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Pictet-Spengler route to Praziquantel
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17th June 2010 @ 06:55
Preparation of starting material for the Ugi reaction(MeO)2-derivative of PZQ

Reaction Scheme


Table1


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

Start time: 4:50 PM 17/06/2010
End time: 11:07 AM 21/06/2010

To a mixture of 3,4-dimethoxyphenethylamine (1.00 g, 5.52 mmol), benzyltriethylammonium chloride (TEBACl) (64 mg, 276 µmol, 5 mol%) and NaOH (442 mg, 11.0 mmol, 2 eq.) in CH2Cl2 (20 mL) was added chloroform (1.0 g, 0.67 mL, 8.79 mmol, 1.5 eq.) and heated to reflux. After 1 h added more NaOH (442 mg, 11.0 mmol, 2 eq.) – two equivalents of NaOH could be too less, see result MW37-2
- after 12 h the solution was cooled to room temperature and stirred vigorously for 3 d.
TLC (hexane:EA, 3:1, stain: KMnO4) – some side products, starting material?

Work-up: quenched with water, extracted with DCM, washed with 1 N aq. HCl-solution, dried over magnesium sulfate, concentrated.
- dark brown oil
- purification by column chromatography (silica gel, hexane/EA, 3:1, stain: KMnO4, Rf = 0.25)

Result:
Product MW37-1: 525 mg (2.75 mmol, 50%) brown liquid

Analytical data:[2]
Rf (hexane:EA, 3:1) = 0.25.
1H NMR (CDCl3, 200 MHz): δ = 2.92 (t, J=6.9 Hz, 2H), 3.58 (t, J=6.9 Hz, 2H), 3.86 (s, 3H), 3.88 (s, 3H), 6.75-6.86 (m, 3 H).
IR (neat): nu = 3004 cm-1, 2939, 2836, 2147, 1592, 1515, 1454, 1260, 1236, 1140, 1024, 802, 762.
MS (APCI (+)) m/z (%): 192 (100) [M]+.
HRMS (ESI (+)) Calcd. for [C33H40N3O6]+ (for [M3H]+): 574.2912, found: 574.2914.
C11H14NO2 (192.2).

Convenient one-step synthesis to the isocyanide MW37
--> upscale reaction
--> starting material for reaction MW40
Alternative procedure:Preparation of 2-(3,4-Dimethoxyphenyl)ethyl isocyanide (MW37-2)

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

[2] "Microwave-Assisted Synthesis of Isonitriles: A General Simple Methodology" A. Porcheddu, G. Giacomelli and M. Salaris, J. Org. Chem. 2005, 70, 6, 2361–2363, DOI: 10.1021/jo047924f.

Analytical data: (from reference [2])
8:
IR: (neat) 2999, 2924, 2850, 2147, 1674, 1590, 1516, 1261, 1025.
1H NMR (CDCl3): delta (ppm) 6.72 (m, 3H), 3.84 (s, 6H), 3.63 (t, J = 7 Hz, 2H), 2.71 (t, J = 7 Hz, 2H).
13C NMR (CDCl3): delta (ppm) 156.5, 150.1, 146.5, 132.9, 122.2, 115.7, 113.1, 56.8, 56.1, 45.7, 37.1.
Anal. Calcd for C11H13NO2: C, 69.09; H, 6.85; N, 7.32.
Found: C, 69.01; H, 6.89; N, 7.24.
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Attached Files
Reaction Scheme
Table1
1H NMR MW37-1
IR MW37-1