4-Bromobutyryl chloride → N-[4-(3-Piperidin-1-ylpropoxy)-benzoyl]-5-(2-oxo-pyrrolidin-1-yl)-isoindoline hydrochloride

Participants

Reaction Steps

A stirred mixture of diethylaminomethyl polystyrene (247 mg, 3.2 mmol/g) and N-[4-(3-piperidin-1-ylpropoxy)-benzoyl]-5-aminoisoindoline hydrochloride (E13) (150 mg) in DCM (5 ml) at rt was treated with 4-bromobutanoyl chloride (0.05 ml) for 30 mins. The mixture was filtered and evaporated. The residue was redissolved in DMF (5 ml) and treated with sodium hydride (18 mg of a 60% suspension in mineral oil) and stirred for 2 h. A further portion of sodium hydride (18 mg) was added and the mixture stirred for 1 h. The reaction was partitioned between EtOAc (10 ml) and saturated sodium hydrogen carbonate solution (10 ml). The organic layer was washed with water (2×10 ml), brine (10 ml), dried (MgSO4) and evaporated. After chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM)] fractions containing the required product were evaporated, then redissolved in DCM, treated with excess 4M HCl in dioxan and evaporated. Crystallisation from EtOH/diethyl ether afforded the title compound (E15) (77 mg). MS electrospray (+ion) 448 (MH+). 1H NMR δ (DMSO-d6): 10.15 (1H, s), 7.60 (4H, m), 7.34 (1H, m), 7.0 (2H, d, J=8.5 Hz), 4.80 (4H, m), 4.13. (2H, t, J=6 Hz), 3.80 (2H, m), 3.05-3.58 (6H, m), 2.91 (2H, m), 2.21 (2H, m), 2.06 (2H, m), 1.28-1.90 (6H, m).

Provenance & Evidence