Sodium hydride → HCID 67374486, compound

HRID 1971989Notes

Reaction equation

HRID 1971989 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[N:23]=[N:22][C:21]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:20]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:32][CH:31]=2)[CH:19]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[N:23]=[N:22][C:21]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[C:20]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:34][CH:35]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 643502Tert-butyl 4-hydroxypiperidine-1-carboxylateHCID 86657818HCID 86657818, compound

Product 1

HCID 67374486HCID 67374486, compoundYield 83%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.40 mmol, 0.08 g) in THF (0.45 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (0.54 mmol, 0.022 g) and continued stirring for 10 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 6-chloro-3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-pyridazine (0.27 mmol, 0.10 g) in THF (0.45 mL). After completion of addition, the reaction mixture was warmed to 65° 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 (1×2 mL). The ethyl acetate layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 4 g SiO2 cartridge eluting with an ethyl acetate/hexanes gradient to give 4-[6-cyclohexyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 81%). To a solution of 4-[6-cyclohexyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.22 mmol, 0.12 g) in DCM (1.5 mL) was added 4 N HCl in dioxane (0.5 mL) and the reaction was stirred for 30 min. The solvents were removed under reduced pressure and the residue was triturated with anhydrous ethyl ether (50 mL) and filtered to give 3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.095 g).

Workup

  1. additionAfter completion of addition
  2. temperaturethe reaction mixture was warmed to 65° 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 (1×2 mL)
  8. dry with materialThe ethyl acetate layer was dried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was purified on a 4 g SiO2 cartridge
  12. washeluting with an ethyl acetate/hexanes gradient

Sources & evidence

ORD record
ord-d02dce9564c0463983903d3b17676a78
Source dataset
uspto-grants-2013_04
Patent number
US08431575B2

Reaction notes

Loading…