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30th June 2014 @ 02:02

Repeat synthesis of JU 1-12 as more starting material is needed.

Reaction Scheme

Procedure

Started 11:50am

2,6-Dichloropyrazine (Aldrich, 1.00 g, 6.8 mmol) was dissolved in ethanol (10 mL) to give a clear solution. The solution was heated to 80°C (bath temperature) before hydrazine hydrate (0.35 mL, 360 mg, 7.2 mmol) was added resulting in a pale yellow solution. The resulting mixture was heated at reflux (bath temperature 80˚C) for 3.5 h. Analysis by TLC showed the reaction has stopped.

TLC JU 1-13 30:70 EtOAc:Hex 3.5 h.jpg

The reaction was left to cool to room temperature before the solvent was removed by rotary evaporation and the crude product (yellow) dried in vacuo (1.47 g). The crude product was analysed by NMR and was unfortunately not the correct product. Hypothesised due to excess time spent on the rotary evaporator. A TLC at greater polarity was also run, showing more than 1 product.

TLC JU 1-13 50:50 EtOAc:Hex 3.5 h.jpg
TLC JU 1-13 50:50 EtOAc:Hex 3.5 h anisaldehyde.jpg

1H NMR, crude, DMSO, 200 MHz

JU 1-13 crude 200 MHz.pdf
JU 1-13 crude.zip

The crude product was purified so that a crystallisation can be attempted for determination of the structure by crystallography. Run details below.

JU 1-13_arch.pdf

The pure product (788 mg, % yield unknown as product unknown) was analysed by 1H NMR.

1H NMR, pure, DMSO, 200 MHz

JU 1-13 pure 200 MHz.pdf
JU 1-13 pure.zip

 

HIRAC & Risk Assessment

See JU 1-1

InChI strings

InChI=1S/C4H2Cl2N2/c5-3-1-7-2-4(6)8-3/h1-2H

to

InChI=1S/C4H5ClN4/c5-3-1-7-2-4(8-3)9-6/h1-2H,6H2,(H,8,9)

SMILES

ClC1=CN=CC(Cl)=N1

to

ClC1=CN=CC(NN)=N1

Attached Files
26th June 2014 @ 07:37

Procedure:

6-Chloropyrazine-2-carboxylic acid (1 g, 6.31 mmol) was dissolved in MeOH (10 mL) and a few drops of H2SO4 were added and then the reaction heated to 80 ˚C.

Data:

Hazard and Risk Assessment:

InChi:

InChI=1S/C5H3ClN2O2/c6-4-2-7-1-3(8-4)5(9)10/h1-2H,(H,9,10)

to

InChI=1S/C6H5ClN2O2/c1-11-6(10)4-2-8-3-5(7)9-4/h2-3H,1H3

Attached Files
26th June 2014 @ 07:32

Crude AEW 94-10 was submitted to the reaction (CRO prep used crude material with no NMR ref). 

 

Crude AEW 94-9 (2.5 g) was stirred in dioxane (10 mL) and 50% aq. H2SO4 (40 mL) was added and the reaction mixture was heated to 90 ºC for 1h.

Reaction mixture removed from heat, allowed to cool to rt then poured into water (40 mL), extracted with EtOAC (3 x 40 mL). Combined organic layers were dried over MgSO4, filtered and evaporated to give an amber oil.

 

Data:

 

Hazard and Risk Assessment:

See Synthesis of 2-(3,4-difluorophenyl)-2-oxoacetic acid (AEW 102-2) 

10 x the scale

HIRAC AEW 102-1.pdf

InChI:

InChI=1S/C11H13F2NOSi/c1-16(2,3)15-11(7-14)8-4-5-9(12)10(13)6-8/h4-6,11H,1-3H3

to

InChI=1S/C8H6F2O3/c9-5-2-1-4(3-6(5)10)7(11)8(12)13/h1-3,7,11H,(H,12,13)

26th June 2014 @ 01:43

This is a test reaction to try to work out why JU 1-11 failed while JU 1-10a/b did not. As the solution cools, the product crashes out. In JU 1-11 this began to happen, and the product was yellow (indicating the correct product). Once it was put on the rotavap while still warm it turned orange (indicating the undesired product).

In this experiement the method for JU 1-10b will be followed. When the reaction is complete the solution will be left to cool completely, followed by cooling in an ice bath before filtering. The filtrate will then be concentrated on the rotary evaporator.

Reaction Scheme

Procedure

Started 11am

2,6-Dichloropyrazine (Aldrich, 255 mg, 1.70 mmol) was dissolved in ethanol (2.5 mL) to give a clear solution. The solution was heated to 80°C (bath temperature) before hydrazine hydrate (0.09 mL, 93 mg, 1.9 mmol) was added resulting in a pale yellow solution. The resulting mixture was heated at reflux (bath temperature 80˚C) for 3 h. Analysis by TLC showed the reaction was complete.

TLC JU 1-12 30:70 EtOAc:Hex 3 h.jpg

The yellow (indicating correct product) solution was cooled to room temperature then further cooled on ice. The product was filtered and washed with ice cold ethanol (3 x 1.5 mL) and ice cold water (3 x 1.5 mL) then dried in vacuo. The crude product was analysed by 1H NMR.

1H NMR, crude, DMSO, 200 MHz

JU 1-12 crude 200 MHz.pdf
JU 1-12 crude.zip

The solvent from the filtrate was removed by rotary evaporation and the product (yellow) dried in vacuo. The crude product was analysed by 1H NMR and found to contain the same two peaks at ~8.04 ppm and 7.71 ppm that are indicative of the hydrazinyl pyrazine. Note that water and the protons attached to Nitrogen are not consistent.

1H NMR, crude filtrate, DMSO, 200 MHz

JU 1-12 filtrate crude 200 MHz.pdf
JU 1-12 filtrate.zip

Total yield = 307 mg (>100% yield, likely a hydrate). Next time I carry out this reaction I will try not filtering it, just cooling completely to room temp before removing the solvent by rotary evaporation. This should be the same method as used prior to JU 1-7.

 

HIRAC & Risk Assessment

See JU 1-1

InChI strings

InChI=1S/C4H2Cl2N2/c5-3-1-7-2-4(6)8-3/h1-2H

to

InChI=1S/C4H5ClN4/c5-3-1-7-2-4(8-3)9-6/h1-2H,6H2,(H,8,9)

SMILES

ClC1=CN=CC(Cl)=N1

to

ClC1=CN=CC(NN)=N1

Attached Files
25th June 2014 @ 08:34

Repeat of JU 13-1 for more material using remaining amount of JU 1-5. 

Reaction Scheme

Procedure

Started 6:15pm

JU 1-5 (crude, 599 mg, 4.14 mmol) was stirred into a solution of AcOH (0.25 mL) and MeCN (7.2 mL).  4-Pyridinecarboxaldehyde (0.4 mL, 445 mg, 4.2 mmol) was added and the reaction mixture (bright yellow) was stirred at room temperature for 15.5 h. Analysis by TLC showed the reaction was incomplete.

TLC JU 13-2 30:70 EtOAc:Hex 15.5 h.jpg

4-Pyridinecarboxaldehyde (0.08 mL, 90 mg, 0.83 mmol, 0.2 equiv) was added along with acetonitrile (2 mL, to aid in stirring) and the reaction mixture was stirred at room temperature for a further 2 h. Analysis by TLC showed the reaction was incomplete.

TLC JU 13-2 30:70 EtOAc:Hex 17.5 h.jpg

4-Pyridinecarboxaldehyde (0.08 mL, 90 mg, 0.83 mmol, 0.2 equiv) was added along with acetonitrile (2 mL, to aid in stirring) and the reaction mixture was stirred at room temperature for a further 2 h. Analysis by TLC showed the reaction was incomplete.

TLC JU 13-2 30:70 EtOAc:Hex 19.5 h.jpg

The reaction mixture was stirred for a further 20 h. Analysis by TLC showed the reaction was incomplete, and hadn't changed.

TLC JU 13-2 30:70 EtOAc:Hex 39.5 h.jpg
 

The reaction was stopped and the solvent removed by rotary evaporation and the product dried in vacuo. The crude product (bright yellow) was analysed by 1H NMR.

1H NMR, crude, DMSO, 200 MHz

JU 13-2 crude 200 MHz.pdf
JU 13-2 crude.zip

NB: next time try the reaction without adding the acetic acid. It's possible that the N in the pyridine is being protonated causing side reactions.

The crude product was purified using the biotage isolera, see run details below.

JU 13-2_arch.pdf

The pure product (x g, x% yield) was analysed by 1H NMR.

1H NMR, pure, DMSO, 200 MHz

JU 13-2 pure DMSO 200 MHz.pdf
JU 13-2 pure red frac.zip

1H NMR, yellow frac, DMSO, 200 MHz

JU 13-2 yellow frac DMSO 200 MHz.pdf
JU 13-2 pure yellow frac.zip

13C NMR, pure, DMSO, 300 MHz

JU 13-2 pure 13C 300 MHz.pdf
JU 13-2 pure 13C.zip

IR data


JU 13-2.pdf


HIRAC

See JU 13-1

InChI strings

InChI=1S/C4H5ClN4/c5-3-1-7-2-4(8-3)9-6/h1-2H,6H2,(H,8,9)

and

InChI=1S/C6H5NO/c8-5-6-1-3-7-4-2-6/h1-5H

to

InChI=1S/C10H8ClN5/c11-9-6-13-7-10(15-9)16-14-5-8-1-3-12-4-2-8/h1-7H,(H,15,16)/b14-5+

SMILES

ClC1=CN=CC(NN)=N1

and

[H]C(C1=CC=NC=C1)=O

to

ClC1=CN=CC(N/N=C/C2=CC=NC=C2)=N1

Attached Files