4-Methylmorpholine → (2E)-2-(3-chloro-4-methylsulfonylphenyl)-2-cyclopentyloxyimino-N-pyrazin-2-ylacetamide

Participants

Reaction Conditions

Reaction Steps

(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 97 mg, 0.28 mmol), pyrazin-2-ylamine (29 mg, 0.31 mmol) and 4-methylmorpholine (123 μL, 1.12 mmol) were combined in N,N-dimethylformamide (1.5 mL) and cooled to 0° C. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (117 mg, 0.31 mmol) was added and the ice bath was removed. After stirring 16 h, further portions of pyrazin-2-ylamine (10 mg, 0.11 mmol), 4-methylmorpholine (41 μL, 0.37 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (39 mg, 0.10 mmol) were added. After stirring an additional 3 h, the reaction mixture was treated with ethyl acetate (100 mL) and saturated aqueous brine solution (200 mL). The phases were separated and the organic phase was washed with a 0.2 M aqueous potassium bisulfate solution and saturated aqueous brine solution (50 mL) and a 1:1 mixture of saturated aqueous sodium bicarbonate solution and saturated aqueous brine solution (50 mL) then dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-pyrazin-2-yl-acetamide (62 mg, 52%) as a clear, colorless film which was then lyophilized from aqueous acetonitrile to afford a white solid: LC-MS (ESI) m/e calcd for C18H19ClN4O4S [M+] 422.08, found 423 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.68 (m, 4 H, 2×CH2), 1.91 (m, 4 H, 2×CH2), 3.32 (s, 3 H, SO2CH3), 4.98 (m, 1 H, OCH), 7.57 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.68 (d, Jm=1.5 Hz, 1 H, Ar), 8.22 (d, Jo=8.2 Hz, 1 H, Ar), 8.33 (m, 1 H, Ar), 8.41 (m, 1 H, Ar), 9.29 (brs, 1 H, Ar), 9.56 (s, 1 H, NH).

Provenance & Evidence