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31st May 2010 @ 09:03
Preparation of the "Ugi intermediate" of PZQ as starting material for the Pictet-Spengler cyclisation

See also: N-Cyclohexanoyl-protection of the amine intermediate MW7-2-27 of PZQ: Upscale (MW29-4)

N-(2,2-dimethoxyethyl)-N-(2-oxo-2-(phenethylamino)ethyl)cyclohexanecarboxamide

Reaction Scheme



Table1



Hazard and Risk Assessment:
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 MW7-2-27 (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
TLC (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?


MW29-2/MW29-3

Reaction Scheme2


Table2



Start time: 6:15 pm 1/06/2010
End time: 8:30 pm

MW29-2:
To a solution of MW7-2-27 (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 (TLC EA, 100%; stain: Ceric ammonium molybdate) = 0.50.
1H NMR: quite pure, 2 rotamers ~ 1:1
MW29 (345.5).


MW29-3:
MW7-2-27 (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
TLC (EA = 100%, stain: Ceric ammonium molybdate)
1H NMR: product + impurities, 2 rotamers

--> upscale the conditions of MW29-2: see MW29-4
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Attached Files
Reaction Scheme
Table1
Table2
Reaction Scheme2
TLC 29-1
TLC 29-2 / 29-3
1H NMR MW29-2
1H_NMR MW29-3