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2nd December 2011 @ 06:07
NOTE: USED DIETHOXYETHYLAMINE INSTEAD OF DIMETHOXYETHYLAMINE.


Preparation of the PZQ N-benzoyl analogue Ugi intermediate (KAB6-1) from 4 components:

Scheme%206-1%20(amended).png

Table%206-1.tjpg


Risk Assessment
HR KAB6-1


02/12/11

Procedure - Performed simultaneously with the preparation of KAB5-1

Benzoic acid (7.5 g) and paraformaldehyde (1.67 g) were added to methanol (65 mL) before the addition of 2,2-dimethoxyethylamine (5.87 g), to make a cloudy, colourless solution. The benzoic acid had not completely dissolved at this stage. (2-isocyanoethyl)benzene (KAB4-1) (7.5 g) was added, dropwise with stirring at 0 C, before the reaction mixture was warmed to room temperature (~5:10 pm). The solution gradually turned yellow after 15 minutes and some undissolved benzoic acid remained in the flask. The solution was left to stir at room temperature over the weekend.

NOTE: The yellow reaction mixture was slightly darker than that of the PZQ Ugi-intermediate preparation reaction mixture (KAB5-1).

Perform TLC: hexane:ethylacetate, 1:2 or 1:1


Reaction Setup:

(Flask on Left) 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) and ethyl acetate (50 mL). The solution was washed with water (3 x 50 mL) and brine (50 mL), then dried over magnesium sulfate. The solvent was removed under reduced pressure to give crude KAB6-1 as a yellow-brown, viscous oil (13.6 g).

Crude TLC

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.

06/12/11
Attempt at column. Yellow crystals formed in combined fractions 9-12 (ethyl acetate in hexane, 20%).
Will need to re-column some fractions (Possibly combined 15-17. Flush column and reload?).

07/12/11
A total of 18 fractions were collected. Fractions 1-2, 3-4, 5-7, 8-9, 10-12, 13-14 and 15-17 were combined. Fraction 18 was obtained following flushing of the column with neat methanol. All samples were concentrated under reduced pressure. The H-NMR of the fractions were recorded.

NMR of all samples indicated the desired product, N-(2,2-dimethoxyethyl)-N-(2-oxo-2-(2-phenylethylamino)ethyl)benzamide was in final fraction, 18.
H-NMR of KAB6-1


Fractions 1-2: NMR suggested a mix of products.
Fractions 3-4: NMR contained peaks corresponding to (2-isocyanoethyl)benzene (KAB4-1) and ethyl acetate. Total amount ~1.2 g.
Fractions 5-7: NMR indicated a high concentration of benzoic acid. Product was fine pale yellow crystals suggesting the presence of impurities. The fractions 24 hours earlier had the slight odour of (2-isocyanoethyl)benzene, which was absent when concentrated.
Fractions 8-9:
Fractions 10-12:
Fractions 13-14:
Fractions 15-17:

Purified TLC

TLC of columned product. From left to right (1)Pure KAB6-1, (2)MW51, (3)Pure KAB6-1, MW5-1 and benzoic acid from combined fractions 5-7, (4)Benzoic acid from combined fractions 5-7

Final KAB6-1



08/12/11
Mass spectrum recorded
MS KAB6-1

Peak 420.87 -> M+Na
The MS indicated that the product was most likely the intermediate containing the ethoxy acetal:
KAB6-1 (amended)

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.
Product was used in the experiment: 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)
Characterisation ongoing.


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


Related Experiments
Preparation of the N-benzoyl-protected 'Ugi-intermediate' (MW51-1)
Preparation of (2-isocyanoethyl)benzene (KAB4-1)
Linked Posts
Attached Files
Scheme KAB6-1
HR KAB6-1
Table KAB6-1
(Flask on Left) 20 minutes after the addition of KAB4-1
Crude TLC
Purified TLC
Final KAB6-1
H-NMR of KAB6-1
Raw KAB6-1 H-NMR data
H-NMR of fractions 3-4
MS KAB6-1
MS KAB6-1
Scheme KAB6-1 (amended)
KAB6-1 (amended)