(5-CHLOROPYRAZIN-2-YL)METHANOL

(5-chloropyrazin-2-yl)methyl methanesulfonate; [00369] To a solution of 5-chloropyrazine-2-carboxylic acid (3.21 g, 20.3 mmol) in diethyl ether (20 mL) and methanol (20.0 mL) was added a 2M solution in diethyl ether of trimethylsilyldiazomethane (20.3 mL, 40.5 mmol). A vigorous bubbling was observed initially, and LCMS after 30 minutes indicated that the reaction was complete.Concentration of the reaction mixture afforded methyl 5-chloropyrazine-2-carboxylate (3.53 g, 20.5 mmol, 101percent yield) as a tan solid. This material was shown to be >95percent pure by NMR analysis and was used in the subsequent step without any purification. To a solution of methyl 5-chloropyrazine-2-carboxylate (8.00 g, 46.40 mmol) in THF (100 mL) was added NaBH4 (3.51 g, 93.00 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0 °C for 5 h. The reaction was quenched with water (200 mL) and extracted with ethyl acetate ( 3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Redisep-40 g, 30-40percent EtOAc/n-hexane) to obtain Intermediate 112A (2.00 g, 29.80percent) as a yellow solid.Diisobutylaluminum hydride (4.29 mL, 4.29 mmol) was added dropwise over 5 min to a solution of methyl 5-chloropyrazine-2-carboxylate (185 mg, 1.07 mmol) in tetrahydrofuran (10 mL) at -70 . (5-Chloropyrazin-2-yl)methanol (0.3 g, 1 eq., 2.08 mmol) and iodoethane (0.17 mL, 1 eq., 2.08 mmol) were dissolved in THF (10 mL) and the solution was cooled to 0C. Sodium hydride (0.25 g, 3 eq., 6.24 mmol) was then added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with a saturated solution of NHCO3 (15 mL) and extracted with EtOAc (215 mL). The organic extracts were dried over Na2SO4 and concentrated in vacuo to furnish the crude product, which was purified by flash chromatography eluting with cyclohexane/EtOAc (0 to 80%) to give the pure title compound as colourless oil (0.03 g, 9%). UPLC-MS (method A): Rt. 1.69 min (TIC); ionization ES+173 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.77 (d, J=1.4 Hz, 1H), 8.53 (d, J=1.3 Hz, 1H), 4.62 (s, 2H), 3.59 (q, J=7.0 Hz, 2H), 1.19 (t, J=7.0 Hz, 3H).To a solution of Intermediate 112A (2.00 g, 13.84 mmol) in CHCl3 (20 mL) was added active manganese dioxide (4.81 g, 55.3 mmol) and the resulting suspension was refluxed for 2 h. The reaction mixture was cooled to ambient temperature, filtered through Celite and washed with CHCl3 (200 mL). The combined filtrates were washed with brine (200 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Redisep-24 g, 20-30 % EtOAc/ n-hexane) to obtain Intermediate 112B (1.00 g, 50.70%) as a white solid.1H NMR (400 MHz, DMSO-d6) delta ppm 8.98 (d, J = 1.51 Hz, 1 H), 9.04 (d, J = 1.51 Hz, 1 H), 10.07 (s, 1 H). LCMS: The compound did not ionize well. (780 mg, 5.40 mmol), ethyl 4-pyrazolecarboxylate(765 mg, 5.46 mmol) and potassium carbonate (283 mg, 2.05 mmol) andtriphenylphosphine (1.57 g, 6.01 mmol) are suspended in anhydrous tetrahydrofuran(20 mL) and cooled to 000. Diisopropyldicarboxylate (1.18 mL, 6.01 mmol) is added, the mixture allowed to warm to room temperature and stirred for three hours. The solvent is evaporated and the residue partitioned between dichloromethane and water and the phases separated. The organic extracts are washed with brine, dried over sodium sulfate and the solvent removed under vacuum. The residue is purifiedby flash chromatography (30-50% ethyl acetate in cyclohexane) to give the desired intermediate as an impure product (Yield 2.12 g).LC (Method 5): tR = 0.95 mm; Mass spectrum (ES+): mlz = 267 [M+H].To a stirred solution of

Molecular Weight:144.56
XLogP3:-0.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:144.0090405
Monoisotopic Mass:144.0090405
Topological Polar Surface Area:46
Heavy Atom Count:9
Complexity:91
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes