(5-CHLOROPYRAZIN-2-YL)METHANOL Chemical Properties

Melting point:

62-63 °C

Boiling point:

255.7±35.0 °C(Predicted)

Density 

1.422±0.06 g/cm3(Predicted)

storage temp. 

under inert gas (nitrogen or Argon) at 2-8°C

pka

12.39±0.10(Predicted)

Appearance

Off-white to light yellow Solid

Safety Information

HS Code 

2933399990

(5-CHLOROPYRAZIN-2-YL)METHANOL Usage And Synthesis

Synthesis

1. Methylation reaction: 5-chloropyrazine-2-carboxylic acid (3.21 g, 20.3 mmol) was dissolved in a solvent mixture of ether (20 mL) and methanol (20.0 mL), and 2M trimethylsilyl diazomethane ether solution (20.3 mL, 40.5 mmol) was added slowly. Intense bulging was observed at the beginning of the reaction, and the completion of the reaction was confirmed by LCMS analysis after 30 min. The reaction mixture was concentrated to give methyl 5-chloropyrazine-2-carboxylate (3.53 g, 20.5 mmol, 101% yield) as a tan solid.NMR analysis showed that the product was >95% pure and could be used directly in the next step of the reaction.1H NMR (400 MHz, CDCl3) δ (ppm): 9.09 (s, 1H), 8.70 (s, 1H), 4.04 (s, 3H). 4.04 (s, 3H). 2. 2. Reduction reaction: To a solution of methyl 5-chloropyrazine-2-carboxylate (3.50 g, 20.3 mmol) in tetrahydrofuran (101 mL) was added dropwise 1M diisobutylaluminum hydride in tetrahydrofuran (42.6 mL, 42.6 mmol) at 0 °C. The reaction was stirred for 2 hours. The reaction was stirred at 0 °C for 2 h and then quenched by the addition of methanol (2 mL). Subsequently, saturated potassium sodium tartrate solution was added and the reaction mixture was extracted with ethyl acetate (3 x 100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a brown residue. Purification by silica gel column chromatography (Luknova 120 g, 20 mL/min) with an elution gradient of 30 to 100% ethyl acetate in hexane solution over 60 min gave (5-chloropyrazin-2-yl)methanol (1.45 g, 10.0 mmol, 50% yield) as a tan solid.1H NMR (400 MHz, CDCl3) δ (ppm): 8.56 (s, 1H NMR): 8.56 (s, 1H NMR). ): 8.56 (s, 1H), 8.45 (s, 1H), 4.84 (s, 2H), 2.79 (br.s, 1H). 3. Methylsulfonylation: To a solution of (5-chloropyrazin-2-yl)methanol (648 mg, 4.48 mmol) in dichloromethane (12 mL) was added triethylamine (1.87 mL, 13.5 mmol) followed by dropwise addition of methanesulfonyl chloride (0.699 mL, 8.97 mmol) at 0 °C. After 20 min, LCMS analysis showed the reaction was completely converted to the methanesulfonate product. The reaction mixture was concentrated to afford (5-chloropyrazin-2-yl) methyl methanesulfonate (787 mg, 3.53 mmol, 79% yield) as an oil, which could be used in subsequent steps without further purification.

References

[1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 23, p. 5674 - 5678
[2] Patent: WO2012/88469, 2012, A1. Location in patent: Page/Page column 151-152
[3] Patent: WO2018/93569, 2018, A1. Location in patent: Page/Page column 195; 196
[4] Patent: WO2008/130320, 2008, A2. Location in patent: Page/Page column 151
[5] Patent: WO2012/81736, 2012, A1. Location in patent: Page/Page column 44

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