Water → Tert-butyl 4-(4-ethoxy-4-oxobutyl)piperidine-1-carboxylate

HRID 2376842Notes

Reaction equation

HRID 2376842 reaction equation
C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)(=O)=O)=CC=1.C(OCC)(=O)[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].[O-]CC.[Na+].[Cl-].[NH4+].[Cl-].[Li+].O>C(O)C>[CH2:32]([O:31][C:29]([CH2:28][CH2:11][CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]1)=[O:30])[CH3:33]

Participants

8

Reactant 6

HCID 962WaterHCID 7761Diethyl MalonateHCID 25517Ammonium ChlorideHCID 433294Lithium ChlorideHCID 2723922Sodium ethoxideHCID 21936070N-Boc-4-[2-(4-Toluenesulfonyloxy)ethyl]piperidine

Product 1

HCID 10334920Tert-butyl 4-(4-ethoxy-4-oxobutyl)piperidine-1-carboxylateYield 44.2%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

tert-Butyl 4-(2-(toluene-4-sulfonyloxy)ethyl)piperidine-1-carboxylate (7.55 g, 19.7 mmol, CAS No. 89151-45-1) as described in WO 02/32872 was dissolved in ethanol; diethyl malonate (3.3 ml, 21.3 mmol) and sodium ethoxide (1.45 g, 21.3 mmol) were added; and the reaction mixture was heated to reflux under nitrogen atmosphere for 2.5 hours. After naturally cooled to room temperature, the saturated aqueous solution of ammonium chloride was added; this was subjected to extraction with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. After the residue was dissolved in dimethyl sulfoxide (20 ml); lithium chloride (1.7 g, 40 mmol) and water (0.36 ml, 20 mmol) were added; and the reaction mixture was stirred at 185° C. for 1.5 hours and further stirred at 195° C. for 2 hours. After naturally cooled to room temperature, the reaction mixture was partitioned between ethyl acetate-brine. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, hexane-ethyl acetate system) to yield the title compound (2.60 g, 8.7 mmol, 43%) as a pale yellow oil.

Workup

  1. temperatureand the reaction mixture was heated
  2. temperatureto reflux under nitrogen atmosphere for 2.5 hours
  3. extractionthis was subjected to extraction with ethyl acetate
  4. washwashed with brine
  5. dry with materialdried over anhydrous magnesium sulfate
  6. concentrationconcentrated under reduced pressure
  7. dissolutionAfter the residue was dissolved in dimethyl sulfoxide (20 ml)
  8. stirringfurther stirred at 195° C. for 2 hours
  9. temperatureAfter naturally cooled to room temperature
  10. customthe reaction mixture was partitioned between ethyl acetate-brine
  11. washThe organic layer was washed with brine
  12. dry with materialdried over anhydrous magnesium sulfate
  13. concentrationconcentrated under reduced pressure
  14. customThe residue was purified by silica gel column chromatography (Fuji Silysia BW-300, hexane-ethyl acetate system)

Sources & evidence

ORD record
ord-04f8144a0b954c949109380a10a030bc
Source dataset
uspto-grants-2008_12
Patent number
US07468380B2

Reaction notes

Loading…