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20th February 2014 @ 03:56


6-Chloropyrazine-2-carboxylic acid (300 mg, 1.89 mmol, 1 eq.), 3-chloro-2-fluoroaniline (0.21 mL, 1.89 mmol, 1 eq.) and DIEA (0.66 ml, 3.78 mmol, 2 eq.) were stirred in DMF (1.8 mL) at 0 ˚C. T3P (50 % by wt in EtOAc,  1.5 eq.) was added dropwise at 0 ˚C. The reaction mixture was stirred for 15 min at this temperature and then allowed to reach room temperature. The mixture was left stirring for 18 h. A TLC and NMR of a mini work up showed that the reaction had not gone to completion. Thus, more T3P (1 mL, 50 % by wt in EtOAc, 1.70 mmol) was added at 0 ˚C to the reaction mixture and it was left to stir at room temperature over the weekend..

Hazard Assessment

Synthesis of IT 5 6-chloro-N-(3-chloro-2-fluorophenyl)pyrazine-2-carboxamide.docx

InChI

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

and

InChI=1S/C6H5ClFN/c7-4-2-1-3-5(9)6(4)8/h1-3H,9H2

to

InChI=1S/C11H6Cl2FN3O/c12-6-2-1-3-7(10(6)14)17-11(18)8-4-15-5-9(13)16-8/h1-5H,(H,17,18)

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12th February 2014 @ 23:56

I am following the method used by Eduvie Omene (Repeat of Synthesis of 6-chloropyrazine-2-carboxylic Acid EO 7-3, Repeat of Synthesis of 6-chloropyrazine-2-carboxylic Acid EO 7-2 and Synthesis of 6-chloropyrazine-2-carboxylic Acid EO 7-1)

Methyl 6-chloro-2-pyrazinecarboxylate (5.70 g, 33 mmol, from IT 3-1) was dissolved in ethanol (80 mL). Sodium hydroxide (80 mL, 160 mmol, 2 M, aq.) was added and the reaction mixture left stirring at room temperature for 2 h. Hydrochloric acid (2 M, aq, ~100 mL) was added until pH 3 was reached. The reaction mixture was diluted with water (480 mL) and extracted into ethyl acetate (4 x 320 mL). The organic extracts were washed with brine (320 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford a pale yellow powder of 6-chloropyrazine-2-carboxylic acid (1.45 g, 9.15 mmol, 27.7 %, m.p. 151.7 - 153.3 °C (commercial m.p. 154.8 - 158.2 °C).

The NMR of this product showed the presence of a small amount of impurities (8.3-7.3 ppm). A recrystallisation from hexane was conducted to yield pure 6-chloropyrazine-2-carboxylic acid (0.5950 g, 3.75 mmol, 11.4 %).

Hazard Assessment

Synthesis of IT 4 6-chloropyrazine-2-carboxylic acid.docx

IT 4-1.png

InChI

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

to

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

1H NMR (200 mHz, CDCl3)

After column:

H NMR IT 4-1 after column CDCl3.pdf

Commercial 6-chloropyrazine-2-carboxylic acid:

H NMR 6-chloropyrazine-2-carboxylic acid_commercial_CDCl3.pdf

After recrystallisation from hexane:

1H NMR IT 4-1 after recryst ppt CDCl3.pdf
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6th February 2014 @ 04:39

5.80 g of methyl 6-chloro-2-pyrazinecarboxylate was synthesised which will be used in the synthesis of 6-chloropyrazine-2-carboxylic acid (see Synthesis of 6-chloropyrazine-2-carboxylic acid (IT 4-1).

I am followed the method used in this paper (DOI: 10.1021/jm201045m, see p. 7688).

Methyl 4-oxy-2-pyrazinecarboxylate (13.0 g, 84.3 mmol, from IT 2-1, impure) was dissolved in SOCl2 (80 mL) and the mixture heated at reflux for 22 h (however, a mini work-up of reaction mixture after 4 h of heating suggested that the reaction had probably already gone to completion after this amount of time). After the solution had cooled to ambient temperature, the SOCl2 was removed under vacuum and the residue quenched with the dropwise addition of water (80 mL) at 0 oC. The reaction mixture was neutralised by the addition of K2CO3 (1 M, aq.) and extracted with dichloromethane (3 x 180 mL). The organic extracts were washed with brine (180 mL), dried over anhydrous magnesium sulfate, filtered and then concentrated in vacuo. The brown-orange residue was purified by silica column chromatography (eluent: 100 % hexane to 50:50 ethyl acetate:hexane). This yielded a yellow oil of methyl 6-chloro-2-pyrazinecarboxylate (5.80 g) shown to contain slight impurities by 1H NMR.

