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7th July 2016 @ 02:07

IMG_1615.JPG
 

Procedure:

For details of synthesis of hydrazinylpyrazine, see Synthesis of 2-Chloro-6-hydrazinylpyrazine (AEW 85-7)

Hydrazinylpyrazine can also be purchased commercially.

Hydrazinylpyrazine (8.00g, 55.3mmol, 1 equiv.), triethyl orthoformate (16.40g 18.4 ml, 111 mmol, 2 equiv.), and tosylic acid (476mg, 2.77 mmol, 0.05 equiv.) were dissolved in toluene (158ml, 0.35 M with respect to Hydrazinylpyrazine) and heated at reflux for about 24 hours

Volatiles were removed under reduced pressure, remaining orthoester was blown off under a gentle stream of nitrogen. NMR of the crude showed that purification is needed. TLC showed that 6 fractions were spotted. The reaction mixture was dissolved in ethyl acetate and mixed with slica. The solvent (ethyl acetate) was evaporated under reduced pressure. Purified by column chromatography (30 to 100% ethyl acetate in hexanes). All fractions are yellow solid.

 Data:

From Tianyi Synthesis of 5-Chloro-[1,2,4]triazolo[4,3-a]pyrazine (TZ 2-1)Synthesis of 5-Chloro-[1,2,4]triazolo[4,3-a]pyrazine (TZ 2-1)

 

TLC(ethyl acetate: petrol=50: 50)

TZ 2-1 TLC.jpg

NMR (product)

NMR TZ 2-1 product dmso.pdf
NMR data TZ 2-1 product CDCl3.pdf

NMR (fractions)

TZ 2-1 Frac5.pdf
TZ 2-1 Frac1.pdf

Hazard and Risk Assessment:

 

Strings:

ClC1=CN=CC(NN)=N1

and

CCOC(OCC)([H])OCC

to

ClC1=CN=CC2=NN=CN21

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

and  

InChI=1S/C7H16O3/c1-4-8-7(9-5-2)10-6-3/h7H,4-6H2,1-3H3  

to  

InChI=1S/C5H3ClN4/c6-4-1-7-2-5-9-8-3-10(4)5/h1-3H


Log


The reaction mixture started with a brown solution with much precipitant.

The precipitant dissolved and the mixture turned purple when the bath temperature was about 50℃.

Reflux started at about 15:30 on 7th Jul 2016.

The oil tub was found out crack, and oil leakage was observed on the morning of 8th Jul 2016. So the reaction was swithed off at 9:37a.m.

   

The reaction mixture cooled down to room temperature and TLC test turned out as the following photo which showed the reaction hadn't finished yet because the starting material still existed. 

Reaction was started again at 11:30 a.m.(7th Jul 2016)

Another 0.05 equivalence of tosylic acid(476mg, with respect to the initial amount of SM)was added at 17:00 8th Jul 2016, because the reaction will continune for another two days. 

11th Jul 2016

An error was found in thermocontrol and  the reaction was switched off. TLC showed there was still some SM left.

After removing solvent, the solid left was quite sticky and difficult to transfer. So dichloromethane was added to the solid. 

 

There was still much fine precipitant left after sonicating. After filtering the mixture, both solid and liquid sample was tested by TLC which showed the same spots. However, the solid sample was quite difficult to dissolve, corresponding spots might result from some solution left on the surface of the solid.  

For the liquid part, the solvent was removed under reduced pressure then dissolved in ethyl acetate and mixed with slica. Ethyl acetate was then again evaporated under reduced pressure.Purified by column chromatography (petroleum benzin/ethyl acetate = 2:5 )

12th Jul 2016

The fith fraction seemed promising which was proved by 1H-NMR though impurity existed. Fraction 6 is not very soluable in CD3Cl, so was not detected by NMR. As for Fraction 1, there was a signal of oxethyl group in NMR, which showed the reaction was incomplete.

F1

NMR-HM1-1 F1.png
HM 1-1 F1.zip

Data embedded from Synthesis of 5-chloro-[1,2,4]triazolo[4,3-a]pyrazine (HM 1-1).

F5 (200MHz,DMSO)  δ: 9.683(1H,s), 9.438(1H,s), 8.161(1H,s) 

NMR-HM1-1 F5.png
HM 1-1 F5.zip

Data embedded from Synthesis of 5-chloro-[1,2,4]triazolo[4,3-a]pyrazine (HM 1-1).

F6(solvent CD3Cl)

NMR-HM1-1 F6.png
HM 1-1 F6.zip

Data embedded from Synthesis of 5-chloro-[1,2,4]triazolo[4,3-a]pyrazine (HM 1-1).

 

 14th Jul 2016

The assuming product of the second column was collected and combined.  four NMR data was collected, which correspond to crude sticky solid(before column), filted  solid(the first column), filtered liquid(the first column),and assumed product(the second column) respectively.

    NMR Data

HM 1-1 filtered solid (after column).zip
HM 1-1 filtered liquid (after column).zip
HM 1-1 crude sticky solid filtered before column.zip
HM 1-1 second column product.zip
HM 1-1 filtered liquid(after column).png
HM 1-1 filtered solid(after column).png
HM 1-1 second column product.png
sticky solid.png

The filtered solid after column was no doubt the desired product and was quite pure 1HNMR (200MHz,DMSO)  δ: 9.683(1H,s), 9.438(1H,s), 8.161(1H,s)

By paralleling these four spectrum we can clearly see that there was almost no product in the sticky solid, which means we can simply filter the reaction mixture of HM 1-2 making the column procedure easier. Further more, recystallization is needed for the filtered liquid(after column) in order to get purer product.

HM 1-1 paralleling 4 spectrums.png

 

18th Jul

The recrystalised product was filtered out, and TLC showed it's should be the same as the pure one though there was some difference in color(the right one is the pure one).

       

19th Jul

According to NMR data, recrystalisation failed, further purifing method needed to be considered.

  NMR DATA

  

HM1-1 recrystalisation.png
HM1-1 recrytalisation.zip



 

Linked Entries
Attached Files
HM 1-1.cdx
HM 1-1.png
HIRAC_Synthesis of 5-chloro-[1,2,4]triazolo[4,3-a]pyrazine HM 1-1.doc
IMG_1615.JPG
IMG_1629.JPG
IMG_1630.JPG
IMG_1617.JPG
IMG_1635.JPG
QQ图片20160708115634.jpg
picture 7.11IMG_1789(1).JPG
picture 7.11IMG_1793.JPG
picture 7.11IMG_1795.JPG
picture 7.11IMG_1799.JPG
picture 7.11IMG_1802.JPG
NMR-HM1-1 F1.png
NMR-HM1-1 F5.png
NMR-HM1-1 F6.png
HM 1-1 filtered liquid(after column).png
HM 1-1 filtered solid(after column).png
HM 1-1 second column product.png
sticky solid.png
HM 1-1 paralleling 4 spectrums.png
HM 1-1 filtered solid (after column).zip
HM 1-1 filtered liquid (after column).zip
HM 1-1 crude sticky solid filtered before column.zip
HM 1-1 second column product.zip
HM 1-1 F1.zip
HM 1-1 F5.zip
HM 1-1 F6.zip
comparison.jpg
TLC.jpg
HM1-1 recrystalisation.png
HM1-1 recrytalisation.zip
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