MeOH) (lit. [2] 167° (c=1, MeOH))
see: Synthesis of (+)-Di-p-anisoyl-D-tartaric acid (MW46-2)

Procedure from reference: [1]
EXAMPLE 53 (p. 42)
[0327] Add p-anisic acid (77 g, 0.55 mol) to 100 mL SOCl2 and stir overnight at room temperature. Evaporate the excess SOCl2 to give p-anisoyl chloride. Add (2R,3R)-(+)-tartaric acid (25 g, 166 mmol) and stir the mixture and heat at 170.deg.C for an hour. Allow the mixture to cool to 100.deg.C and add 200 mL toluene. Cool the mixture to room temperature and add another 100 mL toluene. Collect the precipitate, rinse with toluene and dry. Reflux the crude product in a mixture of 300 mL acetone and 20 mL water for two hours. Then add 200 mL water and evaporate the acetone. Add another 200 mL water and collect the precipitate, rinse with water and dry. Reflux the product in 200 mL toluene for 15 minutes and collect the precipitate while the mixture is hot. Rinse the precipitate with 50 mL warm toluene and dry to give (2R,3R)-(-)-di-(p-anisoyl)tartaric acid.



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]

[2] „Über die Reduktion der China-Ketone zu China-Alkoholen und über die sterische Umlagerung von China-Alkaloiden. Stereochemische Forschungen. II.“, P. Rabe, Justus Liebigs Annalen der Chemie, 1932, 492, 242–266. doi: 10.1002/jlac.19324920112.