1-溴-3-(2-甲基丙-2-磺酰基)丙

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 6-butyl-8-[(3R)-3-pyrrolidinyloxy]quinoline (for example, as prepared for Intermediate 10) (0.130 g, 0.481 mmol), in DMF (3 ml) was added a mixture of 3-bromopropyl 1,1-dimethylethyl sulfone and 3-chloropropyl 1,1-dimethylethyl sulfone (for example, as prepared for Intermediate 17) (1:1, 0.215 g, 0.96 mmol), sodium iodide (0.144 g, 0.96 mmol), then potassium carbonate (0.133 g, 0.96 mmol). The suspension was heated to 150° C. for 15 min in a Smith Creator™ microwave oven with fixed hold time on. The mixture was applied to an SCX-2 cartridge (20 g), preconditioned with methanol, and the cartridge washed with methanol (2 column volumes). The cartridge was eluted with 10% 0.88 s.g. ammonia in methanol (2 column volumes) and the basic fraction concentrated in vacuo. The residue (0.2 g) was purified by MDAP and the appropriate fractions combined and concentrated in vacuo. The residue (0.113 g) was further purified by Flashmaster II chromatography (50 g cartridge) eluting with 0-25% methanol in DCM over 40 min. The appropriate fractions were combined and the solvent removed in vacuo (70 mg, 33%). To a portion of this material (29 mg, 0.067 mmol) in methanol (0.5 ml) was added 1.25 M hydrogen chloride in methanol (0.3 ml). The solvent was removed using a stream of nitrogen to leave the title compound as white solid (34 mg). LCMS RT=2.97 min, ES+ve m/z 433 (M+H)+. the cartridge washed with methanol (2 column volumes) The cartridge was eluted with 10% 0.88 s ammonia in methanol (2 column volumes) and the basic fraction concentrated in vacuo The residue (0.2 g) was purified by MDAP concentrated in vacuo The residue (0.113 g) was further purified by Flashmaster II chromatography (50 g cartridge) eluting with 0-25% methanol in DCM over 40 min the solvent removed in vacuo (70 mg, 33%) The solvent was removed

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared for Intermediate 4) (28 mg, 0.10 mmol), sodium iodide (34 mg, 0.23 mmol) and sodium bicarbonate (60 mg, 0.7 mmol) was treated with a mixture of 3-bromopropyl 1,1-dimethylethyl sulfone and 3-chloropropyl 1,1-dimethylethyl sulfone (for example, as prepared for Intermediate 17) (1:1, 40 mg) in DMF (1.5 ml) and heated to at 150° C. for 15 min in a Smith Creator™ microwave oven. The reaction mixture was applied to an SCX-2 cartridge (10 g), preconditioned with methanol, and eluted with methanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol. The ammoniacal fractions were combined and concentrated in vacuo and the residue was purified by MDAP to give the title compound (20 mg, 40%): LCMS RT=2.76 min, ES+ve m/z 447 (M+H)+; 1H NMR δ (CD3OD) 8.78 (1H, dd, J=4, 2 Hz), 8.44 (1.6H, s), 8.24 (1H, dd, J=8, 2 Hz), 7.52 (1H, dd, J=8, 4 Hz), 7.32 (1H, br s), 7.19 (1H, br s), 5.03-4.96 (1H, m), 3.68-3.59 (2H, m), 3.40-3.26 (4H, obscured by CD3OD), 3.22 (2H, t, J=7 Hz), 2.79 (2H, t, J=7 Hz), 2.35-2.21 (6H, m), 1.75-1.67 (2H, m), 1.45-1.35 (2H, m), 1.40 (9H, s), 0.96 (3H, t, J=7 Hz). eluted with methanol followed by 10% aqueous 0.88 s concentrated in vacuo the residue was purified by MDAP