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8th December 2010 @ 03:39
10g-scale racemic resolution of rac-PZQamine

scheme MW49-5.png


See related experiments:
  • Optimizing the racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-14)
  • 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)

    Start time: 3:15 PM 8/12/2010
    End time: 6:15 PM 8/12/2010

    Procedure:
    rac-Praziquanamine (10.0 g, 49.5 mmol, M.W. 202.1 g/mol) and (-)-dibenzoyl-L-tartaric acid* 2 i-PrOH (23.7 g, 49.5 mmol, M.W. 478.5 g/mol) were dissolved in a mixture of 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%

    Yield of the diasteromeric salt: 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

    Mother liquor: 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%

    2. Crystallization:
    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.
    Yield of the diasteromeric salt: 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)

    Liberation:
    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.

    Results:
    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: 1H NMR MW49-13 (-)-PZQamine.pdf
    -> ee = 97% (determined by chiral HPLC from the (R)-PZQ derivative)

    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: 1H NMR MW49-13 Remaining PZQamine.pdf

    Recovered (-)-dibenzoyl-L-tartaric acid* 2 i-PrOH[/url] (crude):
    21.1 g (89%, 44.1 mmol)
    m.p. 108-110°C
    1H NMR: Data: 1H NMR MW49-13 Resolving agent.pdf
    Data: 1H NMR MW49-13 recovered resolving agent (recrystallized).pdf

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


    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]
    Linked Posts
    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