Sodium hydride → HCID 86657812, compound

HRID 2168692Notes

Reaction equation

HRID 2168692 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH:14]([F:16])[F:15])[C@H:10]([OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:20]([C:24]1[N:25]=[N:26][C:27](Cl)=[CH:28][C:29]=1[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:32][CH:31]=1)[CH2:21][CH2:22][CH3:23]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH:14]([F:15])[F:16])[C@H:10]([O:17][C:27]2[N:26]=[N:25][C:24]([CH2:20][CH2:21][CH2:22][CH3:23])=[C:29]([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:28]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 866577793-Butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazineHCID 86657810HCID 86657810, compound

Product 1

HCID 86657812HCID 86657812, compoundYield 74.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a stirred solution of (±)-trans-4-difluoromethyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.52 mmol, 0.13 g) in anhydrous THF (1 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (1.08 mmol, 0.043 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 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 0.43 mmol, 0.15 g) in anhydrous THF (1 mL). After completion of addition, the reaction mixture was warmed to room temperature and stirred for 12 hours. The reaction was quenched with water (2 mL). The reaction was then extracted with ethyl acetate (5 mL). The ethyl acetate layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 12 g SiO2 cartridge using a gradient of ethyl acetate/hexanes to give (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-4-difluoromethyl-piperidine-1-carboxylic acid tert-butyl ester (0.18 g). LCMS: m/z 561 [M+1].

Workup

  1. additionAfter completion of addition
  2. temperaturethe reaction mixture was warmed to room temperature
  3. stirringstirred for 12 hours
  4. customThe reaction was quenched with water (2 mL)
  5. extractionThe reaction was then extracted with ethyl acetate (5 mL)
  6. dry with materialThe ethyl acetate layer was dried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified on a 12 g SiO2 cartridge

Sources & evidence

ORD record
ord-88be921b2afb41f995f06783e05da7e3
Source dataset
uspto-grants-2015_06
Patent number
US09045461B2

Reaction notes

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