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13th April 2011 @ 07:07
Repetition of the racemization experiments on enantioenrichend (S)-(+)-PZQamine with Rhodium on charcoal to verify the results

Scheme MW50-8.png


See also:
  • Racemization of S-(+)-PZQamine with Pd/C (MW50-1 to MW50-3)
  • Racemization of S-(+)-PZQamine with Pd/C (MW50-4)
  • Racemization of S-(+)-PZQamine with Raney Nickel (MW50-6, MW50-7)
  • Thiyl radical-mediated racemization of S-(+)-PZQamine (MW50-8)
  • Racemization of S-(+)-PZQamine (MW50-9) and (R) -(-)-PZQ (MW55-5) with sodium naphthalide
  • Repetition: Racemization of S-(+)-PZQamine (MW50-10) and R -(-)-PZQ (MW55-6) with sodium naphthalide
  • Racemization of S-(+)-PZQamine with Raney Nickel under high pressure and high temperature (MW50-11)

    Hazard and Risk Assessment:
  • HRAF MW50.pdf


    Start time: 5:30 PM 13/04/2011
    End time: 9:30 AM 15/04/2011

    To a solution of enantioenrichend (S)-PZQamine (50 mg, 247 µmol, MW: 202.3 g/mol) in toluene (2 mL) was added Rhodium on Charcoal (50.9 mg, 49.4 µmol, 0.2 eq.; 10% Rh on C, M.W. (Rh) 102.9 g/mol) and heated to 100°C for 39 h.

    TLC:

    - column (silica gel; ethyl acetat, 100% then ethyl acetate, methanol, triethylamine, 10:1:0.1)
    PZQamine: 13.2 mg (26%)
    [α]D20 = +161° (c=1, DCM)
    Data: 1H NMR MW50-13 fr_2.pdf

    unpolar 'side product': 23.9 mg
    Rf=0.45 (ethyl acetate, stain: potassium permanganate)
    [α]D20 = +90° (c=1, DCM)
    1H NMR: Data: 1H NMR MW50-13 fr_1.pdf
    13th April 2011 @ 06:20
    Synthesis of rac-PZQamine by an acidic hydrolysis of rac-PZQ

    MW2-13.png


    See also:
  • Hydrolysis of rac-PZQ (MW2-14)
  • Hydrolysis of rac-PZQ (MW2-13)
  • Optimizing the acid cleavage conditions II

    Hazard and Risk Assessment:
  • Data: HIRAC MW2

    Start time: 5:00 PM 13/04/2011
    End time: 10:00 AM 14/04/2011

    Procedure:
    rac-PZQ (20.0 g, 64.0 mmol, M.W. 312.4 g/mol) 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 17 h. Reaction monitored by TLC showed a complete consumption of PZQ (TLC, ethyl acetate, Rf ~0.5 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.
    - the pale yellow oil became a solid after 1 h under high vac

    Yield:
    11.0 g (54.5 mmol, 85%) colourless solid (turning pale red/orange after a few hours at r.t.)
    [M.W. = 202.1 g/mol]
    12th April 2011 @ 01:06
    Experiments on the oxidation of PZQamine to the enamide/imine by molten sulfur.
    See related experiments on rac-PZQ: Sulfur melt data smogasbord

    Scheme MW57.png


    Hazard and Risk Assessment:
    HRAF MW57.pdf


    Start time: 11:30 AM 12/04/2011

    MW57-1:
    rac-PZQamine (40 mg, 198 µmol, M.W. 202.3 g/mol) and sulfur (12.7 mg, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 5 min.

    MW57-2:
    rac-PZQamine (40 mg, 198 µmol, M.W. 202.3 g/mol) and sulfur (12.7 mg, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 10 min.
    1H NMR MW57-2.pdf


    MW57-3:
    rac-PZQamine (40 mg, 198 µmol, M.W. 202.3 g/mol) and sulfur (12.7 mg, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 15 min.

    TLC57-3.jpg
    TLC57-3a.jpg
    1H NMR MW57-3.pdf



    Start time: 11:30 AM 12/04/2011

    MW57-4:
    rac-PZQamine (20 mg, 99 µmol, M.W. 202.3 g/mol) and sulfur (6.4 mg, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 30 min.

    MW57-5:
    rac-PZQamine (20 mg, 99 µmol, M.W. 202.3 g/mol) and sulfur (6.4 mg, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 1 h.

