tert-Butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate → 4-[6-Butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester

HRID 401955Notes

Reaction equation

HRID 401955 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:16])([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[CH2:23]([C:27]1[N:28]=[N:29][C:30](Cl)=[CH:31][C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:35][CH:34]=1)[CH2:24][CH2:25][CH3:26]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][O:15][C:30]2[N:29]=[N:28][C:27]([CH2:23][CH2:24][CH2:25][CH3:26])=[C:32]([C:33]3[CH:34]=[CH:35][C:36]([O:39][CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)=[CH:37][CH:38]=3)[CH:31]=2)([F:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 22248400tert-Butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylateHCID 23665647Potassium tert-butoxideHCID 866577793-Butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine

Product 1

HCID 673744624-[6-Butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-fluoro-piperidine-1-carboxylic acid tert-butyl esterYield 33.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirred solution of 4-fluoro-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.5 mmol, 0.116.g) in THF (2 mL) at room temperature was added potassium tert-butoxide (0.5 mmol, 0.5 mL, 1M solution in THF) and continued stirring for 30 min. 3-Butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 0.5 mmol, 0.172 g) was taken THF (1 mL) and added to the reaction and stirred for 10 h at room temperature. The reaction was quenched with slow addition of water (2 mL) and the product was extracted with ethyl acetate (2×5 mL), Organic layer was washed with water (5 mL), brine (5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a SiO2 cartridge with 30% ethyl acetate in hexanes to provide 4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester (90 mg).

Workup

  1. additionadded to the reaction
  2. stirringstirred for 10 h at room temperature
  3. customThe reaction was quenched with slow addition of water (2 mL)
  4. extractionthe product was extracted with ethyl acetate (2×5 mL), Organic layer
  5. washwas washed with water (5 mL), brine (5 mL)
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified on a SiO2 cartridge with 30% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-a03ce73345a14e64918c814a2484c318
Source dataset
uspto-grants-2014_06
Patent number
US08741900B2

Reaction notes

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