Reaction Steps
To a stirred solution of all-trans retinoic acid (ATRA) (130 mg, 0.43 mmol) in a mixture of DMF (1 ml) and DCM (6.5 ml) at 0° C. under nitrogen was added dropwise oxalyl chloride (76 μl, 0.87 mmol). The reaction mixture was stirred at rt for 50 min. DCM was removed under reduced pressure (no heat!) and the remaining solution was diluted with DMF (2 ml). To a stirred solution of 49 (150 mg, 0.29 mmol) and triethylamine (120 μl, 0.87 mmol) in DMF (5 ml) at 0° C. under nitrogen was slowly added the solution of the acyl chloride intermediate. After one hour, the reaction mixture at 0° C. was quenched by addition of water. The resulting suspension was shaken then the solid was collected by filtration, rinsed with water and air-dried. The crude material was purified twice by Biotage (Snap 25 g cartridge; MeOH/DCM: 0/100 to 5/95 over 30 CV, then 05/95 to 10/90 over 10 CV; Snap 25 g cartridge; MeOH/DCM: 1/99 to 10/90 over 30 CV). The desired fractions were combined and concentrated. The residue was dissolved in MeOH, concentrated until precipitation was occurred. The solid was collected by filtration, rinsed with MeOH and dried to afford the desired product 548 (56 mg, 0.07 mmol, 24% yield) as a bright yellow fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.72 (s, 1H), 8.57 (bd, J=1.8 Hz, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.34 (s, 1H), 8.26 (d, J=8.2 Hz, 1H), 7.88 (dd, J=8.2, 1.9 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.1 Hz, 1H), 7.19 (dd, J=9.0, 1.4 Hz, 1H), 6.82 (dd, J=15.3, 11.3 Hz, 1H), 6.65 (dd, J=5.5, 0.8 Hz, 1H), 6.59 (bd, J=2.5 Hz, 1H), 6.39 (d, J=15.1 Hz, 1H), 6.25-6.10 (m, 4H), 3.60 (s, 2H), 3.57-3.43 (m, 4H), 2.59-2.51 (m, 1H), 2.45-2.34 (m, 4H), 2.04-1.96 (m, 5H), 1.95 (s, 3H), 1.68 (s, 3H), 1.61-1.52 (m, 2H), 1.46-1.40 (m, 2H), 1.00 (s, 6H), 0.72-0.58 (m, 2H), 0.49-0.36 (m, 2H). MS (m/z): 801.8 (M+H).
