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2nd June 2010 @ 07:48
Preparation of the "Ugi intermediate" of PZQ as starting material for the Pictet-Spengler cyclisation

Optimized conditions from previous experiments: See procedure MW29-2

Reaction Scheme



Table1 corrected



Start time: 4:30 pm 2/06/2010
End time: 7:00 pm

To a solution of MW7-2-27 (1.0 g, 3.30 mmol) and Et3N (836 mg, 8.26 mmol) in DCM (15 mL) was added dropwise a solution of cyclohexanecarboxylic acid chloride (53.3 mg, 363 µmol) in DCM (5 mL) at 0°C. After 5 min the ice bath was removed and the solution was stirred for 2.5 h at room temperature.
- orange solution: TLC (EA = 100%) --> complete conversion of the starting material, no side products visible.

Work-up: quenched with water, extracted with DCM, washed with aq. ammonium chloride, dried over sodium sulfate, concentrated.
-crude product: 1.37 g orange oil, crude 1H NMR shows less impurities
-column chromatography (silica gel, EA, 100%), Rf (EA, 100%) = 0.50 (fast elution)
- high vac (3 days)

Result:
Product MW29-4: pale yellow high-viscous oil 1.22 g (3.24 mmol, 98%)
– trace amount of solvent, which can’t be removed in high vacuum; no other impurities.


Analytical data:
Rf (EA 100%) = 0.50.
1H NMR (CDCl3, 200 MHz): δ = 1.24-1.76 (m, 10H), 2.20-2.30/2.53-2.64 (m, 1H), 2.78/2.82 (t, J= 7.4Hz, 2H) 3.33/3.38 (s, 6H), 3.39-3.60 (m, 4H), 3.98/3.99 (s, 2H), 4.39/4.57 (t, J=5.2 Hz, 1H), 6.50/7.00 (bs, 1H), 7.16-7.33 (m, 5H), two rotamers, ratio=1:1.
13C NMR (CDCl3, 50.3 MHz): δ = 25.6, 25.7, 25.8, 29.4 (2C), 35.6, 40.3/40.5, 40.7/41.1, 50.4/51.6, 52.1/54.1, 55.1/55.5 (2C), 102.8/103.5, 126.5/126.7, 128.6-128.8 (4C), 138.6/138.9, 169.3/169.6, 177.9/178.1, two rotamers, ratio 1:1.
Data: HSQC MW29-4
IR (neat): nu = 3304 cm-1, 2929, 2854, 1626, 1451, 1124, 1064, 748, 699.
MS (ESI (+)) m/z (%): 775 (100, [M2Na]+), 399 (12, [MNa]+).
HRMS (ESI (+)) Calcd. for [C20H29N2O3Na]+: 399.2254, found: 399.2256.
C21H32N2O4 (376.5).
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Attached Files
Reaction Scheme
Table1
1H NMR MW29-4
1H NMR MW29-4 JCAMP-DX
13C NMR MW29-4
13C NMR MW29-4 JCAM-DX.dx
IR
Table1 corrected
HSQC MW29-4