Water → tert-Butyl 3-[4-cyano-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate

HRID 1712347Notes

Reaction equation

HRID 1712347 reaction equation
Cl[C:2]1[CH:42]=[CH:41][C:5]([CH2:6][O:7][CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:9]2)=[CH:4][C:3]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48].[C-:49]#[N:50].[Na+].C1OCCOCCOCCOCCOC1.O>C1(C)C=CC=CC=1.[Ni]>[C:49]([C:2]1[CH:42]=[CH:41][C:5]([CH2:6][O:7][CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:9]2)=[CH:4][C:3]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])#[N:50]

Participants

7

Reactant 4

HCID 962WaterHCID 8929Sodium CyanideHCID 3633615-Crown-5HCID 68504735Tert-butyl 3-[4-chloro-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate

Product 1

HCID 68634565tert-Butyl 3-[4-cyano-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 935NickelCatalyst3×HCID 1140TolueneSolvent

Procedure

The mixture, prepared under argon, of 0.280 g of tert-butyl 3-[4-chloro-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 31a), 0.080 g of sodium cyanide and 0.005 ml of 15-crown-5 in 2 ml of toluene is initially charged at room temperature with stirring and admixed with 0.75 ml of Ni-catalyst solution (preparation described below). The reaction mixture is stirred at 80° C. for 24 hours and then admixed with a further 0.75 ml of Ni catalyst solution. The reaction mixture is stirred at 80° C. over a further 24 hours and then admixed once more with 0.75 ml of Ni catalyst solution. After stirring for a further 24 hours, the mixture is cooled, admixed with water (30 ml) and extracted with ethyl acetate (2×30 ml). The organic phases are washed with brine (1×30 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.38 (2:1 EtOAc-heptane); Rt=6.10.

Workup

  1. additionis initially charged at room temperature
  2. stirringThe reaction mixture is stirred at 80° C. for 24 hours
  3. stirringThe reaction mixture is stirred at 80° C. over a further 24 hours
  4. stirringAfter stirring for a further 24 hours
  5. temperaturethe mixture is cooled
  6. extractionextracted with ethyl acetate (2×30 ml)
  7. washThe organic phases are washed with brine (1×30 ml)
  8. dry with materialdried over sodium sulphate
  9. filtrationfiltered
  10. concentrationconcentrated by evaporation

Sources & evidence

ORD record
ord-83427a82e09446f593e031b0ad58c55d
Source dataset
uspto-grants-2010_09
Patent number
US07790715B2

Reaction notes

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