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Pictet-Spengler route to Praziquantel
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10th February 2011 @ 04:36
Preparation of starting material for the Ugi reaction via an alternative route to MW37-1

See also:
Preparation of 2-(3,4-dimethoxyphenyl)ethyl isocyanide (MW37-1)
Preparation of 2-phenylethyl isocyanide - alternative route (MW34-3)
Upscaling - Preparation of 2-Phenylethyl isocyanide (MW34-2)

Scheme MW37-2.png


Hazard and Risk Assessment:
HRAF MW37-2.pdf


Start time: 4:00 PM 10/02/2011
End time: 3:00 PM 11/02/2011

Problems to access the website from 11/02/2011 to 14/02/2011

A solution of 3,4-dimethoxyphenethylamine (2.00 g, 11.0 mmol, M.W. 181.2 g/mol) was heated to reflux in ethyl formate (10 mL, M.W. 74.1 g/mol, bp 52-54°C) and heated to reflux for 18 h.
The remaining ethyl formiate and the by-product ethanol were removed under reduced pressure obtaining a yellow liquid.
2-(3,4-Dimethoxyphenyl)ethylformamide and triethylamine (3.35 g, 33.1 mmol, 4.62 mL, 3.0 eq., M.W. 101.2, d=0.726 g/mL) were dissoved in dry DCM (20 mL) and phosphoryl chloride (1.69 g, 11.0 mmol, 1.03 mL, 1.0 eq., M.W. 153.3, d=1.645 g/mL) was dropwise added at 0°C. The mixture was stirred for 1 h at 0°C and a further 4 h at room temperature.
The mixture was quenched with water and neutralized with NaHCO3 solution. The organic layer was seperated and the aqueous solution was extracted 3 times with DCM. The combined organic layers were dried over magnesium sulfate and evaporated afforded a dark brown oil.

- purification by column chromatography (silica gel, hexane/EA, 3:1, stain: KMnO4, Rf = 0.25)

Yield: 1.39 g (7.27 mmol, 66%) orange liquid
[M.W. = 191.2 g/mol]

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).
Data: 1H NMR MW37-2.pdf

-> better yield than procedure (MW37-1) but more reagents were used and the preparation required more effort.

Used for starting material for:
Preparation of the dimethoxybenzyl-N-benzoyl-derivative of the ‘Ugi-intermediate’ (MW52-1)
Preparation of the dimethoxy ‘Ugi-intermediate’ via Ugi reaction (MW40)

References:
[1] “Novel Synthesis of Praziquantel“, A. Dömling, Patent Application 2009, WO 2009/11533(A1), Language: German.
Attached Files
Scheme MW37-2.png
HRAF MW37-2.pdf
1H NMR MW37-2.pdf
1H NMR MW37-2 JCAMP-DX.dx
Comments
Re: Preparation of 2-(3,4-Dimethoxyphenyl)ethyl isocyanide (MW37-2) by Matthew Todd
10th February 2011 @ 11:24
Nice. I hope this works smoothly. This is the likeliest route to a benzoyl analog of PZQ via the P-S I think.