1,4-Dioxane → HCID 136377181, compound

HRID 1027292Notes

Reaction equation

HRID 1027292 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1.FC(F)(F)S(O[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[N:32][C:33]([N:36]([CH3:47])[CH:37]3[CH2:42][C:41]([CH3:44])([CH3:43])[NH:40][C:39]([CH3:46])([CH3:45])[CH2:38]3)=[CH:34][CH:35]=2)=[C:26]([OH:48])[CH:25]=1)(=O)=O.C(=O)(O)[O-].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:31]=[N:32][C:33]([N:36]([CH3:47])[CH:37]4[CH2:42][C:41]([CH3:43])([CH3:44])[NH:40][C:39]([CH3:46])([CH3:45])[CH2:38]4)=[CH:34][CH:35]=3)=[C:26]([OH:48])[CH:25]=2)[CH:6]=[N:5][CH:4]=1

Participants

7

Reactant 4

HCID 312751,4-DioxaneHCID 516892Sodium BicarbonateHCID 38661613-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineHCID 136377155HCID 136377155, compound2×

Product 1

HCID 136377181HCID 136377181, compoundYield 60%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

Following GENERAL METHOD 1-3 for Suzuki Coupling, to a 25 mL microwave vial, was added 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (94 mg, 0.400 mmol), 3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl trifluoromethanesulfonate (Intermediate 9-2, 105 mg, 0.2 mmol), sodium bicarbonate (50.4 mg, 0.600 mmol) and Pd(PPh3)4 (11.56 mg, 10.00 μmol), followed by dioxane (2 mL) and water (0.5 mL). The reaction mixture was purged with N2 for 10 minutes, and heated in a microwave at 100° C. for 1 h, then diluted with EtOAc and filtered through celite. The filtrate was acidified to pH ˜3 with 1N HCl, and loaded onto an SCX column. The column was washed with MeOH, and eluted with 2N NH3 in MeOH. After concentration, the residue was purified by preparative HPLC to provide 5-(5-methoxypyridin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol (55 mg, 0.120 mmol, 60% yield), LCMS: Rt=0.50 min [Method Q]; MS (M+1)=448.4; 1H NMR (METHANOL-d4) δ 8.17 (d, J=5.1 Hz, 1H), 8.11 (d, J=9.1 Hz, 1H), 7.85 (d, J=7.1 Hz, 1H), 7.22-7.33 (m, 4H), 7.06 (s, 1H), 5.10 (m, 1H), 3.97 (s, 3H), 3.03 (s, 3H), 1.74 (dd, J=12.6, 3.0 Hz, 2H), 1.59 (t, J=12.4 Hz, 2H), 1.42 (s, 6H), 1.26 (s, 6H).

Workup

  1. customThe reaction mixture was purged with N2 for 10 minutes
  2. additiondiluted with EtOAc
  3. filtrationfiltered through celite
  4. washThe column was washed with MeOH
  5. washeluted with 2N NH3 in MeOH
  6. concentrationAfter concentration
  7. customthe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-e23c937a15354f52873431ec998b906b
Source dataset
uspto-grants-2014_05
Patent number
US08729263B2

Reaction notes

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