Trifluoroacetic acid → HCID 57797448, compound

Participants

Reaction Steps

To the solution of 5-(2,4-difluoro-phenoxy)-2-(2-ethoxy-vinyl)-benzoic acid methyl ester 9 (2.09 g, 6.3 mmol) in dichloromethane (20 mL) was added 2 mL of TFA and five drops of water. The reaction was stirred at room temperature for ten minutes, at which time the solvent was removed. The crude reaction mixture was re-suspended in 100 ml of dichloromethane, extracted twice with 50 ml of saturated NaHCO3. The organic layer was dried with sodium sulfate and the solvent removed. The crude intermediate was re-suspended in 100 ml of dichloroethane and added drop wise to a 100 ml solution of dichloroethane containing cyclopropyl(6-vinylpyridin-2-yl)methanamine A20 (1.2 g, 6.9 mmol) and sodium triacetoxyborohydride (3.3 g, 15.7 mmol). The mixture was stirred at 70° C. during the drop wise addition and for additional 2 hours. The reaction was diluted with 500 mL dichloromethane and extracted with saturated brine (300 mL). The organic layer was concentrated and loaded onto a silica gel column and eluted with dichloromethane followed by separation of the enatiomers (AD-H column, 10% IPA/Hex) to give 115 mg of (R)-2-(cyclopropyl(6-vinylpyridin-2-yl)methyl)-7-(2,4-difluorophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 74 as clear oil. The sterochemical configuration was assigned based on the compound 11 TLC, Rf=0.25 (CH2Cl2); Rt=20.2 min (45 min. run, AD-H chiral analalytical column, 1 ml/min, 5% IPA/Hex); 1H NMR (Methanol-D4) δ 7.69 (t, J=7.6, 1H), 7.42 (s, 1H), 7.35 (d, J=7.5, 1H), 7.29 (d, J=7.6, 1H), 7.25 (d, J=8.3, 1H), 7.09 (m, 3H), 6.97 (m, 1H), 6.78 (dd, J=10.7, 17.4, 1H), 6.18 (d, J=17.4, 1H), 5.39 (d, J=10.7, 1H), 4.99 (d, J=10.1, 1H), 3.8 (m, 2H), 2.9 (m, 2H), 1.63 (m, 1H), 0.81 (m, 1H), 0.66 (m, 1H), 0.56 (m, 1H), 0.46 (m, 1H), M+1 found 433.1; C26H22F2N2O2 requires 432.2

Provenance & Evidence