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17th June 2010 @ 07:55
Preparation of starting material for the [url=http://www.ourexperiment.org/racemic_pzq/386]Ugi reaction[/url] – [url=http://www.thesynapticleap.org/node/301](MeO)2-derivative of PZQ[/url] [data=size:500x150]206[/data] [data=size:500x150]208[/data] [b]Hazard and Risk Assessment:[/b] 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 [url=http://www.ourexperiment.org/racemic_pzq/338/][b]MW37-2[/b][/url] - 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, [i]R[/i]f = 0.25) [b]Result:[/b] Product [b]MW37-1[/b]: 525 mg (2.75 mmol, 50%) brown liquid [b]Analytical data:[/b][2] Rf (hexane:EA, 3:1) = 0.25. [url=http://www.ourexperiment.org/data/222.html]1H NMR[/url] (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). [url=http://www.ourexperiment.org/data/224.html]IR[/url] (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 [b]MW37 [/b] --> upscale reaction -->[url=http://www.ourexperiment.org/racemic_pzq/386] starting material for reaction[b] MW40[/b] [/url] [*] Alternative procedure:[url=http://www.ourexperiment.org/racemic_pzq/1587]Preparation of 2-(3,4-Dimethoxyphenyl)ethyl isocyanide (MW37-2)[/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://dx.doi.org/10.1021/jo047924f][2] "Microwave-Assisted Synthesis of Isonitriles: A General Simple Methodology" A. Porcheddu, G. Giacomelli and M. Salaris, [i]J. Org. Chem.[/i] [b]2005[/b], [i]70[/i], 6, 2361–2363, DOI: 10.1021/jo047924f.[/url] [b]Analytical data:[/b] (from reference [2]) [b]8:[/b] 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.
Attached Files
Reaction Scheme
Table1
1H NMR MW37-1
IR MW37-1