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6th December 2016 @ 10:08

AT-1-025

Cyclisation of (E)-2-chloro-6-(2-(4(pyrrolindin-1-yl)benzylidene)hydrazine)pyrazine (AT-01-23) to form 5-chloro-3-(4-(pyrronlidin-1-yl)phenyl)-[4,3-a]pyrazine (AT-01-25) 

reaction scheme 

Reagent

Eq

Mw

mmol

w/vol

AT-01-23

1

300.79

0.7989

0.2403g

DCM

~

84.39

~

15ml

PIDA

1

322.1

0.7989

0.2573g

NaHCO3

~

~

~

30ml

Mg2CO3

~

~

~

~

 

Experimental Procedure

 

(E)-2-chloro-6-(2-(4(pyrrolindin-1-yl)benzylidene)hydrazine)pyrazine (240.3mg, 0.7989mmol) was added to DCM (15ml) in a round bottom flask. PIDA (257.3mg, 0.7989mmol) was also added and the reaction was left to stir at room temperature. On addition to the PIDA, the reaction changed from a bright red solution to a rusty red colour.

IMG_2841.png

The reaction was stirred at room temperature for 7 days, over which time the reaction changed from pale yellow to orange.

IMG_2848 (1).png

Upon completion of the reaction, which was determined by TLC analysis, (5:3 Pet. Ether: Diethyl ether for first TLC, 1:1 hexane: EtOAc for the second TLC plate and 70:30 EtOAc/ Pet. Ether for the third)

IMG_2847.png

The mixture was placed into a separating funnel and the solution was separated into the inorganic and organic layers by the addition of NaHCO3 (30ml). The organic layer was tapped off and the inorganic layer was put to one side. The  organic layer was then washed with DCM (4x30ml). The mixture was then dried by Mg2CO3 and filtered. From the resulting solution a crude NMR was taken.

The solvent from the crude was in vacuo. Silica and EtOAc were added, solvent removed via in vacuo again and then Flash columned, to purify the product.

column.png

Solvent system for the column started at 1:1 Pet. Ether/ EtOAc, but was changed to 70/30 EtOAc/ Pet. Ether to increase the mobile phase. 57 Test tubes were taken. Products appeared in test tubes 3-6, 9-11, 17-20, 21-23, 24, 27-29, 30-33 and 37-57.  

TLC of column.png

The Final product was given as a yellow solid for each of the fractions. None of the products produced were pure, they were all a mix of isomers. No yield was recorded but each fraction from 21-23 onwards had a yield. (0.0202-0.0277g, 9-10%).

 1H NMR showed that the material contained many different isomers of the correct product in the same fractions. Most of them also had water, EtOAc and Pet. Ether impurities.

 

A-1-025.

 

Reference:

  1. Open source malaria: our experiment, http://malaria.ourexperiment.org/triazolopyrazine_se/9259/Synthesis_of_5Chloro124triazolo43apyrazine_TZ_61.html, date accessed: 04/11/16
Attached Files
IMG_2848 (1).png
IMG_2841.png
IMG_2847.png
cyclisation with ethanol chemdraw.png
TLC of column.png
column.png