Pictet-Spengler route to Praziquantel

 

Experiments for the preperation of the N-benzoyl 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)

N-Cyclohexanoyl-protection of the amine intermediate MW7-2-27 of PZQ (MW29-1 to MW29-3) (alternative approach to the Ugi-intermediate via Shin Poong route)


Hazard and Risk Assessment:

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:
1H NMR (CDCl3, 200 MHz, T=328K):Data: 1H NMR MW51-1.pdf: NMR at higher temperature -> rotamers
1H NMR (CDCl3, 200 MHz, T=328K): δ = 2.85 (t, J=6.9Hz, 2 H), (t, J=6.9Hz, 2 H), 3.47 (d, J=5.0 Hz, 2H), 3.57 (td, J=6.8, J=6.2, 2H), 4.05, (s, 2H), 4.59 (br s, 1H), 6.61 (br s, 1H), 7.19-7.48 (m, 10H). Data: 1H NMR MW51-1 T=328K.pdf
1H NMR (CDCl3, 50.3 MHz): δ = 35.5, 40.6, 51.0 (br s), 52.1 (br s), 55.0 (2C), 102.8, 126.5, 126.9 (2C), 128.5 (2C), 128.6 (2C), 128.7 (2C), 130.0, 135.2, 138.8 (br s), 168.8, 173.1. Data: 13C NMR MW51-1.pdf,
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.


Following reactions:

Acid-mediated Pictet-Spengler of the N-benzoyl-Ugi intermediate (MW53-1 to MW53-3)

Synthesis of the N-benzoyl-derivative of PZQ via Pictet-Spengler reaction (MW53-4)


References:

[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)