Reaction Steps
A solution of (4-bromo-8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-yl)-carbamic acid tert-butyl ester (100.0 mg, 0.2694 mmol) in trifluoroacetic acid (1 mL) was stirred at r.t. for 40 min and evaporated. LC-MS 07-07-2008 12-11-51.wiff:ca 2:1 mixture of the desired intermediate 2-amino-4-bromo-8-fluoro-3-methyl-2H-isoquinolin-1-one [B] (tR=1.01, m/z MH+271.3 & 273.3) and presumably its trifluoroacetyl derivative (tR=1.19, m/z MH+ 367.2 & 369.2). Alternatively, deprotection of BOC group was successfully carried out in conc. HCl solution in methanol under reflux (5 min). It was mixed with 2 ml methanol, 0.3 ml 20% KOH in water, refluxed for 5 min, allowed to cool and quenched with water (3 ml). The precipitate was filtered to 46.2 mg of pale yellow solid as 4:1 mixture of the above compounds. It was suspended in MeOH (3 ml), acetaldehyde (0.20 mL, 3.6 mmol) was added, followed by sodium cyanoborohydride (100.0 mg, 1.591 mmol) and acetic acid (0.4 mL, 7 mmol). It was stirred for 90 min and diluted with 5% aq. KOH (10 ml), allowed to stir for 20 min and filtered to give 20 mg of the title product. LC-MS (m/z) 299.4 & 301.4 (MH30), tR=1.42. 1H NMR (CDCl3, TMS=0 ppm): 1.21 (t, J=7.2 Hz, 3H, Et), 2.77 (overlapping s, 3H, Me), 2.68-3.2 (overlapping very br. d, 2H, Et), 5.89 (t, J=6.8 Hz, 1H, NH), 7.13 (dd, J=8.3, J (HF)=10.9, 1H, C7H), 7.63 (dt, J (d, H—F)=5.05 Hz, J (t)=8.1 Hz, 1H, C6H), 7.74 (d, J=8.3 Hz, 1H, C5H). 13C APT (CDCl3=77.44 ppm): 13.0 (Me of Et), 19.95 (Me), 46.26 (CH2), 99.72 (d, J (C—F)=3.5 Hz, C), 113.78 (d, J (C—F)=21.7 Hz, C7H), 122.24 (d, J (C—F)=4.1 Hz, C5H), 134.03 (d, J (C—F)=10.2 Hz, C6H), 138.02 (C), 142.16 (C3), 158.7 (d, J (C—F)=4.6 Hz, C), 162.56 (d, J (C—F)=264 Hz, C8F). 19F NMR (CFCl3=0 ppm): −110.92 (dd, J=4.5 Hz, J=10.9 Hz).
