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15th April 2014 @ 06:09

scheme

See Resynthesis of methyl 6-chloro-2-pyrazinecarboxylate (TM 5-2), Synthesis of methyl 6-chloro-2-pyrazinecarboxylate (TM 5-1).

Crude TM 4-3 (Repeat synthesis of 3-(methoxycarbonyl)pyrazine 1-oxide (TM 4-3), 27.9 g, seemingly a 1:1 mixture of TM 4-3 and m-chlorobenzoic acid. Assume 90 mmol) was dissolved in thionyl chloride (90 mL), and heated to 55 oC for 16 hours. Thionyl chloride was then removed under vacuum, and the crude product remaining neutralised with saturated sodium carbonate solution. This was then extracted with DCM (5 x 200 mL), with the combined organic layers then washed with brine (2 x 100 mL) and dried over anhydrous sodium sulphate. Solvents removed under vacuum to give crude TM 5-3 as a brown liquid, 32.2 g.

Crude NMR (1H, CDCl3, 500 MHz):

TM 5-3 crude 1H CDCl3 500 MHz.pdf

A number of purification techniques were used, as columning 32.2 g of oil would be awful. A 3.0 g sample was purified by silica chromatography, eluted by 10 % EtOAc in petroleum ether ramped up to neat EtOAc: 1.8 g of pure TM 5-3 was recovered as the second fraction. A similar column was performed on 7.5 g of crude TM 5-3, where it was noticed that pure petroleum ether only moved the (still unknown) m-chlorobenzoic compound, leaving both TM 5-3 and the non-chlorinated starting material present.

 

From this, a simpler purification was performed: ~2cm of silica was put over a fritted filter funnel, petroleum ether was added, and 10 g of crude TM 5-3 was pipetted on top. The system was washed with petrolem ether until no more of the m-chlorobenzoic product eluted, then 20 % EtOAc/pet. ether was used to slowly bring through the desired material. When the solution coming through changed from the pale yellow of pure TM 5-3 to the golden orange of TM 2 (2-methyl pyrazine carboxylate), the receiving flask was changed. This simple extraction gave clean separations, and was far less time-intence than running a column. 2.17 g of pure TM 5-3 obtained (lower than expected).

 

Finally, the remaining crude was purified using the same washing technique. 11.9 g of crude compound was placed on silica, washed with petroleum ether until no UV activity was observed (~ 1.5 L), then eluted with 10 % EtOAc / pet ether, collecting 250 mL samples until the desired product (RF 0.7, EtOAc) was replaced by unchlorinated pyrazine ester (RF 0.45). 3.97 g recovered.

 

It seems that the quick and dirty purification method, while giving pure product by NMR and TLC, results in some product loss along the way: around 30 % of the mass of the crude product was recovered by washing, while 60 % was recovered by column separation.

More spectra:

M-chlorobenzoic compound:

TM 5-3 column f2 1H CDCl3 200 MHz.pdf
TM 5-3 f2 12-5-14.zip

Pure TM 5-3 (1H, CDCl3, 200 MHz)

TM 5-3 10g wash p1 1H CDCl3 200 MHz.pdf
TM 5-3 10g wash p1.zip

Recovered pyrazine 2-methyl carboxylate:

TM 5-3 10g wash p2 1H CDCl3 200 MHz.pdf
TM 5-3 10g wash p2.zip

 

 

HIRAC: see TM 5-1.

HIRAC.pdf
Linked Posts
Attached Files
TM 5-3 crude 1H CDCl3 500 MHz.pdf
TM 5-3 columned f2.pdf
TM 5-3 columned f2.zip
TM 5-3 10g wash p1 1H CDCl3 200 MHz.pdf
TM 5-3 10g wash p2 1H CDCl3 200 MHz.pdf
TM 5-3 10g wash p3 1H CDCl3 200 MHz.pdf
TM 5-3 column f2 1H CDCl3 200 MHz.pdf
TM 5-3 10g wash p2.zip
TM 5-3 10g wash p3.zip
TM 5-3 f2 12-5-14.zip
TM 5-3 10g wash p1.zip
Comments
Re: Resynthesis of methyl 6-chloro-2-pyrazinecarboxylate (TM 5-3) by Alice Williamson
16th April 2014 @ 03:25
HIRAC seen and approved. Remember to use Class 3 pocket for your reaction card.