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7th February 2011 @ 07:56
Experiments for the preperation of the N-benzoyl-protected derivative of the 'Ugi-intermediate' (MW36) via Ugi reaction

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


Ugi-approach to PZQ – testing the patented route to the ‘Ugi-intermediate’

Reaction Scheme correction



Hazard and Risk Assessment:
HRAF MW51.pdf


Start time: 5:10 PM 8/02/2011
End time: 7:00 PM 9/02/2011

To a mixture of paraformaldehyde (114 mg, 3.81 mmol, 1.0 eq.), 2,2-dimethoxyethylamine (aminoacetaldehyde dimethyl acetal (401 mg, 3.81 mmol, 412 µL, 1.0 eq., M.W. 105.1 g/mol, d=0.973 g/mL) and benzoic acid (465 mg, 3.81 mmol, 1.0 eq., M.W. 122.12 g/mol) in methanol (2 mL) was added slowly 2-phenylethyl isocyanide (MW34-1) (500 mg, 3.81 mmol, 1.0 eq., M.W. 131.2, d=0.95 g/mL) and stirred at room temperature for 26 h.

Note: 2-phenylethyl isocyanide was purified before use by flush chromatography (silica gel, hexane:ethyl acetate = 4:1), because the pale brown oil became a dark brown gel while stored in the fridge for 6 month.

- solvent evaporated
- column chromatography (silica gel, ethyl acetate 100%)

Yield: 1.37 g (3.69 mmol, 97%) yellow oil (solvent impurities -> high vac)
[M.W. 370.4 g/mol]
Data: 1H NMR MW51-1.pdf: strong signal broadening due to rotamers, small impurity
-> other NMR solvent, change temperature
Data: 13C NMR MW51-1.pdf

Yield after 8 h high vac: 1.25 g (3.36 mmol, 88%) yellow high viscous oil

Analytical data:
Data: 1H NMR MW51-1.pdf: NMR at higher temperature -> rotamers
Data: 13C NMR MW51-1.pdf: higher resolution NMR
IR (neat): nu = 2924 cm-1, 3316, 2937, 1623, 1549, 1454, 1239, 1123, 1073, 1024, 976, 698, 551. Data: IR MW51-1.pdf
MS (ESI, +) m/z (%): 763 [2M + Na]+ (59), 393 [M + Na] (100).
HRMS (ESI (+)) Calcd. for [C21H26N2NaO4]+: 393.1785, found: 393.1785.

b]References:[/b]
[1] “Novel Synthesis of Praziquantel“, A. Dömling, Patent Application 2009, WO 2009/11533(A1), Language: German.

[2] "Efficient Multicomponent Reaction Synthesis of the Schistosomiasis Drug Praziquantel", H. Cao, H. Liu, A. Dömling, Chem. Eur. J. 2010, 16, (2296 – 12298. DOI: 10.1002/chem.201002046)

[3] "Polycyclic Compounds by Ugi−Pictet−Spengler Sequence", W. Wang, S. Ollio, E. Herdtweck, A. Doemling, J. Org. Chem. 2011, 76 2, 637–644. (DOI: 10.1021/jo102058)
Linked Posts
Attached Files
Scheme
HRAF MW51.pdf
Reaction Scheme correction
1H NMR MW51-1.pdf
1H NMR MW51-1 JCAMP-DX.dx
13C NMR MW51-1.pdf
IR MW51-1.pdf