Urea → HCID 22220352, compound

HRID 1794911Notes

Reaction equation

HRID 1794911 reaction equation
NC(N)=O.S(Cl)(Cl)(=O)=O.Cl.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.[Cl:25][C:26]1[C:27]([O:36][C:37]2[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=2)=[N:28][CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1.C1CCNCC1>C1COCC1.C(Cl)Cl.C(Cl)Cl.C(N(CC)CC)C>[Cl:25][C:26]1[C:27]([O:36][C:37]2[CH:38]=[CH:39][C:40]([S:43]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:19][CH2:20][C:21](=[O:24])[CH2:22][CH2:23]4)=[CH:14][CH:13]=3)(=[O:44])=[O:45])=[CH:41][CH:42]=2)=[N:28][CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=1

Participants

9

Reactant 5

HCID 1176UreaHCID 8082PiperidineHCID 24648Sulfuryl chlorideHCID 27830394-{[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]oxy}benzene-1-sulfonyl chlorideHCID 222202401-(4-Amino-phenyl)-piperidin-4-one hydrochloride

Product 1

HCID 22220352HCID 22220352, compound

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8471TriethylamineSolventHCID 21919333Tetrahydrofurane dichloromethaneSolvent

Procedure

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 (piperidinomethyl)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-piperidin-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, 2 H), 2.50–2.80 (m, 5 H), 3.45–3.60 (m, 2 H), 3.80–4.00 (m, 3 H), 4.95 (brs, 1 H), 5.24 (brs, 1 H), 6.81 (d, J=9.0 Hz, 2 H), 6.88 (d, J=9.0 Hz, 2 H), 6.85–7.00 (m, 3 H), 7.25–7.35 (m, 2 H), 7.41 (d, J=9.0 Hz, 2 H), 7.75 (d, J=9.0 Hz, 2 H), 8.53 (d, J=2.0 Hz, 1 H), 8.62 (d, J=2.0 Hz, 1 H); 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.

Workup

  1. customfor preparing compounds of the present invention in matrix fashion
  2. waitthe reaction was continued for another day
  3. customThe resins were removed by filtration
  4. washwashed with CH2Cl2 (3×1 mL)
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-9dd86603833c4410a3d3d4850bd6d4d6
Source dataset
uspto-grants-2006_04
Patent number
US07022716B2

Reaction notes

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