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31st May 2010 @ 09:03
Preparation of the [url=http://www.thesynapticleap.org/node/317]"Ugi intermediate"[/url] of PZQ as starting material for the Pictet-Spengler cyclisation See also: [url=http://www.ourexperiment.org/racemic_pzq/241]N-Cyclohexanoyl-protection of the amine intermediate MW7-2-27 of PZQ: Upscale (MW29-4)[/url] [b]N-(2,2-dimethoxyethyl)-N-(2-oxo-2-(phenethylamino)ethyl)cyclohexanecarboxamide[/b] [data=size:500x180]110[/data] [data=size:500x120]112[/data] [b]Hazard and Risk Assessment:[/b] Reaction Class: 2 Hazards: X Irritant, C Corrosive Risk rating: U = Unlikely Start time: 5:00 pm End time: 10:15 am 1/06/2010 To a suspension of [b]MW7-2-27[/b] (100 mg, 330 µmol) and Na2CO3 (87.5 mg, 826 µmol) in DCM (5 mL) was added cyclohexanecarboxylic acid chloride (53.3 mg, 363 µmol) at 0°C and warmed to room temperature. - after 2 h / 4 h: TLC (EA:MeOH:TEA = 1:1:0.02) --> slow reaction, starting material left - after 17 h: yellow solution, work-up: quenched with water, extracted with DCM, dried over sodium sulfate, concentrated Yellow oil, crude yield: 151 mg [url=http://www.ourexperiment.org/data/122.html]TLC[/url] (EA:MeOH:TEA = 1:1:0.02, stain: ninhydrin): still some starting material left + other impurities - base to weak to liberate amine effectively from the hydrochloride? [b]MW29-2/MW29-3[/b] [data=size:500x180]116[/data] [data=size:500x150]114[/data] Start time: 6:15 pm 1/06/2010 End time: 8:30 pm [b]MW29-2:[/b] To a solution of [b]MW7-2-27[/b] (100 mg, 330 µmol) and Et3N (83.6 mg, 826 µmol) in DCM (5 mL) was added cyclohexanecarboxylic acid chloride (53.3 mg, 363 µmol) at 0°C, warmed to room temperature and stirred for 2 h. - pale yellow solution: TLC (EA:MeOH:TEA = 1:1:0.02) [better eluent: EA = 100%] --> complete conversion, no starting material or side products Work-up: quenched with water, extracted with DCM, washed with aq. ammonium chloride, dried over sodium sulfate. Crude yield: 119 mg (344 µmol, 104%) pale yellow oil, impurities of cyclohexanecarboxylic acid chloride? Rf ([url=http://www.ourexperiment.org/data/124.htm]TLC[/url] EA, 100%; stain: Ceric ammonium molybdate) = 0.50. [url=http://www.ourexperiment.org/data/126.html]1H NMR[/url]: quite pure, 2 rotamers ~ 1:1 [b]MW29[/b] (345.5). [b]MW29-3:[/b] [b]MW7-2-27[/b] (100 mg, 330 µmol) was dissolved in a mixture of DCM (5 mL) and 2 N NaOH (1 mL) and cyclohexanecarboxylic acid chloride (53.3 mg, 363 µmol) was added at 0°C. The cooled solution was stirred for 2 h. - pale yellow solution: TLC (EA:MeOH:TEA = 1:1:0.02) --> complete conversion, no starting material but one side product (? Similar Rf, faintly visible) Work-up: quenched with water, extracted with DCM, washed with aq. ammonium chloride, dried over sodium sulfate. Crude yield: 112 mg (324 µmol, 98%) yellow oil [url=http://www.ourexperiment.org/data/124.html]TLC[/url] (EA = 100%, stain: Ceric ammonium molybdate) [url=http://www.ourexperiment.org/data/128.html]1H NMR[/url]: product + impurities, 2 rotamers --> upscale the conditions of [b]MW29-2[/b]: [url=http://www.ourexperiment.org/racemic_pzq/241] see [b]MW29-4[/b][/url]
Attached Files
Reaction Scheme
Table1
Table2
Reaction Scheme2
TLC 29-1
TLC 29-2 / 29-3
1H NMR MW29-2
1H_NMR MW29-3