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23rd June 2010 @ 08:45
Ugi-approach to PZQ – synthesis of the non-patented (MeO)2 ‘Ugi-intermediate’ following a patented procedure [1]
Alternative approach to MW32

See also:
Preparation of the Ugi-intermediate via Ugi reaction (MW36-1)
Optimizing conditions for the Ugi reaction (MW36-2 to MW36-5)

Reaction Scheme


Table1



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

Start time: 5:30 PM 23/06/2010
End time: 5:01 PM 24/06/2010

Procedure:
To a mixture of paraformaldehyde (76 mg, 2.54 mmol, 1.0 eq.), 2,2-dimethoxyethylamine (267 mg, 2.54 mmol, 1.0 eq.) and cyclohexanecarboxylic acid (326 mg, 2.54 mmol, 1.0 eq.) in methanol (3 mL) was added slowly 2-(3,4-Dimethoxyphenyl)ethyl isocyanide MW37-1 (489 mg, 2.54 mmol, 1.0 eq.) and stirred at room temperature for 24 h.
-TLC (EA = 100%, stain: Ceric ammonium molybdate, Rf = 0.29): complete conversion of the isocyanide MW37, less side products

TLC1
TLC2


- 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: 962 mg orange-brown high viscous oil
- purification by column chromatography (silica gel, EA = 100%), Rf (EA, 100%) = 0.25.
- high vac

Result:
Product MW40-1: 805 mg (1.84 mmol, 73%) orange-brown high viscous oil
1H NMR: traces of solvent (ethyl acetate)

-> high-yielded one-step procedure to the ‘Ugi-intermediate’

Analytical data:
Rf (EA, 100%) = 0.25.
1H NMR (CDCl3, 200 MHz): δ = 1.17-1.71 (m, 10H), 2.21/2.54 (m, 1H), 2.66-2.74 (m, 2H), 3.30 (s, 3H), 3.34 (s, 3H), 3.37-3.52, 3.80 (s, 3H), 3.83 (s, 3H), 3.93/3.95 (2H), 4.36/4.52 (t, J=5.0 Hz, 1H), 6.45/6.91 (bs, NH), 6.66-6.76 (m, 3H);rotamers, ratio 1:1.
Data: 1H NMR MW40-1
13C NMR (CDCl3, 75.5 MHz): δ = 25.53, 25.65, 25.74, 29.32, 29.38, 35.22, 40.29/40.62, 40.78/41.03, 50.26/51.52, 52.07/54.02, 55.04, 55.45, 55.90 (2C), 102.83/103.55, 111.39/111.47, 111.80/112.01, 120.55/120.62, 131.04/131.33, 147.73/147.86, 149.09/149.20, 169.25/169.53, 177.78/177.97; rotamers, ratio 1:1.
Data: 13C_NMR MW40-1
IR (neat): nu = 3305 cm-1, 2931, 2855, 1644, 1515, 1418, 1260, 1235, 1124, 1065, 1026, 728.
Data: IR MW40-1
MS (ESI (+)) m/z (%): 895 (100, [M2Na]+), 883 (59), (24, [MNa]+), 405 (34).
HRMS (ESI (+)) Calcd. for [C23H36N2O6Na]+: 459.2466, found: 459.2467.
C23H36N2O6 (436.5).


References:
[1] “Novel Synthesis of Praziquantel“, A. Dömling, Patent Application 2009, WO 2009/11533(A1), Language: German.
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Attached Files
Reaction Scheme
Table1
TLC1
TLC2
1H NMR MW40-1
1H NMR MW40-1 JCAMP-DX
13C_NMR MW40-1
13C_NMR MW40-1 JCAMP-DX
IR MW40-1