Hazard Assessment

Synthesis of IT 3 methyl 6-chloro-2-pyrazinecarboxylate.docx

IT 3-1.png

InChI

InChI=1S/C6H6N2O3/c1-11-6(9)5-4-8(10)3-2-7-5/h2-4H,1H3

to

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

TCL plate from column chromatography (eluent EtOAc: petroleum ether 1:4, product spot Rf = 0.7)

1H NMR

1H MNR IT 3-1 fractions 40-52 methyl 6-chloro-2-pyrazinecarboxylate CDCl3.pdf
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3rd February 2014 @ 00:33

13.12 g of impure methyl 4-oxy-2-pyrazine carboxylate was synthesised. Purification by column chromatography will be carried out after the next step of the reaction (see Synthesis of methyl 6-chloro-2-pyrazinecarboxylate (IT 3-1))

This synthesis is following the method used by Eduvie Omene: Repeat of Synthesis and purification of Methyl 4-oxy-2-pyrazinecarboxylate (EO 5-2) and Synthesis and purification of Methyl 4-oxy-2-pyrazinecarboxylate (EO 5-1), who seems to have been following the method used in this paper (DOI: 10.1021/jm201045m, see p. 7688).

Methyl-2-pryrazinecarboxylate (8.24 g, 59.7 mmol) was suspended in 1,2-dichloroethane (80 mL) and m-CPBA (24 g, 118 mmol, 85 % purity) was added. The reaction was stirred at 60 °C for 20 h. Starting material was still present (as seen by TLC) so more m-CPBA (1.352 g, 6.66mmol, 85 % purity) was added. After a further 5 h of heating, the temperature was raised to 70 °C because starting material was still present in the reaction mixture (seen by TLC). The mixture was cooled to RT after a total of 40 h heating and diluted with dichloromethane (250 mL). The precipitate was isolated by filtration and washed with dichloromethane (3 x 30 mL). The filtrates were dried over anhydrous potassium carbonate then concentrated in vacuo. The residue was suspended in hexane (40 mL) and the methyl 4-oxy-2-pyrazine carboxylate isolated by filtration. The crude product was washed with hexane (2 x 40 mL) to afford a pale yellow powder (13.12 g, 85.1 mmol, 143 %).

Hazard Assessment

Synthesis of methyl 4-oxy-2-pyrazine carboxylate.docx

Class 3 IT 2-1.png

InChI:

InChI=1S/C6H6N2O2/c1-10-6(9)5-4-7-2-3-8-5/h2-4H,1H3

to

InChI=1S/C6H6N2O3/c1-11-6(9)5-4-8(10)3-2-7-5/h2-4H,1H3

1H NMR

IT 2-1 workup today DMSO.pdf
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22nd January 2014 @ 03:27

Using the following method, 8.34 g of methyl pyrazine-2-carboxylate (Preparation of OSM-S-147) was synthesised with a percentage yield of 60 %.

Experimental Procedure
Pyrazine-2-carboxylic acid (12.5 g, 101 mmol) was added to methanol (100 mL) and the solution cooled to 0 oC. Concentrated sulfuric acid (0.625 mL) was then added dropwise with stirring, ensuring the temperature did not exceed 5 oC. The mixture was refluxed at 85 oC for 22 h then cooled to room temperature (TCL plate). The methanol was then removed in vacuo and dichloromethane (50 mL) and water (25 mL) were added. Saturated sodium bicarbonate solution (~150 mL) was added until a pH of approximately 7.5 was reached. The organic layer was isolated and the remaining water layer extracted once more with dichoromethane (25 mL). The bright yellow organic layers were combined and dried over anhydrous magnesium sulfate. The crude product was isolated under vacuum. Purification by column chromatography was carried out with an eluent system of ethyl acetate and petroleum benzine (1:1) to yield pure white crystalline methyl pyrazine-2-carboxylate (yield: 8.34 g, 60.4 mmol, 59.9 %).

Hazard Assessment:

Synthesis of methyl pyrazine-2-carboxylate.docx

InChI:

InChI=1S/C5H4N2O2/c8-5(9)4-3-6-1-2-7-4/h1-3H,(H,8,9)

to

InChI=1S/C6H6N2O2/c1-10-6(9)5-4-7-2-3-8-5/h2-4H,1H3

TLC plate:

1H NMR:

1H NMR IT 1-1 pure DMSO.pdf
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