Urea → HCID 22220352, compound

Participants

Reaction Steps

Example 346 illustrated a solution phase combinatorial methodology for preparing compounds of the present invention in matrix fashion. A 3×3 grid of 20 mL Teflon lined screw cap vials was arranged. To each vial was added the amino ketone, the solvents, and the base, then one sulfonyl chloride per row, one arylethanolamine or aryloxypropanolamine per column, was added according to the following detailed procedure: To a suspension of 1-(4-aminophenyl)-4-piperidone hydrochloride (which was obtained in Example 224) (79 mg, 0.3 mmol) in 10 mL of THF/CH2Cl2 (1:1) was added 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)benzenesulfonyl chloride (167 mg,0.45 mmol), triethylamine (0.1 mL), and (piperidineomethyl)polystyrene (462 mg, 2.6 mmol/g). The mixture was shaken for 1 day. Aminomethylated polystyrene resin (95 mg, 2.6 mmol/g) was added to the reaction along with 1 mL of CH2Cl2 and the reaction was continued for another day. The resins were removed by filtration and washed with CH2Cl2 (3×1 mL). The filtrate and washings were combined and concentrated to give 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy) -N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzenesulfonamide which was redissolved in 10 mL of trimethyl orthoformate/methanol (1:1). To the solution was added (2S)-1-amino-3-phenoxy-propan-2-ol (75 mg, 0.45 mmol). The mixture was shaken for 18 hours and then Amberlite IRA-400 borohydride resin (360 mg, 2.5 mmol/g) was added to the mixture and reaction was continued for 5 hours. To the mixture was then added formylpolystyrene (1 g, 0.5 mmol/g) and 1 mL of CH2Cl2. The reaction was continued for 18 hours. The resins were removed by filtration and washing extensively with methanol and CH2Cl2. The filtrate and washings were combined and concentrated. The residue was purified by thin layer chromatography (12% MeOH/CH2Cl2) to give the title compound as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.70-1.90 (m, 2H), 2.50-2.80 (m, 5H), 3.45-3.60 (m, 2H), 3.80-4.00 (m, 3H), 4.95 (brs, 1H), 5.24 (brs, 1H), 6.81 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 6.85-7.00 (m, 3H), 7.25-7.35 (m, 2H), 7.41 (d, J=9.0 Hz, 2H), 7.75 (d, J=9.0 Hz, 2H), 8.53 (d, J=2.0 Hz, 1H), 8.62 (d, J=2.0 Hz, 1H); MS (ES) m/z: 677.0 (MH+); HRMS Calcd. for C32H33F3N4O5SCl (MH+): 677.1812. Found: 677.1816. Anal. Calcd. for C32H32F3N4O5SCl: C, 56.70; H, 4.76; N, 8.27. Found: C, 56.58; H, 4.90; N, 8.03.

Provenance & Evidence