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15th June 2010 @ 10:04
Ugi-approach to PZQ – testing the patented route to the ‘Ugi-intermediate’

Reaction Scheme correction

Table1 corrected

Hazard and Risk Assessment:
Reaction Class: 2
Hazards: T Toxic, X Irritant, C Corrosive
Risk rating: U = Unlikely

Start time: 6:51 PM 15/06/2010
End time: 6:30 PM 16/06/2010

To a mixture of paraformaldehyde (114 mg, 3.81 mmol, 1.0 eq.), 2,2-dimethoxyethylamine (401 mg, 3.81 mmol, 1.0 eq.) and cyclohexanecarboxylic acid (489 mg, 3.81 mmol, 1.0 eq.) in methanol (2 mL) was added slowly 2-phenylethyl isocyanide (MW34-1) (500 mg, 3.81 mmol, 1.0 eq.) and stirred at room temperature for 24 h.
-TLC (EA = 100%, stain: Ceric ammonium molybdate, Rf = 0.45): good conversion, some remaining starting material
TLC reaction control

- addition of water: two layers of a liquid and an oil, no solid precipitate

Work-up: extraction with ethyl acetate, organic layer washed with 1 N HCl, sat. NaCO3 solution and brine, dried over MgSO4, concentrated.

Crude product MW36-1: 945 mg (2.17 mmol, 66%) orange oil, high purity, Reference yield: 89% [1]
1H NMR: no visible impurities

Analytical data:
- see MW29-4

-> Convenient one-step synthesis for the preparation of the ‘Ugi intermediate’,
-> next step: optimization of the reaction parameters: see MW36-X

Is this synthetic route useful for the synthesis of derivatives of PZQ?
- Yes, it's a high yielded multi-step reaction, which allows the synthesis of PZQ or its derivatives over 2 steps (3 steps, if the synthesis of the isocyanide is taken into account)

Further experiments
Optimizing conditions for the Ugi reaction (MW36-2 to MW36-5)
Preparation of the dimethoxy ‘Ugi-intermediate’ via Ugi reaction (MW40)

[1] “Novel Synthesis of Praziquantel“, A. Dömling, Patent Application 2009, WO 2009/11533(A1), Language: German.
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Attached Files
Reaction Scheme
Reaction Scheme correction
1H NMR MW36-1
TLC reaction control
Table1 corrected