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2nd December 2011 @ 06:11
***Still performing characterisation. Undergoing regular updates.

NOTE: USED DIETHOXYETHYLAMINE INSTEAD OF DIMETHOXYETHYLAMINE. WILL FIX SCHEME/TABLE ETC ASAP.

Preparation of the PZQ Ugi intermediate from the 4 components.

Scheme%205-1.png

Table%205-1.tjpg

Risk Assessment
HR KAB5-1



02/12/11

Procedure - Performed simultaneously with the preparation of KAB6-1

Cyclohexanecarboxylic acid (6.0 g) and paraformaldehyde (1.41 g) were dissolved in methanol (65 mL) before the addition of 2,2-dimethoxyethylamine (4.97 g) to make a cloudy, colourless reaction mixture. (2-isocyanoethyl)benzene (KAB4-1) (6.6 g) was added dropwise, with stirring, at 0 C. The reaction mixture was warmed to room temperature (at ~5:15 pm). The reaction mixture gradually turned yellow over the next few minutes, then left to stir at room temperature over the weekend.

NOTE: The yellow reaction mixture was slightly lighter than that of the PZQ N-benzoyl analogue Ugi-intermediate preparation reaction mixture (KAB6-1).

Expected TLC: hexane:ethylacetate, 1:2 - Rf = 0.33

Reaction Setup:

(Flask on Right) 20 minutes after the addition of KAB4-1



05/12/11 - 68 hours after reaction start
The reaction mixture was concentrated under reduced pressure to give a dark yellow-brown, viscous oil, which was dissolved in diethyl ether (75 mL). The solution was washed with water (50 mL) and brine (50 mL), then dried over magnesium sulfate. The solvent was removed under reduced pressure to give crude KAB5-1 as a dark yellow, viscous oil (12 g).

TLC of crude product

From bottom to top: (1)MW29-4 (2)Crude KAB5-1 (3)KAB5-1 (4)KAB4-1 (5)All (6)KAB6-1 (7)MW51 (8) Crude KAB6-1, in ethylacetate/hexane (2:1) with KMnO4 stain.

Murray ran column. (ADD PROCEDURE)

06/12/11
NMR fractions 9-12, 13-14.
KAB5-1 H-NMR of fractions 9-12
KAB5-1 H-NMR of fractions 13-14

(RAW NMR DATA TO BE UPLOADED)


08/12/11
Product used in reaction: Acid-mediated PS cyclisation to give racemic PZQ (KAB3-3), the dimethoxy N-benzoyl PZQ analogue (KAB8-1), the dimethoxy PZQ analogue (KAB1-2) and the N-benzoyl PZQ analogue (KAB7-1)
Mass spectrum recorded (MASS SPECTRUM TO BE UPLOADED) - The MS indicated that the product was most likely the intermediate containing the ethoxy acetal (ADD FIGURE). This agrees with the low yield obtained, compaired to the expected yield, and the unreacted benzoic acid and (2-isocyanoethyl)benzene, which were separated by the column. Revised calculations to be performed and uploaded.
Characterisation ongoing --> C-NMR, UV-Vis, IR. Crystallise?

23/01/12
The final, purified product was the expected peptide acetal intermediate. Reduced yield was attributed to the miscalculation of the substrate amounts.

References
[1] H. Cao, H. Liu, A. Doemling, Chemistry-a European Journal 2010, 16, 12296. DOI: 10.1002/chem.201002046

Following Experiments
Acid-mediated PS cyclisation to give racemic PZQ (KAB3-3), the dimethoxy N-benzoyl PZQ analogue (KAB8-1), the dimethoxy PZQ analogue (KAB1-2) and the N-benzoyl PZQ analogue (KAB7-1)

Related Experiments
Preparation of the Ugi-intermediate via Ugi reaction (MW36-1)
N-Cyclohexanoyl protection of the amine intermediate MW7-2-27 of PZQ: Upscale (MW29-4)
Preparation of (2-isocyanoethyl)benzene (KAB4-1)
Linked Posts
Attached Files
Scheme KAB5-1
HR KAB5-1
Table KAB5-1
(Flask on Right) 20 minutes after the addition of KAB4-1
TLC of crude product
KAB5-1 H-NMR of fractions 9-12
KAB5-1 H-NMR of fractions 13-14