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8th December 2010 @ 03:39
10g-scale racemic resolution of [i]rac[/i]-PZQamine [data=size:500x180]667[/data] See related experiments: [*] [url=http://www.ourexperiment.org/racres_pzq/1523]Optimizing the racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-14)[/url] [*] [url=http://www.ourexperiment.org/racres_pzq/1265]Scale-up: Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-12)[/url] [*] [url=http://www.ourexperiment.org/racres_pzq/1237]Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-5 - MW49-11)[/url] [*] [url=http://www.ourexperiment.org/racres_pzq/1206]Racemic resolution of praziquanamine with (+)-Dibenzoyl-D-tartaric acid (MW49)[/url] [*] [url=http://www.ourexperiment.org/racres_pzq/687]Synthesis of (-)-Dibenzoyl-L-tartaric acid (MW10-1-30)[/url] -> [i]S[/i]-(+)-PZQamine [*] [url=http://www.ourexperiment.org/racres_pzq/1110]Diastereomeric salt resolution of praziquanamine with (-)-di-p-anisoyl-L-tartaric acid obtainig [i]S[/i]-(+)-PZQamine (MW47-3)[/url] Start time: 3:15 PM 8/12/2010 End time: 6:15 PM 8/12/2010 [b]Procedure:[/b] [url=http://www.thesynapticleap.org/node/296][i]rac[/i]-Praziquanamine[/url] (10.0 g, 49.5 mmol, M.W. 202.1 g/mol) and [url=http://www.ourexperiment.org/racres_pzq/687](-)-dibenzoyl-L-tartaric acid* 2 [i]i[/i]-PrOH[/url] (23.7 g, 49.5 mmol, M.W. 478.5 g/mol) were dissolved in a mixture of [i]i[/i]-PrOH (450 mL) and water (90 mL) by heating the stirred mixture (yellow solution from impurities of the PZQamine (decomposition under irradiation/light)). To accelerate the cooling process, the solution was placed in a water bath on room temperature (fast formation of nice crystals). After 2 h the crystalline precipitate was filtered of and dried. The mother liquor was placed in the fridge overnight (5°C), but only a few more crystals precipitated. (almost fully precipitated) -> right concentration of the solution, maybe could be a bit more concentrated to obtain a yield around 50% [u]Yield of the diasteromeric salt:[/u] 12.1 g (21.6 mmol, 44%) of a pale yellow crystalline solid [M.W. diastereomeric salt = 560.6 g/mol] m.p.=143-145°C [u]Mother liquor:[/u] Solvent was evaporated and solid residue was dried under high vac. diastereomeric salt: 15.9 g (28.4 mmol, 57%) of a pale yellow solid -> right concentration of the solution, maybe could be a bit more concentrated to obtain a yield around 50% [u]2. Crystallization:[/u] The salt (12.1 g, 21.6 mmol) was dissolved in a mixture of i-PrOH (180 mL) and water (90 mL) by heating. After 2 h the crystalline precipitate was filtered off. [u]Yield of the diasteromeric salt:[/u] 9.54 g (17.0 mmol, 79%, 34% overall yield) of a colorless crystalline solid m.p.=143.5-145.5°C mother liquor stored in the fridge over 3 days, obtained crystals were filtered off: yield 703 mg (1.25 mmol, 6%, 3% overall yield) - combined with the first precipitaton -> Summary of the 2. crystallization: 10.2 g (18.3 mmol, 85%, 37% overall yield) [u]Liberation:[/u] To the diatereomeric salt (10.4 g) was added 100 mL of water and the stirred suspension was carefully made basic to pH 11 by adding 2 N NaOH solution. When the salt was completely dissolved the solution was extracted with DCM (4 x 15 mL). The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. - same procedure for the combined mother liquors after the solvents was evaporated To combined basic aq. solution was added i-PrOH (5 mL) and the solution was made acidic to pH 1-2 by adding 2 N HCl. The precipitate was filtered off and dried in vacuum. [b]Results:[/b] Resolved (-)-PZQamine: 3.32 g (33% overall yield, 16.4 mmol) as a colorless solid m.p. 122-123°C [α]D20 = -305° (c=1, DCM) 1H NMR: [data=text]713[/data] -> [i]ee[/i] = 97% (determined by chiral HPLC from the [url=http://www.ourexperiment.org/racres_pzq/1468](R)-PZQ derivative[/url]) Recovered PZQamine from the mother liquor (crude): 5.34 g (53%, 26.4 mmol) as a yellow solid m.p. 102-104°C [α]D20 = +170° (c=1, DCM) 1H NMR: [data=text]717[/data] Recovered (-)-dibenzoyl-L-tartaric acid* 2 [i]i[/i]-PrOH[/url] (crude): 21.1 g (89%, 44.1 mmol) m.p. 108-110°C 1H NMR: [data=text]721[/data] [data=text]833[/data] See subsequent experiment: [url=http://www.ourexperiment.org/racres_pzq/1468]N-Cyclohexanoyl-protection of the enantiopure R-(-)-PZQamine in a multigram scale (MW48-4)[/url] [b]References:[/b] [url=http://v3.espacenet.com/publicationDetails/biblio?DB=EPODOC&adjacent=true&locale=en_EP&FT=D&date=20021017&CC=US&NR=2002151717A1&KC=A1][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. [/url] [Example 20, p. 27-28]
Attached Files
1H NMR MW49-13 (-)-PZQamine.pdf
1H NMR MW49-13 (-)-PZQamine.dx
1H NMR MW49-13 Remaining PZQamine.pdf
1H NMR MW49-13 Remaining PZQamine.dx
1H NMR MW49-13 Resolving agent.pdf
1H NMR MW49-13 recovered resolving agent (recrystallized).pdf
1H NMR MW49-13 recovered resolving agent (recrystallized) JCAMP-DX.dx