    MW57-6:
    rac-PZQamine (20 mg, 99 µmol, M.W. 202.3 g/mol) and sulfur (12.7 mg, 4 eq., M.W. 32.1 g/mol) were heated at 180°C for 15 min.

    MW57-7:
    rac-PZQamine (20 mg, 99 µmol, M.W. 202.3 g/mol) and sulfur (12.7 mg, 4 eq., M.W. 32.1 g/mol) were heated at 180°C for 30 min.


    References:
    [1] Spectral and Chemical Properties of Pyrazino-[2,1-a]-isoquinolin-4-one Derivatives, K. Kiec'-Kononowicz, Arch. Pharm. 1989, 322,795-799. DOI: 10.1002/ardp.19893221104.
    7th April 2011 @ 08:37
    Racemization experiments on (R)-(-)-PZQ with Rhodium on charcoal

    Scheme MW50-8 PZQ.png


    See also:
  • Experiments on the racemization of (R)-PZQ (MW55-1 to MW55-3)
  • Experiments on the racemization of (R)-PZQ with Raney Nickel (MW55-4)
  • Racemization of S-(+)-PZQamine (MW50-9) and (R) -(-)-PZQ (MW55-5) with sodium naphthalide
  • Repetition: Racemization of S-(+)-PZQamine (MW50-10) and R -(-)-PZQ (MW55-6) with sodium naphthalide
  • Racemization of S-(+)-PZQamine with Raney Nickel under high pressure and high temperature (MW50-11)

    Hazard and Risk Assessment:
  • HRAF MW50.pdf


    Start time: 7:00 PM 7/04/2011
    End time: 10:00 AM 11/04/2011

    To a solution of (R)-(-)-PZQ (20.0 mg, 64.0 µmol) in toluene (2 mL) was added Rhodium/Charcoal (6.6 mg, 6.40 µmol, 0.1 eq.; 10% Rh on C, M.W. (Rh) 102.9 g/mol) and heated to 70°C for 4 d.

    Chiral HPLC (Chiralcel OD-H, hexane/iso-propanol/Et3N = 60/40/0.1, 0.7 ml/min flow rate): RT: (R)-PZQ: 12.4 min, (S)-PZQ: 15.0 min
    HPLC MW55-8.jpg
    HPLC MW55-8 + rac-PZQ.jpg


    -> no racemization
    7th April 2011 @ 08:19
    Racemization experiments on enantioenrichend (S)-(+)-PZQamine with Rhodium on charcoal

    Scheme MW50-8.png


    See also:
  • Racemization of S-(+)-PZQamine with Pd/C (MW50-1 to MW50-3)
  • Racemization of S-(+)-PZQamine with Pd/C (MW50-4)
  • Racemization of S-(+)-PZQamine with Raney Nickel (MW50-6, MW50-7)
  • Thiyl radical-mediated racemization of S-(+)-PZQamine (MW50-8)
  • Racemization of S-(+)-PZQamine (MW50-9) and (R) -(-)-PZQ (MW55-5) with sodium naphthalide
  • Repetition: Racemization of S-(+)-PZQamine (MW50-10) and R -(-)-PZQ (MW55-6) with sodium naphthalide
  • Racemization of S-(+)-PZQamine with Raney Nickel under high pressure and high temperature (MW50-11)

    Hazard and Risk Assessment:
  • HRAF MW50.pdf


    Start time: 7:00 PM 7/04/2011
    End time: 10:00 AM 11/04/2011

    To a solution of enantioenrichend (S)-PZQamine (20 mg, 98.9 µmol, MW: 202.3 g/mol) in toluene (2 mL) was added Rhodium/Charcoal (10.2 mg, 9.89 µmol, 0.1 eq.; 10% Rh on C, M.W. (Rh) 102.9 g/mol) and heated to 70°C for 4 days.
    The mixture was filtered and evaporated under reduced pressure to give 18.8 mg of PZQamine.

    TLC (ethyl acetate/methanol/triethylamine, 1:1:0.02, stain: ninhydrin)
    TLC MW50-12.jpg


    Data: 1H NMR MW50-12.pdf: PZQamine /no side products visible
    [α]D20 = +98° (c=1, DCM)

    -> Racemization ?! (it's not clear if the lower [α] is a result of a reacemization or lower concentration of (S)-PZQamine caused by solvent impurities/ other impurities)

    -> Repeat a scaled-up reaction with an higher catalyst load, longer reaction time and higher temperature, see: Repetition: Racemization of (S)-PZQamine (MW50-13) with Rh/C