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Pictet-Spengler route to Praziquantel
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10th February 2011 @ 04:36
Preparation of starting material for the [url=http://www.thesynapticleap.org/node/317]Ugi reaction[/url] via an alternative route to [url=http://www.ourexperiment.org/racemic_pzq/357][b]MW37-1[/b][/url] See also: [*] [url=http://www.ourexperiment.org/racemic_pzq/357]Preparation of 2-(3,4-dimethoxyphenyl)ethyl isocyanide (MW37-1)[/url] [*] [url=http://www.ourexperiment.org/racemic_pzq/1564]Preparation of 2-phenylethyl isocyanide - alternative route (MW34-3)[/url] [*] [url=http://www.ourexperiment.org/racemic_pzq/338]Upscaling - Preparation of 2-Phenylethyl isocyanide (MW34-2)[/url] [data=size:500x150]785[/data] [b]Hazard and Risk Assessment:[/b] [data]787[/data] 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=text]793[/data] -> better yield than [url=http://www.ourexperiment.org/racemic_pzq/357]procedure (MW37-1)[/url] but more reagents were used and the preparation required more effort. Used for starting material for: [*] [url=http://www.ourexperiment.org/racemic_pzq/1597]Preparation of the dimethoxybenzyl-N-benzoyl-derivative of the ‘Ugi-intermediate’ (MW52-1)[/url] [*] [url=http://www.ourexperiment.org/racemic_pzq/386]Preparation of the dimethoxy ‘Ugi-intermediate’ via Ugi reaction (MW40)[/url] [b]References:[/b] [url=http://v3.espacenet.com/publicationDetails/biblio?CC=WO&NR=2009115333A1&KC=A1&FT=D&date=20090924&DB=EPODOC&locale=en_ep][1] “Novel Synthesis of Praziquantel“, A. Dömling, [i]Patent Application[/i] [b]2009[/b], WO 2009/11533(A1), Language: German.[/url]
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.