Sodium hydride → HCID 58438400, compound

HRID 1971985Notes

Reaction equation

HRID 1971985 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:12]1[N:17]=[N:16][C:15]([CH:18]2[CH2:20][CH2:19]2)=[C:14]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:23][CH:22]=2)[CH:13]=1>C1COCC1>[CH:28]1([O:27][C:24]2[CH:25]=[CH:26][C:21]([C:14]3[CH:13]=[C:12]([O:8][CH:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[N:17]=[N:16][C:15]=3[CH:18]3[CH2:19][CH2:20]3)=[CH:22][CH:23]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 660484-Piperidinol, 1-methyl-HCID 86657817HCID 86657817, compound

Product 1

HCID 58438400HCID 58438400, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a stirred solution of 1-methyl-piperidin-4-ol (0.50 mmol, 0.06 g) in THF (1 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (0.75 mmol, 0.03 g) and continued stirring for 15 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 6-chloro-4-(4-cyclohexyloxy-phenyl)-3-cyclopropyl-pyridazine (0.25 mmol, 0.082 g) in THF (0.5 mL). After completion of addition, the reaction mixture was warmed to 50° C. and stirred for 2 hours. After cooling the reaction to room temperature, the reaction was quenched with water (1 mL) and extracted with ethyl acetate (1×5 mL). The ethyl acetate layer was washed with brine (2 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on 4 g SiO2 cartridge 4-6% (2N NH3 in MeOH) in DCM to give 4-(4-cyclohexyloxy-phenyl)-3-cyclopropyl-6-(1-methyl-piperidin-4-yloxy)-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (0.5 mL) and DCM (0.5 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.030 g). LCMS: m/z 409 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.48-7.58 (2H, m), 7.30-7.48 (1H, m), 7.04-7.14 (2H, m), 5.30-5.54 (1H, m), 4.37-4.48 (1H, m), 3.60-3.70 (1H, m), 3.14-3.51 (3H, m), 2.93 (3H, s), 2.54 (1H, d), 2.41 (1H, d), 2.16-2.31 (2H, m), 1.96-2.10 (3H, m), 1.76-1.89 (2H, m), 1.27-1.67 (6H, m), 1.09-1.24 (4H, m).

Workup

  1. additionAfter completion of addition
  2. temperaturethe reaction mixture was warmed to 50° C.
  3. stirringstirred for 2 hours
  4. temperatureAfter cooling
  5. customthe reaction to room temperature
  6. customthe reaction was quenched with water (1 mL)
  7. extractionextracted with ethyl acetate (1×5 mL)
  8. washThe ethyl acetate layer was washed with brine (2 mL)
  9. dry with materialdried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe residue was purified on 4 g SiO2 cartridge 4-6% (2N NH3 in MeOH) in DCM

Sources & evidence

ORD record
ord-c97f544f8fe6429280a534deb6382d9f
Source dataset
uspto-grants-2013_04
Patent number
US08431575B2

Reaction notes

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