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7th February 2011 @ 07:56
Experiments for the preperation of the [i]N[/i]-benzoyl derivative of the [url=http://www.ourexperiment.org/racemic_pzq/321]'Ugi-intermediate' (MW36)[/url] via [url=http://www.thesynapticleap.org/node/317]Ugi reaction[/url] [data=size:500x180]769[/data] See also: [*] [url=http://www.ourexperiment.org/racemic_pzq/404]Optimizing conditions for the Ugi reaction (MW36-2 to MW36-5)[/url] [*] [url=http://www.ourexperiment.org/racemic_pzq/386]Preparation of the dimethoxy ‘Ugi-intermediate’ via Ugi reaction (MW40)[/url] [*] [url=http://www.ourexperiment.org/racemic_pzq/228]N-Cyclohexanoyl-protection of the amine intermediate MW7-2-27 of PZQ (MW29-1 to MW29-3)[/url] (alternative approach to the Ugi-intermediate via Shin Poong route) [b]Hazard and Risk Assessment:[/b] [data]767[/data] 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 ([url=http://www.ourexperiment.org/racemic_pzq/309][b]MW34-1[/b][/url]) (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. [u]Note:[/u] 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%) [u]Yield:[/u] 1.37 g (3.69 mmol, 97%) yellow oil (solvent impurities -> high vac) [M.W. 370.4 g/mol] [data=text]779[/data]: strong signal broadening due to rotamers, small impurity -> other NMR solvent, change temperature [data=text]783[/data] Yield after 8 h high vac: 1.25 g (3.36 mmol, 88%) yellow high viscous oil [b]Analytical data:[/b] 1H NMR (CDCl3, 200 MHz, T=328K):[data=text]779[/data]: 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=text]935[/data] 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=text]783[/data], IR (neat): nu = 2924 cm-1, 3316, 2937, 1623, 1549, 1454, 1239, 1123, 1073, 1024, 976, 698, 551. [data=text]789[/data] MS (ESI, +) m/z (%): 763 [2M + Na]+ (59), 393 [M + Na] (100). HRMS (ESI (+)) Calcd. for [C21H26N2NaO4]+: 393.1785, found: 393.1785. Following reactions: [*] [url=http://www.ourexperiment.org/racemic_pzq/1617]Acid-mediated Pictet-Spengler of the N-benzoyl-Ugi intermediate (MW53-1 to MW53-3)[/url] [*] [url=http://www.ourexperiment.org/racemic_pzq/1654]Synthesis of the N-benzoyl-derivative of PZQ via Pictet-Spengler reaction (MW53-4)[/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] [url=http://onlinelibrary.wiley.com/doi/10.1002/chem.201002046/abstract][2] "Efficient Multicomponent Reaction Synthesis of the Schistosomiasis Drug Praziquantel", H. Cao, H. Liu, A. Dömling, [i]Chem. Eur. J.[/i] [b]2010[/b], [i]16[/i], (2296 – 12298. DOI: 10.1002/chem.201002046)[/url] [url=http://dx.doi.org/10.1021/jo102058s][3] "Polycyclic Compounds by Ugi−Pictet−Spengler Sequence", W. Wang, S. Ollio, E. Herdtweck, A. Doemling, [i]J. Org. Chem.[/i] [b]2011[/b], [i]76[/i] 2, 637–644. (DOI: 10.1021/jo102058)[/url]
Attached Files
Scheme
HRAF MW51.pdf
Reaction Scheme correction
1H NMR MW51-1.pdf
1H NMR MW51-1 JCAMP-DX.dx
13C NMR MW51-1.pdf
IR MW51-1.pdf
1H NMR MW51-1 T=328K.pdf
1H NMR MW51-1 (T=328K) JCAMP-DX.dx
13C NMR MW51-1 (lb=1).pdf
13C NMR MW51-1.dx