反应详情

6-Fluoro-2-methyl-3-((3R,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)benzonitrile 2,2,2-trifluoroacetate (1404 mg, 3.610 mmol) was suspended in DCM (20 mL) then TEA (2.011 ml, 14.43 mmol) was added. The mixture was stirred for 5 min, and then HOBT (828 mg, 5.41 mmol), 2-(5-(1H-tetrazol-1-yl)pyridin-2-yl)acetic acid (740 mg, 3.61 mmol), and EDC (1383 mg, 7.21 mmol) were added and the resulting mixture was stirred for 2 h. The reaction was poured into a brine/NaHCO3 mixture. The DCM layer was separated and dried over Na2SO4 then filtered and concentrated. The residue was purified by chromatography using 120 g ISCO Redisep column eluting with a 5% (NH4OH: MeOH 1:9)/95% DCM solvent system to yield 3-((3R,9aS)-8-(2-(5-(1H-tetrazol-1-yl)pyridin-2-yl)acetyl)octahydropyrazino[2,1-c][1,4]oxazin-3-yl)-6-fluoro-2-methylbenzonitrile: LC-MS: M+1=463: 1H-NMR (600 MHz, CDCl3) δ ppm 9.10 (s, 0.5H), 9.084 (s, 0.5H), 8.919 (dd, J=14.4, 2.5 Hz, 1H), 8.053 (m, 1H), 7.681 (m, 1H), 7.609 (t, J=8.25 Hz, 1H), 7.048 (t, J=8.5 Hz, 1H), 4.785 (d, J=10.1 Hz, 1H), 4.587 (d, J=13.2 Hz, 0.5H), 4.484 (d, J=12.8 Hz, 0.5H), 3.947-4.095 (m, 4H), 3.497 (t, J=11 Hz, 0.5H), 3.477 (t, J=11.1 Hz, 0.5H), 3.384 (t, J=12.6 Hz, 0.5H), 2.94-2.875 (m, 1H), 2.83-2.777 (m, 2H), 2.548 (s, 3H), 2.409 (t, J=11.2 Hz, 0.5H), 2.251-2.16 (m, 2H), 2.129-2.084 (m, 1H).

1. stirringthe resulting mixture was stirred for 2 h
2. customThe DCM layer was separated
3. dry with materialdried over Na2SO4
4. filtrationthen filtered
5. concentrationconcentrated
6. customThe residue was purified by chromatography
7. washeluting with a 5% (NH4OH: MeOH 1:9)/95% DCM solvent system