Thiophenol → 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol

HRID 1027167Notes

Reaction equation

HRID 1027167 reaction equation
C1(S)C=CC=CC=1.C[O:9][C:10]1[CH:15]=[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[CH:13]=[CH:12][C:11]=1[C:21]1[N:26]=[N:25][C:24]([N:27]([CH3:38])[CH:28]2[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]2)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:38][N:27]([CH:28]1[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]1)[C:24]1[N:25]=[N:26][C:21]([C:11]2[CH:12]=[CH:13][C:14]([N:16]3[CH:20]=[CH:19][CH:18]=[N:17]3)=[CH:15][C:10]=2[OH:9])=[CH:22][CH:23]=1

Participants

5

Reactant 3

HCID 7969ThiophenolHCID 11430Potassium CarbonateHCID 867105586-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

Product 1

HCID 1362530412-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
190 °C

Procedure

As described in GENERAL METHOD 3-1, thiophenol (0.127 mL, 1.24 mmol) was added to a microwave vial containing 6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (520 mg, 1.24 mmol) and K2CO3 (171 mg, 1.24 mmol) in NMP (5 mL). The microwave vial was evacuated and filled with N2 (2×). The reaction mixture was heated in the microwave at 190° C. for 30 min. The reaction mixture was filtered through celite (pre-packed filter funnel) washing with MeOH. The filtrate was acidified to pH 3 using 1 M HCl aqueous solution and then adsorbed onto a methanol conditioned SCX (10 g) column. The column was washed several times with methanol then eluted with 2 N ammonia in methanol solution. The product was collected and concentrated in vacuo to afford the crude product which was purified by preparative HPLC under basic conditions to provide 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol (198 mg, MS: 407.25 [M+H+], LC/MS Rt=0.53 min (LCMS method Q); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.86 (d, J=2.02 Hz, 1H), 7.71 (d, J=10.11 Hz, 1H), 7.63 (d, J=1.52 Hz, 1H), 7.54 (d, J=8.59 Hz, 1H), 7.21-7.30 (m, 2H), 6.91 (d, J=9.60 Hz, 1H) 6.31-6.41 (m, 1H), 4.76-4.95 (m, 1H), 2.89-3.01 (m, 3H), 1.62 (dd, J=12.13, 3.54 Hz, 2H), 1.34 (br. s, 2H), 1.27 (s, 6H), 1.10 (s, 6H).

Workup

  1. additionwas added to a microwave vial
  2. customThe microwave vial was evacuated
  3. additionfilled with N2 (2×)
  4. filtrationThe reaction mixture was filtered through celite (pre-packed filter funnel)
  5. washwashing with MeOH
  6. washThe column was washed several times with methanol
  7. washthen eluted with 2 N ammonia in methanol solution
  8. customThe product was collected
  9. concentrationconcentrated in vacuo
  10. customto afford the crude product which
  11. customwas purified by preparative HPLC under basic conditions

Sources & evidence

ORD record
ord-f92a2a8b5ea643a4ac1fedd09c701e36
Source dataset
uspto-grants-2014_05
Patent number
US08729263B2

Reaction notes

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