The synthetic route of Pyrazine-2-carboxylic acid has been constantly updated, and we look forward to future research findings.
Synthetic Route of 98-97-5, In the next few decades, the world population will flourish. As the population grows rapidly and people all over the world use more and more resources, all industries must consider their environmental impact. 98-97-5, name is Pyrazine-2-carboxylic acid belongs to pyrazines compound, it is a common compound, a new synthetic route is introduced below.
Example 1 A. 4-Azido-1-thiophen-2-yl-butan-1-one A mixture of 4-chloro-2′-butyrothienone (3.0 g, 15.9 mmol) and sodium azide (2.07 g, 31.8 mmol) in DMF (50 mL) was stirred at 70 C. for 1.5 h. The reaction mixture was then partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was washed with water (100 mL), saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL) and dried over sodium sulfate. Removal of the solvent in vacuo provided the title compound (2.58 g, 83% yield). MS m/e 218; HPLC retention time 0.85 min (Method B). B. 2-(2-Azido-ethyl)-1-pyrazin-2-yl-3-thiophen-2-yl-propane-1,3-dione A suspension of pyrazine 2-carboxylic acid (2.52 g, 20.3 mmol) in dichloromethane (30 mL) at 0 C. was treated with oxalyl chloride (1.95 mL, 22.3 mmol) followed by the addition of catalytic DMF (1 drop). The reaction mixture was allowed to warm to room temperature overnight, then concentrated in vacuo to give pyrazine 2-carbonyl chloride as a violet-colored solid. In a separate reaction flask, LHMDS (1.0 M in THF, 11.28 mL) was added dropwise to a solution of the ketone 1A (1.10 g, 5.64 mmol) in THF (10 mL) at -78 C. The reaction mixture was maintained at that temperature for 20 min. The pyrazine 2-carbonyl chloride (1.0 g, 5.64 mmol)was then rapidly introduced as a solid to the reaction mixture to give a dark brown solution which was maintained at -78 C. for another 20 min. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, then concentrated to give the crude oil. Purification by flash column chromatography (silica, 30% ethyl acetate in hexanes) provided the title compound as a yellow oil (939 mg, 55% yield). MS m/e 324; HPLC retention time 2.78 min (Method A). 1H NMR (400 MHz, CDCl3): delta 2.36 (m, 1 H), 2.58 (m, 1 H), 3.60 (dd, 2 H), 5.82 (dd, 1 H), 7.28 (dd, 1 H), 7.82 (d, 1 H), 8.07 (d, 1 H), 8.67 (s, 1 H), 8.88 (s, 1 H), 9.37 (s, 1 H). C. 2-[4-(2-Azido-ethyl)-5-thiophen-2-yl-2H-pyrazol-3-yl]-pyrazine A solution of the dione 1B (213 mg, 0.71 mmol), hydrazine monohydrate (0.17 mL, 3.54 mmol) and concentrated aqueous HCl (1 drop) in methanol (4 mL) was heated at 70 C. for 1 h. The reaction mixture was then concentrated to give a yellow sticky solid which was purified by flash column chromatography (silica, 1:1 ethyl acetate:hexanes) to give the title compound (142 mg, 67% yield) as a colorless oil. MS m/e 298; HPLC retention time 3.40 min (Method A). 1H NMR (400 MHz, CDCl3): delta 3.29 (t, 2 H), 3.58 (t, 2 H), 7.13 (dd, 1 H), 7.41 (m, 2 H), 8.45 (d, 1 H), 8.59 (b s, 1 H), 9.25 (s, 1 H). D. 2-(5-Pyrazin-2-yl-3-thiophen-2-yl-1H-pyrazol-4-yl)-ethylamine A mixture of the azide 1C (140 mg, 0.47 mmol), and palladium on carbon (10% w/w, 30 mg) in methanol (5 mL) was stirred under an atmosphere of hydrogen gas (1 atm, balloon) for 3 h. The reaction mixture was then flushed with nitrogen and the mixture filtered over celite. Concentration under reduced pressure gave the title compound (104 mg, 82% yield) as a yellow oil. MS m/e 272; HPLC retention time 1.57 min (Method A). E. 2-Chloroethanol (0.095 mL, 1.41 mmol) was added dropwise to a solution of chlorosulfonyl isocyanate (0.122 mL, 1.41 mmol) in dichloromethane at -20 C. The reaction mixture was warmed to 0 C. and maintained at that temperature 1.5 h. The solution was then transferred by canula to a solution of the amine XX (383 mg, 1.41 mmol) and triethylamine (1.38 ml, 9.9 mmol) in dichloromethane at -10 C. The reaction mixture was then stirred 17 h at room temperature under nitrogen to give a clear olive-green solution. A portion of the solution of intermediate sulfamolyoxazolidinone was concentrated to give a greenish solid (30 mg) which was taken up in acetonitrile (3 mL) and treated with triethylamine (0.059 mL, 0.42 mmol) and R-(1-benzyl-pyrrolidin-3-yl)-methyl-amine (0.013 mL, 0.046 mmol). The reaction mixture was heated at 70 C. 16 h, then concentrated and purified by reverse phase preparative HPLC to provide 25 mg of the title compound. MS m/e 525; HPLC retention time 2.31 min (Method A). 1H NMR (CD3OD): delta 1.95 (b s, 2H), 2.52 (b s, 2 H), 3.00 (s, 3 H), 3.10-3.40 (b m, 5 H), 4.15 (b s, 2 H), 4.20-4.40 (b m, 2 H), 6.96 (dd, 1 H), 7.20 (d, 1 H), 7.25 (m, 5 H), 7.33 (d, 1 H), 8.31 (s, 1 H), 8.44 (s, 1 H), 8.93 (s, 1 H). 1H NMR (CDCl3): delta 0.83 (t, 3H), 1.3 (dd, 2H), 1.39 (s, 9H), 1.40 (t, 2H), 1.45 (bm, 2H), 1.75 (bs, 2H), 2.1 (bs, 2H), 2.4 (bs, 2H), 2.76 (s, 3H)
The synthetic route of Pyrazine-2-carboxylic acid has been constantly updated, and we look forward to future research findings.
Reference:
Patent; Ngu, Khehyong; Weinstein, David S.; Robl, Jeffrey A.; US2005/70589; (2005); A1;,
Pyrazine – Wikipedia,
Pyrazine | C4H4N2 – PubChem